Garrett L. Walsh

BACKGROUND: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. METHODS: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10 6 plaque-forming units (PFU) to 10 11 PFU. RESULTS: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. CONCLUSIONS: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Genetic damage has been identified at multiple chromosomal sites (i.e., loci) in lung cancer cells. We questioned whether similar damage could be detected in the bronchial epithelial cells of chronic smokers who do not have this disease.Biopsy specimens from six different bronchial regions were obtained from 54 chronic smokers (40 current smokers and 14 former smokers). The presence of squamous metaplasia and dysplasia (abnormal histologic changes) in the specimens was documented by examination of hematoxylin-eosin-stained sections, and a metaplasia index ([number of biopsy specimens with metaplasia/total number of biopsy specimens] x 100%) was calculated for each subject. Loss of heterozygosity (i.e., loss of DNA sequences from one member of a chromosome pair) involving microsatellite DNA at three specific loci-chromosome 3p14, chromosome 9p21, and chromosome 17p13-was evaluated by means of the polymerase chain reaction. Fisher's exact test and logistic regression analysis were used to assess the data. Reported P values are two-sided.Data on microsatellite DNA status at chromosomes 3p14, 9p21, and 17p13 were available for 54, 50, and 44 subjects, respectively. The numbers of individuals who were actually informative (i.e., able to be evaluated for a loss of heterozygosity) at the three loci were 36 (67%), 37 (74%), and 34 (77%), respectively. DNA losses were detected in 27 (75%), 21 (57%), and six (18%) of the informative subjects at chromosomes 3p14, 9p21, and 17p13, respectively. Fifty-one subjects were informative for at least one of the three loci, and 39 (76%) exhibited a loss of heterozygosity. Forty-two subjects were informative for at least two of the loci, and 13 (31%) exhibited losses at a minimum of two loci. Loss of heterozygosity at chromosome 3p14 was more frequent in current smokers (22 [88%] of 25 informative) than in former smokers (five [45%] of 11 informative) (P = .01) and in subjects with a metaplasia index greater than or equal to 15% (21 [91%] of 23 informative) than in subjects with a metaplasia index of less than 15% (six [46%] of 13 informative) (P = .003). In five informative individuals among nine tested nonsmokers, a loss of heterozygosity was detected in only one subject at chromosome 3p14 (P = .03), and no losses were detected at chromosome 9p21 (P = .05).Genetic alterations at chromosomal sites containing putative tumor-suppressor genes (i.e., 3p14 and the FHIT gene, 9p21 and the p16 gene [also known as CDKN2], and 17p13 and the p53 gene [also known as TP53]) occur frequently in the histologically normal or minimally altered bronchial epithelium of chronic smokers.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.

Object. Anterior approaches to the spine for the treatment of spinal tumors have gained acceptance; however, in most published reports, patients with primary, metastatic, or chest wall tumors involving cervical, thoracic, or lumbar regions of the spine are combined. The purpose of this study was to provide a clear perspective of results that can be expected in patients who undergo anterior vertebral body resection, reconstruction, and stabilization for spinal metastases that are limited to the thoracic region. Methods. Outcome is presented for 72 patients with metastatic spinal tumors who were treated by transthoracic vertebrectomy at The University of Texas M. D. Anderson Cancer Center. The predominant primary tumors included renal cancer in 19 patients, breast cancer in 10, melanoma or sarcoma in 10, and lung cancer in nine patients. The most common presenting symptoms were back pain, which occurred in 90% of patients, and lower-extremity weakness, which occurred in 64% of patients. All patients underwent transthoracic vertebrectomy, decompression, reconstruction with methylmethacrylate, and anterior fixation with locking plate and screw constructs. Supplemental posterior instrumentation was required in seven patients with disease involving the cervicothoracic or thoracolumbar junction, which was causing severe kyphosis. After surgery, pain improved in 60 of 65 patients. This improvement was found to be statistically significant (p < 0.001) based on visual analog scales and narcotic analgesic medication use. Thirty-five of the 46 patients who presented with neurological dysfunction improved significantly (p < 0.001) following the procedure. Thirty-three patients had weakness but could ambulate preoperatively. Seventeen of these 33 regained normal strength, 15 patients continued to have weakness, and one patient was neurologically worse postoperatively. Of the 13 preoperatively nonambulatory patients, 10 could walk after surgery and three were still unable to walk but showed improved motor function. Twenty-one patients had complications ranging from minor atelectasis to pulmonary embolism. The 30-day mortality rate was 3%. The 1-year survival rate for the entire study population was 62%. Conclusions. These results suggest that transthoracic vertebrectomy and spinal stabilization can improve the quality of life considerably in cancer patients with spinal metastasis by restoring or preserving ambulation and by controlling intractable spinal pain with acceptable rates of morbidity and mortality.

The duration of survival in early-stage lung cancer (stages I and II) varies between reports in the literature. Several reasons account for this: patient population heterogeneity, inconsistent staging, anatomic variability, dissimilar tumor morphology, and unpredictable tumor biology. This report addresses some of the issues in early-stage non-small cell lung cancer that relate to variability between estimates of survival in end stage reporting. We review several large series since the introduction of the International Staging System in 1986 and other selected, contemporary reports that address end results in patients with pathologic stage I or stage II lung cancer. Overall survival for patients with pathologic stage I disease is 64.6% (range, 55% to 72%) and 41.2% for patients with stage II disease (range, 29% to 51%). Reducing morphologic differences by placing patients in groups based on the TNM subset and refinement in categorization by matching TNM subsets based on histology and other factors can improve considerably homogeneity and enhance prognostic predictability. The development of more accurate measures for predicting prognosis may serve to clarify the roles of primary and adjuvant treatment, particularly in those patients with early-stage disease associated with poor prognostic factors in whom the potential for long-term survival is reduced.

The purpose of this study was to identify risk factors associated with the onset of atrial fibrillation after thoracic surgery to allow more targeted interventions in patients with the highest risk.A comprehensive prospective database was used to identify patients undergoing major thoracic surgery from January 1, 1998, through December 31, 2002. Data collection was performed at point of contact: at preoperative evaluation, the time of the operation, discharge, and postoperative visits. All patients undergoing resection of a lung, the esophagus, the chest wall, or a mediastinal mass were included in this study. Univariate and multivariate analyses of factors associated with the development of atrial fibrillation were analyzed.There were 2588 patients who met the inclusion criteria. The overall incidence of atrial fibrillation was 12.3% (n = 319). Categories of disease were primary lung cancer, pulmonary metastasis, esophageal cancer, intrathoracic metastasis, benign lung disease, other mediastinal tumors, mesothelioma, chest wall tumors, benign esophagus, and "other." Patients with atrial fibrillation had increased mean lengths of hospital stay, mortality rates, and mean hospital charges. Univariate analysis evaluated age, sex, disease category, comorbidities, preoperative therapy, and procedure, and significant variables were entered into the multivariate analysis. Significant variables (relative risk; 95% confidence interval) in the multivariate analysis were male sex (1.72; 1.29-2.28), age 50 to 59 years (1.70; 1.01-2.88), age 60 to 69 years (4.49; 2.79-7.22), age 70 years or greater (5.30; 3.28-8.59), history of congestive heart failure (2.51; 1.06-6.24), history of arrhythmias (1.92; 1.22-3.02), history of peripheral vascular disease (1.65; 0.93-2.92), resection of mediastinal tumor or thymectomy (2.36; 0.95-5.88), lobectomy (3.89; 2.19-6.91), bilobectomy (7.16; 3.02-16.96), pneumonectomy (8.91; 4.59-17.28), esophagectomy (2.95; 1.55-5.62), and intraoperative transfusions (1.39; 0.98-1.98).The significant variables identified by means of multivariate analysis were associated with the occurrence of atrial fibrillation. Preventive therapies in selected populations might reduce the incidence of atrial fibrillation.

A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND).This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0-2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87% (79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84% (76-93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable analysis.Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended.Varian Medical Systems and US National Cancer Institute (National Institutes of Health).

Enhanced recovery after surgery (ERAS) pathways aim to improve postoperative recovery through evidence-based practices, including early ambulation, multimodal opioid-sparing analgesia, and reduction of surgical stress. This study evaluated outcomes after implementation of ERAS in patients undergoing resection for pulmonary malignancy.A retrospective review compared outcomes for patients undergoing pulmonary resection for primary lung cancer. Analysis was performed between three periods: pre-ERAS (January 1, 2006, to December 31, 2011), transitional period with elements of ERAS (January 1, 2012, to August 31, 2015), and full implementation of ERAS (September 1, 2015, to December 31, 2016).We analyzed 2,886 lung resections (pre-ERAS, n = 1615; transitional, n = 929; ERAS, n = 342). For all patients, length of stay decreased in the ERAS and transitional periods compared with pre-ERAS (4 [3] versus 4 [3] versus 5 [3] days, p < 0.001). Pulmonary complications were decreased with ERAS compared with transitional and pre-ERAS (19.9% versus 28.2% versus 28.7%, p = 0.004). Cardiac complications decreased with ERAS (12.3% versus 13.1% versus 18.1%, p = 0.001). There was less thoracic epidural use (2.9% versus 44.5% versus 75.5%, p < 0.001). There were no differences in hospital readmission (p = 0.772) or mortality rates (p = 0.417). After thoracotomy, ERAS was associated with decreased length of stay, fewer intensive care unit readmissions, and decreased frequency of pneumonia, atrial arrhythmias, and need for home oxygen (all p < 0.05). ERAS was independently associated with decreased pulmonary (p = 0.046) and cardiac (p = 0.001) complications on logistic regression after thoracotomy but not minimally invasive operations.ERAS was associated with improved postoperative outcomes, including decreased length of stay and pulmonary and cardiac morbidity after thoracotomy, but not after minimally invasive operations. ERAS safety was demonstrated by low rates of adverse events without effect on hospital readmission or perioperative deaths.

•Overall T-cell infiltration did not predict prognosis in localized NSCLC.•Analysis of high-dimensional TIL flow cytometry data identified two immunotypes predictive of patient outcomes.•Good prognosis subgroup was associated with T cells lacking inhibitory receptors and presence of tertiary lymphoid structures. BackgroundDespite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established.Patients and methodsFresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features.ResultsWhile neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas.ConclusionsOur study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care. Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Neoadjuvant ipilimumab + nivolumab (Ipi+Nivo) and nivolumab + chemotherapy (Nivo+CT) induce greater pathologic response rates than CT alone in patients with operable non-small cell lung cancer (NSCLC). The impact of adding ipilimumab to neoadjuvant Nivo+CT is unknown. Here we report the results and correlates of two arms of the phase 2 platform NEOSTAR trial testing neoadjuvant Nivo+CT and Ipi+Nivo+CT with major pathologic response (MPR) as the primary endpoint. MPR rates were 32.1% (7/22, 80% confidence interval (CI) 18.7-43.1%) in the Nivo+CT arm and 50% (11/22, 80% CI 34.6-61.1%) in the Ipi+Nivo+CT arm; the primary endpoint was met in both arms. In patients without known tumor EGFR/ALK alterations, MPR rates were 41.2% (7/17) and 62.5% (10/16) in the Nivo+CT and Ipi+Nivo+CT groups, respectively. No new safety signals were observed in either arm. Single-cell sequencing and multi-platform immune profiling (exploratory endpoints) underscored immune cell populations and phenotypes, including effector memory CD8+ T, B and myeloid cells and markers of tertiary lymphoid structures, that were preferentially increased in the Ipi+Nivo+CT cohort. Baseline fecal microbiota in patients with MPR were enriched with beneficial taxa, such as Akkermansia, and displayed reduced abundance of pro-inflammatory and pathogenic microbes. Neoadjuvant Ipi+Nivo+CT enhances pathologic responses and warrants further study in operable NSCLC. (ClinicalTrials.gov registration: NCT03158129 .).

We sought to evaluate the effect of operative volume, hospital size, and cancer specialization on morbidity, mortality, and hospital use after esophagectomy for cancer.Data derived from the Health Care Utilization Project was used to evaluate all Medicare-reimbursed esophagectomies for treatment of cancer from 1994 to 1996 in 13 national cancer institutions and 88 community hospitals. The complications of care, length of stay, hospital charges, and mortality were assessed according to hospital size (>/=600 beds vs <600 beds), cancer specialization (national cancer institution vs community hospital), and operative volume (esophageal [>/=5 Medicare esophagectomies per year vs <5 Medicare esophagectomies per year] and nonesophageal operations [>/=3333 cases per year vs <3333 cases per year]).Mortality was lower in national cancer institution hospitals (4.2% [confidence interval, 2.0%-6.4%] vs 13.3% [confidence interval, 4.2%-26.2%], P =. 05) and in hospitals performing a large number of esophagectomies (3. 0% [confidence interval, 0.09%-5.1%] vs 12.2% [confidence interval, 4.5%-19.8%], P <.05). Multivariate analysis revealed that the independent risk factor for operative mortality was the volume of esophagectomies performed (odds ratio, 3.97; P =.03) and not the number of nonesophageal operations, hospital size, or cancer specialization. Hospitals performing a large number of esophagectomies also showed a tendency toward decreased complications (55% vs 68%, P =.06), decreased length of stay (14.7 days vs 17.7 days, P =.006), and decreased charges ($39,867 vs $62, 094, P <.005).These results demonstrate improved outcomes and decreased hospital use in hospitals that perform a large number of esophagectomies and support the concept of tertiary referral centers for such complex oncologic procedures as esophagectomies.

To determine the safety and tolerability of adenovirus-mediated p53 (Adp53) gene transfer in sequence with cisplatin when given by intratumor injection in patients with non-small-cell lung cancer (NSCLC).Patients with advanced NSCLC and abnormal p53 function were enrolled onto cohorts receiving escalating dose levels of Adp53 (1 x 10(6) to 1 x 10(11) plaque-forming units [PFU]). Patients were administered intravenous cisplatin 80 mg/m(2) on day 1 and study vector on day 4 for a total of up to six courses (28 days per course). Apoptosis was determined by the terminal deoxynucleotidyl- transferase-dUTP nick-end labeling assay. Evidence of vector-specific sequences were determined using reverse-transcriptase polymerase chain reaction. Vector dissemination and biodistribution was monitored using a series of assays (cytopathic effects assay, Ad5 hexon enzyme-linked immunosorbent assay, vector-specific polymerase chain reaction assay, and antibody response assay).Twenty-four patients (median age, 64 years) received a total of 83 intratumor injections with Adp53. The maximum dose administered was 1 x 10(11) PFU per dose. Transient fever related to Adp53 injection developed in eight of 24 patients. Seventeen patients achieved a best clinical response of stable disease, two patients achieved a partial response, four patients had progressive disease, and one patient was not assessable. A mean apoptotic index between baseline and follow-up measurements increased from 0.010 to 0.044 (P =.011). Intratumor transgene mRNA was identified in 43% of assessable patients.Intratumoral injection with Adp53 in combination with cisplatin is well tolerated, and there is evidence of clinical activity.

Purpose: To evaluate tumor resectability after induction chemotherapy and to determine disease-free and overall survival rates of patients with locally advanced unresectable thymoma that received a multimodal treatment regimen. Patients and methods: Twenty-two patients (9 men, 13 women) with histologically confirmed invasive thymoma were treated with a multidisciplinary regimen consisting of three courses of induction chemotherapy, surgical resection, and radiation therapy, followed by three courses of consolidation chemotherapy. The median age was 47 years (range, 25–70). Eleven patients had stage III disease, 10 patients, stage IVA, and one patient, IVB. The most common histologic type was lymphocytic. Induction chemotherapy consisted of 500 mg/m2 of cyclophosphamide on day 1; doxorubicin (20 mg/m2 per day) on days 1–3 via continuous infusion (a total of 60 mg/m2); cisplatin (30 mg/m2 per day) on days 1–3 (a total of 90 mg/m2); and prednisone (100 mg per day) on days 1–5. This cycle was repeated three times at 3–4-week intervals. Patients then underwent surgery for tumor resection and received radiotherapy. Consolidation chemotherapy given at 80% of the induction chemotherapy doses of cyclophosphamide, doxorubicin, and cisplatin and 100% of the dose of prednisone was then repeated every 3–4 weeks for a total of three courses. Results: Induction chemotherapy produced major responses in 17 (77%) of the 22 patients including 3 (14%) complete responses (CR) and 14 (63%) partial responses (PR). Twenty-one patients underwent surgical exploration: 16 (76%) had complete resection and 5 (24%) had incomplete resection; one patient refused surgery. All 22 patients received radiation therapy. Nineteen of 22 patients completed the planned therapy, and all but one had completed consolidation chemotherapy at the time of analysis. With a median follow-up time of 50.3 months, 18 of the 19 patients who completed the multidisciplinary approach were disease-free. Of the 22 patients originally registered, 20 were alive at the time of analysis (one patient died of endocarditis, and one died of recurrent disease). The overall survival rate was 95% at 5 years (95% confidence interval (CI), 0.87–1.0) and 79% at 7 years (95% CI, 0.55–1.0). The progression-free survival rates were 77% at 5 years (95% CI, 0.58–1.0) and 77% at 7 years (95% CI, 0.58–1.0). The major side effect from induction and consolidation chemotherapy was myelosuppression. Nine patients experienced grade III/IV neutropenia, which included neutropenic fever in two patients, and grade III thrombocytopenia in two patients. The most common nonhematologic side effects were fatigue, nausea and vomiting, and decreased appetite. One patient experienced acute respiratory distress syndrome after surgical resection and required a prolonged hospitalization. No patients developed cardiac toxic effects, and no surgical mortality occurred. Conclusions: The use of induction chemotherapy to optimize surgical resectability of thymoma followed by radiation therapy and consolidation chemotherapy lead to good control of residual disease and high overall survival rates. We believe that this combined multidisciplinary approach prolongs lives and may cure locally advanced unresectable malignant thymomas. Future prospective multi-institutional studies are needed to further verify or define the best treatment for this patient population.

BackgroundThis study evaluates the utility of positron emission tomography (PET), endoscopic ultrasonography (EUS), and computed tomographic (CT) scans to predict pathologic response and survival following preoperative chemoradiation (CRT) in esophageal cancer.MethodsOne hundred three sequential patients with locoregionally advanced esophageal cancer, who were treated with CRT and esophageal resection between May 2001 and November 2003 at the University of Texas M.D. Anderson Cancer Center, were retrospectively reviewed. PET, EUS, and CT were performed before (pre) or after (post) CRT and before surgical resection. PET standardized uptake value (SUV) was defined as maximal uptake in primary tumor.ResultsMost patients were male (91 [88%]) with adenocarcinoma (90 [87%]). Pretreatment clinical stages were: IIA (42 [41%]), IIB (5 [5%]), III (50 [49%]), and IVA (6 [6%]). At the time of surgery, 58 patients (56%) had a pathologic response to CRT (≤10% viable cells). Post-CRT measurements that correlated with pathologic response were: CT esophageal wall thickness (13.3 vs 15.3 mm, p = 0.04), EUS mass size (0.7 vs 1.7 cm, p = 0.01) and PET SUV (3.1 vs 5.8, p = 0.01). Post-CRT PET SUV equal to or greater than 4 had the highest accuracy for pathologic response (76%). Univariate and multivariate Cox regression analysis demonstrated that a post-CRT PET SUV equal to or greater than 4 was an independent predictor of survival (HR, 3.5, p = 0.04).ConclusionsThe FDG-PET SUV is the most accurate noninvasive test to predict long-term survival after preoperative CRT and before surgical resection. Post-CRT FDG-PET cannot, however, rule out residual microscopic disease so esophagectomy should remain a therapeutic option even if the post-CRT imaging modalities are normal.

Background. The optimal management of patients with renal cell carcinoma with inferior vena cava tumor thrombus remains unresolved. Traditional approaches have included resection with or without the use of cardiopulmonary bypass. Chemotherapy has played a minor role except for biotherapeutic agents used for metastatic disease.Methods. From January 1989 to January 1996, 37 patients with renal cell carcinoma and inferior vena cava tumor thrombus underwent surgical resection. The 27 men and 10 women had a median age of 57 years (range, 29 to 78 years). Thirty-six patients presented with symptoms; 21 had hematuria. Distant metastases were present in 12 patients. Tumor thrombi extended to the infrahepatic inferior vena cava (n = 16), the intrahepatic inferior vena cava (n = 16), the suprahepatic inferior vena cava (n = 3), and into the right atrium (n = 2). All tumors were resected by inferior vena cava isolation and, when necessary, extended hepatic mobilization and Pringle maneuver, with primary or patch closure of the vena cavotomy. Cardiopulmonary bypass was necessary in only 2 patients with intraatrial thrombus.Results. Complications occurred in 11 patients, and 1 patient died 2 days postoperatively of a myocardial infarction (mortality, 2.7%). Twenty patients are alive; overall 2- and 5-year survival rates were 61.7% and 33.6%, respectively. For patients without lymph node or distant metastases (stage IIIa), 2- and 5-year survival rates were 74% and 45%, respectively. The presence of distant metastatic disease (stage IV) at the time of operation did not have a significant adverse effect on survival, as reflected by 2- and 5-year survival rates of 62.5% and 31.3%, respectively. Lymph node metastases (stage IIIc) adversely affected survival as there were no long-term survivors.Conclusions. Resection of an intracaval tumor thrombus arising from renal cell carcinoma can be performed safely and can result in prolonged survival even in the presence of metastatic disease. In our experience, extracorporeal circulatory support was required only when the tumor thrombus extended into the heart.(Ann Thorac Surg 1997;63:1592–600)

Some patients and oncologists choose to treat localized esophageal cancer with definitive chemotherapy and radiation therapy rather than surgery. A subset of these patients have local relapse without distant metastases and therefore have no other curative intent treatment option but salvage esophagectomy.We reviewed our experience with salvage esophagectomy from 1987 to 2000 at M.D. Anderson Cancer Center (n = 13, salvage after chemotherapy and radiotherapy group) and compared the data with those of patients receiving esophagectomy in a planned fashion 4 to 6 weeks after preoperative chemotherapy and radiation therapy (n = 99, preoperative chemotherapy and radiotherapy group).Increases in morbidity were seen after resection in the salvage after chemotherapy and radiotherapy group relative to the preoperative chemotherapy and radiotherapy group: mechanical ventilation (9.0 days vs 3.3 days, P =.08), intensive care unit stay (11.2 days vs 5.1 days, P =.07), hospital stay (29.4 days vs 18.4 days, P =.03), and anastomotic leak rates (5/13 [39%] vs 7/99 [7%], P =.005). Operative mortality (within 30 days) also tended to be increased statistically nonsignificantly (2/13 [15%] vs 6/99 [6%], P =.2). Salvage esophagectomy resulted in long-term survival (25% 5-year survival) in a subset of patients. Improved survival after salvage esophagectomy was associated with early pathologic stage (T1 N0, T2 N0), prolonged time to relapse, and R0 surgical resection.Patients who undergo salvage esophagectomy for relapse of tumor after definitive chemoradiation therapy have increased morbidity, mortality, and hospital use relative to patients undergoing planned esophagectomy after preoperative chemoradiation. Nevertheless, long-term survival can be achieved in this group, and such treatment should be considered for carefully selected patients at an experienced center.

The current study was performed to assess the value of 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in predicting the pathologic response and survival of patients with esophageal carcinoma treated with preoperative chemoradiation (CRT) and tumor resection. Preliminary reports suggest that FDG-PET may be predictive of the response of esophageal carcinoma patients to preoperative CRT.Eighty-three patients with resectable esophageal carcinoma who underwent preoperative CRT and FDG-PET and tumor resection were evaluated for pathologic response to CRT, percent residual tumor, and survival.The majority of patients in the current study were men (74 of 83 patients; 89%). Most tumors were adenocarcinomas (73 of 83 tumors; 88%) and clinical (EUS)T3/4 (69 tumors; 83%) or N1 (46 tumors; 55%). FDG-PET after preoperative CRT identified pathologic responders but failed to rule out microscopic residual tumor in 13 of 73 cases (18%). Pathologic response was found to correlate with the post-CRT FDG-PET standardized uptake value (SUV) (P = 0.03) and a post-CRT FDG-PET SUV of or 4 was found to be the only preoperative factor to correlate with decreased survival (2-year survival rate of 33% vs. 60%; P = 0.01). On univariate Cox regression analysis, only post-CRT FDG-PET was found to be correlated with post-CRT survival (P = 0.04).Post-CRT FDG-PET was found to be predictive of pathologic response and survival in patients with esophageal carcinoma who undergo preoperative CRT. Esophagectomy should still be considered even if the post-CRT FDG-PET scan is normal because microscopic residual disease cannot be ruled out.

To assess the evolution of treatment and outcome for resected esophageal cancer at a single institution.Strategies for optimizing the treatment of resected esophageal cancer continue to evolve over time. The outcomes of these evolving treatments in the context of improved diagnostic staging and changing epidemiology have not been carefully analyzed in a single institution.One thousand ninety-seven consecutive patients with primary esophageal cancer underwent surgery during the period 1970 to 2001. Nine hundred ninety-four patients underwent curative esophagectomy and were analyzed for changing demographics. Eight hundred seventy-nine patients who did not have systemic metastases and survived the perioperative period were assessed by multivariate analysis for factors associated with long-term survival.During the study period the overall median survival increased from 17 to 34 months, and combined hospital and 30-day mortality decreased from 12% to 6%. The R0 resection rate increased from 78 to 94%, and adenocarcinoma replaced squamous cell carcinoma as the predominant histology (83% vs. 17%). No change in survival with time was noted for patients treated with surgery alone having the same postoperative pathologic stage (pTNM). An increased proportion of patients had preoperative chemoradiation in the last 4 years of the study (59% vs. 2%). Preoperative chemoradiation was associated with a longer survival and increased likelihood of achieving a complete resection. Multivariate analysis showed that long-term survival was associated with a complete resection and the preoperative staging strategy used, while the use of preoperative chemoradiation was the most significant factor associated with ability to achieve an R0 esophageal resection.This study shows favorable trends in the survival of patients with resected esophageal cancer over time. The increased use of preoperative chemoradiation, better preoperative staging, and other time-dependent factors may have contributed to the observed increase in survival.

Background. Previous studies have shown that a chronic indwelling pleural catheter (PC) safely and effectively relieved dyspnea, maintained quality of life, and reduced hospitalization in patients with malignant pleural effusions. Outpatient management of malignant pleural effusion with a PC may reduce length of stay and early (7-day) charges compared with inpatient management with chest tube and sclerosis.Methods. A retrospective review of consecutive PC patients (n = 100; 60 outpatient, 40 inpatient) were treated from July 1, 1994 to September 2, 1998 and compared with 68 consecutive inpatients treated with chest tube and sclerosis between January 1, 1994 and December 31, 1997. Hospital charges were obtained from date of insertion (day 0) through day 7.Results. Demographics were similar in both groups. Pretreatment cytology was positive in 126 of 168 patients (75%), negative in 21 (12.5%), and unknown in 21 (12.5%). Primary histology included lung (n = 61, 36%), breast (n = 39, 23%), lymphoma (n = 12, 7%), or other (n = 56, 34%). Median survival was 3.4 months and did not differ significantly between treatment groups. Overall median length of stay was 7.0 days for inpatient chest tube and inpatient PC versus 0.0 days for outpatient Pleurx. No mortality occurred related to the PC. Eighty-one percent (81/100) of PC patients had no complications. One or more complications occurred in 19 patients (19%). Patients treated with outpatient PC (n = 60) had early (7-day) mean charges of $3,391 ± $1,753 compared with inpatient PC (n = 40, $11,188 ± $7,964) or inpatient chest tube (n = 68, $7,830 ± $4,497, SD) (p < 0.001).Conclusions. Outpatient PC may be used effectively and safely to treat malignant pleural effusions. Hospitalization is not required in selected patients. Early (7-day) charges for malignant pleural effusion are reduced in outpatient PC patients compared with inpatient PC patients or chest tube plus sclerosis patients.

The objective of this review is to determine the outcome of patients with sarcomas involving the main pulmonary artery, pulmonic valve, or right ventricular outflow tract. Survival data were analyzed using an aggregate series derived from the published literature in conjunction with a current series. Median survival was 36.5 +/- 20.2 months for patients undergoing an attempt at curative resection compared with 11 +/- 3 months for those undergoing incomplete resection. Median survival was 24.7 +/- 8.5 months for patients undergoing multimodality treatment compared with 8.0 +/- 1.7 months for patients having single-modality therapy. A complete review of diagnosis, evaluation, treatment, and surveillance of primary pulmonary artery sarcomas follows.

Percutaneous tracheostomy is increasingly being used for patients needing prolonged ventilatory support. The purpose of this study was to assess the feasibility of widespread application of endoscopic guided percutaneous tracheostomy. Sixty-one consecutive ICU patients requiring prolonged mechanical ventilation underwent bedside endoscopic guided percutaneous tracheostomy. Using a modified Ciaglia technique, a #6-10 tracheostomy tube was introduced between the second and third tracheal rings. Bronchoscopic transillumination facilitated identification of the appropriate tracheostomy site, and verified satisfactory placement of dilators and tracheostomy tube. There was one procedure-related death due to arrhythmia. Procedure-related complications included (n= 7): bleeding (controlled with local pressure), two infections, two cuff tears, and two obstructions of the tracheal tube. The tracheostomy was eventually removed in 13 patients. Bronchoscopic evaluation of three patients at 4 months post-tracheostomy removal was normal and there has been no clinical evidence suggestive of tracheal stenosis in the remaining ten extubated patients. There was a 50% reduction in cost when compared to operative tracheostomy. Percutaneous tracheostomy is a simple, safe, cost-effective bedside procedure for critically ill ventilator-dependent patients. Endoscopic guidance appears to increase the safety of this procedure and may prevent complications of pneumothorax, subcutaneous emphysema, and paratracheal false passage previously reported with blinded percutaneous methods.

BackgroundMalignant pleural mesothelioma is a locally aggressive tumor that is usually fatal. Extrapleural pneumonectomy (EPP) followed by hemithoracic irradiation has shown promise, but local failure remains a significant problem. To improve local control, we have used intensity-modulated radiation therapy (IMRT) as it allows better dose distribution to regions at risk of recurrence as well as reduced radiation to surrounding organs.MethodsOne hundred consecutive patients underwent EPP. At a median interval of 2.5 months from surgery, 63 patients received IMRT (median dose 45 Gy) with curative intent. Chemotherapy was not routinely administered.ResultsTumors were right sided in 66 patients (66%) and nonepithelioid in 33 (33%). American Joint Committee on Cancer pathology stage was I in 6 patients (6%), II in 7 (7%), III in 72 (72%), and IV (T4) in 15 (15%). Fifty-four patients (54%) had ipsilateral nodal metastases. Perioperative mortality was 8%. Median overall survival (n = 100) was 10.2 months. For patients who received IMRT (n = 63), median overall and 3-year survival was 14.2 months and 20%. Of these, node-negative patients with epithelioid histology (n = 18) had median and 3-year survival of 28 months and 41%. Distant recurrences occurred in 33 of 61 evaluable patients (54%). Eight patients (13%) had local or regional recurrence, 5 of whom also recurred distally. Only 3 patients (5%) had recurrence within the irradiated field.ConclusionsIntensity-modulated radiation therapy after EPP results in excellent local control for malignant pleural mesothelioma; however, distant metastases remain a significant problem and limit survival. This provides a strong rationale for combining aggressive local regimens with systemic therapy. Malignant pleural mesothelioma is a locally aggressive tumor that is usually fatal. Extrapleural pneumonectomy (EPP) followed by hemithoracic irradiation has shown promise, but local failure remains a significant problem. To improve local control, we have used intensity-modulated radiation therapy (IMRT) as it allows better dose distribution to regions at risk of recurrence as well as reduced radiation to surrounding organs. One hundred consecutive patients underwent EPP. At a median interval of 2.5 months from surgery, 63 patients received IMRT (median dose 45 Gy) with curative intent. Chemotherapy was not routinely administered. Tumors were right sided in 66 patients (66%) and nonepithelioid in 33 (33%). American Joint Committee on Cancer pathology stage was I in 6 patients (6%), II in 7 (7%), III in 72 (72%), and IV (T4) in 15 (15%). Fifty-four patients (54%) had ipsilateral nodal metastases. Perioperative mortality was 8%. Median overall survival (n = 100) was 10.2 months. For patients who received IMRT (n = 63), median overall and 3-year survival was 14.2 months and 20%. Of these, node-negative patients with epithelioid histology (n = 18) had median and 3-year survival of 28 months and 41%. Distant recurrences occurred in 33 of 61 evaluable patients (54%). Eight patients (13%) had local or regional recurrence, 5 of whom also recurred distally. Only 3 patients (5%) had recurrence within the irradiated field. Intensity-modulated radiation therapy after EPP results in excellent local control for malignant pleural mesothelioma; however, distant metastases remain a significant problem and limit survival. This provides a strong rationale for combining aggressive local regimens with systemic therapy.

There are no guidelines for the appropriate follow-up of patients after pulmonary resection for lung cancer.Three-hundred fifty-eight consecutive patients who had undergone complete resections of non-small cell lung cancer between 1987 and 1991 were evaluated for tumor recurrence and development of second primary tumors. Recurrences were categorized by site (local or distant), mode of presentation (symptomatic or asymptomatic), treatment given (curative intent or palliative), and duration of overall survival.Recurrences developed in 135 patients (local only, 32; local and distant, 13; and distant only, 90). Of these, 102 were symptomatic and 33 were asymptomatic (most diagnosed by screening chest roentgenogram). Forty patients received treatment with curative intent (operation or radiation therapy > 50 Gy) and 95 were treated palliatively. The median survival duration from time of recurrence was 8.0 months for symptomatic patients and 16.6 months for asymptomatic patients (p = 0.008). Multivariate analysis shows that disease-free interval (greater than 12 months or less than or equal to 12 months) was the most important variable in predicting survival after recurrence and that mode of presentation, site of recurrence, initial stage, and histologic type did not significantly affect survival. New primary tumors developed in 35 patients.Although detection of asymptomatic recurrences gives a lead time bias of 8 to 10 months, mode of treatment and overall survival duration are not greatly affected by this earlier detection. Disease-free interval appears to be the most important determinant of survival. Screening for asymptomatic recurrences in patients who have had lung cancer is unlikely to be cost-effective. Frequent follow-up and extensive radiologic evaluation of patients after operation for lung cancer are probably unnecessary.

Abstract Purpose: The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin, in a liposome formulation, and to recommend a dosage for a Phase II trial for an 8-week daily treatment schedule. Experimental Design: Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased stepwise from 6.7 up to 26.6 μg/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest. Results: Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85% of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 μg/kg/day. At 20.0 μg/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4 patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin (9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred in 3 patients with primary lung cancer. Conclusions: Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient’s plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 μg/kg/day (equivalent to 0.5 mg/m2/day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of sterile water, Monday to Friday for 8 weeks every 10 weeks.

Integrated computed tomography-positron emission tomography imaging with coregistration of anatomic and functional imaging data may improve the accuracy of malignant pleural mesothelioma staging. We evaluate the use of integrated computed tomography-positron emission tomography in patients with malignant pleural mesothelioma who are being considered for extrapleural pneumonectomy.Twenty-nine patients with malignant pleural mesothelioma who were judged to be candidates for extrapleural pneumonectomy after clinical and conventional radiologic evaluation underwent whole-body integrated computed tomography-positron emission tomography and pathologic staging. Two reviewers blinded to the results of clinical and pathologic staging retrospectively evaluated computed tomography, positron emission tomography, and coregistered computed tomography-positron emission tomography images. Staging was performed according to the International Mesothelioma Interest Group TNM staging system. Histopathology and/or results of further radiologic evaluation or follow-up served as the reference standard.Integrated computed tomography-positron emission tomography provided additional information in 11 of 29 patients that precluded extrapleural pneumonectomy. The overall tumor stage was correctly classified in 21 of 29 patients. The tumor stage was correctly determined in 15 of 24 patients, 6 of whom had T4 (nonresectable) disease. The node stage was accurately determined in 6 of 17 patients. Extrathoracic metastases not identified by routine clinical and conventional radiologic evaluation were detected in 7 of 29 patients and were found to be diffuse (n = 2) or solitary (n = 5).Integrated computed tomography-positron emission tomography increases the accuracy of malignant pleural mesothelioma staging and is important in determining the appropriate therapy in patients being considered for extrapleural pneumonectomy.

Video-assisted thoracoscopic surgery (VATS) is becoming increasingly popular for lung resection in some centers. However, the issue of whether VATS or open thoracotomy is better remains controversial. We compared outcomes of open and VATS lobectomy in a national database.Using the 2004 and 2006 Nationwide Inpatient Sample database, we identified 13,619 discharge records of patients who underwent pulmonary lobectomy by means of thoracotomy (n = 12,860) or VATS (n = 759). Student's t and chi(2) tests were used to compare the two groups. Multivariable analysis was used to identify independent predictors of outcome measures.The two groups of patients had similar demographics and preoperative comorbidities. They also had similar in-hospital mortality rates (3.1% versus 3.4%; p = 0.67); lengths of stay (9.3 +/- 0.1 versus 9.2 +/- 0.4 days; p = 0.84); hospitalization costs ($23,862 +/- $206 versus $25,125 +/- $1,093; p = 0.16); and rates of wound infection (0.8% versus 1.3%; p = 0.15), pulmonary complications (32.2% versus 31.2%; p = 0.55), and cardiovascular complications (3.4% versus 3.9%; p = 0.43). However, multivariable analysis showed that the VATS group had a significantly higher incidence of intraoperative complications than the thoracotomy group (odds ratio, 1.6; 95% confidence interval, 1.0 to 2.4; p = 0.04). A higher percentage of patients with annual income greater than $59,000 underwent VATS lobectomy than patients with income less than $59,000 (35.7% versus 25.4%; p < 0.0001).Patients who underwent VATS lobectomy were 1.6 times more likely to have intraoperative complications than patients who underwent open lobectomy. However, short-term mortality, lengths of stay, and hospitalization costs were similar between the two groups of patients. There seems to be a socioeconomic disparity between VATS and open thoracotomy patients.

The presence of extrapulmonary sarcomatous metastases has traditionally been a contraindication for the resection of pulmonary metastases. We, therefore, reviewed our experience with resection of pulmonary metastases in patients who had documented extrapulmonary metastases to determine long-term outcome.From 1998 to 2006, 234 patients underwent pulmonary metastasectomy. They were grouped as follows: group A (lung metastasectomy only); group B1 (with either synchronous or prior extrapulmonary metastasectomy); group B2 (with nonsurgical treatment of synchronous or prior extrapulmonary metastases); group C1 (with later extrapulmonary metastasectomy); group C2 (with later extrapulmonary metastasis which was not resected).Groups A, B1, and B2 consisted of 147 (62.8%), 26 (11.1%), and 13 (5.6%) patients, respectively. The median survival from lung metastasectomy date was 35.5, 37.8, and 13.5 months in groups A, B1, and B2, respectively. Comparison among the three groups showed no significant survival difference in groups A versus B1 (p = 0.96), but a survival difference was found comparing groups A versus B2 (p < 0.001) and B1 versus B2 (p < 0.001). Prognostic factors for increased survival included 3 or greater redo pulmonary operations, greater than 12 month mean time between pulmonary recurrences, greater than 24 month mean time between extrathoracic recurrences, and a prolonged disease-free interval. Prognostic factors for decreased survival included 3 or greater pulmonary metastases and group B2 patients.These results suggest extrapulmonary metastases should no longer be viewed as a contraindication to resection of sarcomatous pulmonary metastases. Long-term survival can be achieved when a complete resection is possible for both the pulmonary and extrapulmonary metastases.

BackgroundSarcomatoid cancer (SARC) of the lung is a rare histologic type of non-small cell lung cancer (NSCLC). Although believed to be associated with poor prognosis, its effect on survival and recurrence has not been well defined. Our goal was to determine the prognostic significance of SARC histology in patients undergoing pulmonary resection.MethodsWe retrospectively evaluated all patients who underwent pulmonary resection for NSCLC during a 20-year period at the University of Texas MD Anderson Cancer Center and compared recurrence and survival rates of patients with SARC with a cohort of patients with typical NSCLC. To account for known prognostic factors such as smoking status, age, gender, pathologic stage, and adjuvant therapy, we used one-to-one matching based on propensity scores.ResultsThe study included 63 SARC patients and 1133 NSCLC patients with complete data. Propensity score matching identified 63 NSCLC patients that were similar to the 63 SARC patients from known clinical factors. The 5-year survival for SARC patients was 24.5% compared with 46.3% for NSCLC patients (p = 0.01); median time to recurrence was 11.3 months and 61.4 months, respectively (p = 0.001).ConclusionsCompared with other histologic subtypes, SARC behaves in an aggressive fashion. These tumors are frequently symptomatic, are locally advanced, and have higher rates of recurrence. Future investigation of novel treatment approaches is warranted. Nonsurgical treatment modalities may be appropriate for patients with clinically advanced disease. Sarcomatoid cancer (SARC) of the lung is a rare histologic type of non-small cell lung cancer (NSCLC). Although believed to be associated with poor prognosis, its effect on survival and recurrence has not been well defined. Our goal was to determine the prognostic significance of SARC histology in patients undergoing pulmonary resection. We retrospectively evaluated all patients who underwent pulmonary resection for NSCLC during a 20-year period at the University of Texas MD Anderson Cancer Center and compared recurrence and survival rates of patients with SARC with a cohort of patients with typical NSCLC. To account for known prognostic factors such as smoking status, age, gender, pathologic stage, and adjuvant therapy, we used one-to-one matching based on propensity scores. The study included 63 SARC patients and 1133 NSCLC patients with complete data. Propensity score matching identified 63 NSCLC patients that were similar to the 63 SARC patients from known clinical factors. The 5-year survival for SARC patients was 24.5% compared with 46.3% for NSCLC patients (p = 0.01); median time to recurrence was 11.3 months and 61.4 months, respectively (p = 0.001). Compared with other histologic subtypes, SARC behaves in an aggressive fashion. These tumors are frequently symptomatic, are locally advanced, and have higher rates of recurrence. Future investigation of novel treatment approaches is warranted. Nonsurgical treatment modalities may be appropriate for patients with clinically advanced disease.

BACKGROUND Reports are limited regarding clinical and pretreatment features that might predict a pathological complete response (pathCR) after treatment in patients with esophageal cancer (EC). This might allow patient selection for different strategies. This study examines the association of a pathCR with pretreatment variables, overall survival (OS), recurrence‐free survival (RFS), and patterns of recurrence in a large cohort from a single institution. METHODS The baseline clinical features of 911 consecutive patients with EC who were treated with trimodality therapy from January 2000 to November 2013 were analyzed. A pathCR was defined as a surgical specimen with no residual carcinoma (primary or nodes). Logistic regressions were used to identify independent baseline features associated with a pathCR. We applied log‐rank testing and Cox models to determine the association between a pathCR and the time‐to‐event outcomes (OS and RFS). RESULTS Of 911 patients, 218 (23.9%) achieved a pathCR. The pathCR rate was 23.1% for adenocarcinoma and 32.2% for squamous cell carcinoma. A lower pathCR rate was observed for 1) older patients (&gt;60 years), 2) patients with poorly differentiated tumors, 3) patients with signet ring cells (SRCs), and 4) patients with a higher T stage. Patients with a pathCR had longer OS and RFS than those without a pathCR ( P = .0021 and P = .0011, respectively). Recurrences occurred more in non‐pathCR patients. Distant metastases were the most common type of recurrence. PathCR patients developed brain metastases at a marginally higher rate than non‐pathCR patients ( P = .051). CONCLUSIONS In this large cohort study, a pathCR is confirmed to be associated with better OS and RFS. The presence of a poorly differentiated tumor or SRCs reduces the likelihood of a pathCR. Future research should focus on molecular classifiers. Cancer 2017;123:4106–4113. © 2017 American Cancer Society .

Thymic malignancies are relatively uncommon, which mandates that the experience from many different institutions be combined to achieve a better understanding of the disease. Nevertheless, this is hampered by many ambiguities in how results are reported and interpreted. This problem is aggravated by the fact that smaller institutions often encounter these tumors only sporadically. A prerequisite to interinstitutional collaboration is a common language and consistency in the definition of findings (e.g., whether a complete resection was accomplished or not).

Atrial fibrillation (AF) occurs in between 12% and 44% of patients after pulmonary and esophageal surgery. Its occurrence is associated with increased pulmonary complications, increased length of stay, and increased mortality [1, 2]. Although numerous articles have been written on postoperative AF, specific recommendations for the prophylaxis and treatment of AF related to general thoracic surgery (GTS) do not exist. Therefore, The Society of Thoracic Surgeons (STS) Workforce on Evidence Based Surgery formed a taskforce to derive practice recommendations from the literature.

Purpose Small observational studies have shown a survival advantage to undergoing cancer-directed surgery for malignant pleural mesothelioma (MPM); however, it is unclear if these results are generalizable. Our purpose was to evaluate survival after treatment of MPM with cancer-directed surgery and to explore the effect surgery interaction with chemotherapy or radiation therapy on survival by using the National Cancer Database. Patients and Methods Patients with microscopically proven MPM were identified within the National Cancer Database (2004 to 2014). Propensity score matching was performed 1:2 and among this cohort, a Cox proportional hazards regression model was used to identify predictors of survival. Median survival was calculated by using the Kaplan-Meier method. Results Of 20,561 patients with MPM, 6,645 were identified in the matched cohort, among whom 2,166 underwent no therapy, 2,015 underwent chemotherapy alone, 850 underwent cancer-directed surgery alone, 988 underwent surgery with chemotherapy, and 274 underwent trimodality therapy. The remaining 352 patients underwent another combination of surgery, radiation, or chemotherapy. Thirty-day and 90-day mortality rates were 6.3% and 15.5%. Cancer-directed surgery, chemotherapy, and radiation therapy were independently associated with improved survival (hazard ratio, 0.77, 0.74, and 0.88, respectively). Stratified analysis revealed that surgery-based multimodality therapy demonstrated an improved survival compared with surgery alone, with no significant difference between surgery-based multimodality therapies; however, the largest estimated effect was when cancer-directed surgery, chemotherapy, and radiation therapy were combined (hazard ratio, 0.52). For patients with the epithelial subtype who underwent trimodality therapy, median survival was extended from 14.5 months to 23.4 months. Conclusion MPM is an aggressive and rapidly fatal disease. Surgery-based multimodality therapy was associated with improved survival and may offer therapeutic benefit among carefully selected patients.

Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

IntroductionThe combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade.MethodsGenomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73).ResultsNCT was associated with increased infiltration of cytotoxic CD8+ T cells and CD20+ B cells. Moreover, NCT was associated with increases in CD8+CD103+ and CD4+CD103+PD-1+TIM3− tissue resident memory T cells. Gene expression profiling supported memory function of CD8+ and CD4+ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery.ConclusionsOur study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8+ and CD4+ memory helper T cells.

Background Surgical outcomes for non–small cell lung cancer after neoadjuvant immune checkpoint inhibitors continue to be debated. We assessed perioperative outcomes of patients treated with Nivolumab or Nivolumab plus Ipilimumab (NEOSTAR) and compared them with patients treated with chemotherapy or previously untreated patients with stage I-IIIA non–small cell lung cancer. Methods Forty-four patients with stage I to IIIA non–small cell lung cancer (American Joint Committee on Cancer Staging Manual, seventh edition) were randomized to nivolumab (N; 3 mg/kg intravenously on days 1, 15, and 29; n = 23) or nivolumab with ipilimumab (NI; I, 1 mg/kg intravenously on day 1; n = 21). Curative-intent operations were planned between 3 and 6 weeks after the last dose of neoadjuvant N. Patients who completed resection upfront or after chemotherapy from the same time period were used as comparison. Results In the N arm, 21 (91%) were resected on-trial, 1 underwent surgery off-trial, and one was not resected (toxicity-related). In the NI arm, 16 (76%) resections were performed on-trial, one off-trial, and 4 were not resected (none toxicity-related). Median time to operation was 31 days, and consisted of 2 (5%) pneumonectomies, 33 (89%) lobectomies, and 1 (3%) each of segmentectomy and wedge resection. The approach was 27 (73%) thoracotomy, 7 (19%) thoracoscopy, and 3 (8%) robotic-assisted. Conversion occurred in 17% (n = 2/12) of minimally invasive cases. All 37 achieved R0 resection. Pulmonary, cardiac, enteric, neurologic, and wound complications occurred in 9 (24%), 4 (11%), 2 (5%), 1 (3%), and 1 (3%) patient, respectively. The 30- and 90-day mortality rate was 0% and 2.7% (n = 1), respectively. Postoperative complication rates were comparable with lung resection upfront or after chemotherapy. Conclusions Operating after neoadjuvant N or NI is overall safe and effective and yields perioperative outcomes similar to those achieved after chemotherapy or upfront resection.

Appropriately selected patients clearly benefit from resection of colorectal cancer (CRC) pulmonary metastases (PMs). However, there remains equipoise surrounding optimal chest surveillance strategies following pulmonary metastasectomy. We aimed to identify risk factors that may inform chest surveillance in this population.Patients who underwent CRC pulmonary metastasectomy were identified from a single institution's prospectively maintained surgical database. Clinicopathologic and genomic characteristics were collected. Patients were stratified by diagnosis of subsequent PM within 6 months of the index lung resection. Multivariate modeling was used to evaluate risk factors.A total of 197 patients met the study's inclusion criteria, of whom 52.3% (n = 103) developed subsequent PM, at a median of 9.51 months following the index metastasectomy. Patients with KRAS alterations (odds ratio [OR], 3.073; 95% confidence interval [CI], 1.363-6.926; P = .007), TP53 alterations (OR, 3.109; 95% CI, 1.318-7.341; P = .010) were found to be at risk of PM diagnosis within 6 months of the index metastasectomy, while those with an APC alteration (OR, .218; 95% CI, 0.080-0.598; P = .003) were protected. Moreover, patients who received systemic therapy within 3 months of the initial PM diagnosis also were more likely to develop early lung recurrence (OR, 2.105; 95% CI, 0.971-4.563; P = .059).Patients with KRAS alterations, TP53 alterations, and no APC alterations developed early recurrence in the lung following pulmonary metastasectomy, as did those who received chemotherapy after their initial PM diagnosis. As such, these groups benefit from early lung imaging after metastasectomy, as chest surveillance protocols should be based on patient-centered clinicopathologic and genomic risk factors.

We evaluated self-reported financial burden (FB) after lung cancer surgery and sought to assess patient perspectives, risk factors, and coping mechanisms within this population.Patients with lung cancer resected at our institution between January 1, 2016, and December 31, 2021, were surveyed. Descriptive and multivariable analyses were performed to evaluate the association between clinical and financial characteristics with patient-reported major ("significant" or "catastrophic") FB.Of 1477 patients contacted, 31.3% (n = 463) completed the survey. Major FB was reported by 62 (13.4%) patients. multivariable analyses demonstrated increasing age (odds ratio [OR], 0.92; 95% CI, 0.88-0.96), credit score >740 (OR, 0.29; 95% CI, 0.14-0.60), and employer-based insurance (OR, 0.24; 95% CI, 0.07-0.80) were protective factors. In contrast, an out of pocket cost greater than expected (OR, 3.63; 95% CI, 1.67-7.88), decrease in work hours (OR, 4.42; 95% CI, 1.59-12.25), or cessation of work (OR, 5.13; 95% CI, 2.06-12.78), chronic obstructive pulmonary disease diagnosis (OR, 5.39, 95% CI, 1.87-15.50), and hospital readmission (OR, 4.87; 95% CI, 1.11-21.42) were risk factors for FB. To pay for care, some patients reported "often" or "always" decreasing food (n = 102 [23.4%]) or leisure spending (n = 179 [40.7%]). Additionally, use of savings (n = 246 [62.9%]), borrowing funds (n = 72 [16.6%]), and skipping clinic visits (n = 36 [8.3%]) at least once were also reported. Coping mechanisms occurred more often in patients with major FB compared with those without (P < .001).Patients with resected lung cancer may experience major FB related to treatment with several identifiable risk factors. Targeted interventions are needed to limit the adoption of detrimental coping mechanisms and potentially affect survivorship.

To clarify the relationship between the percentage of lung receiving low radiation doses with concurrent chemotherapy and the occurrence of postoperative pulmonary complications in the treatment of esophageal carcinoma.From 117 patients who underwent preoperative chemoradiation for esophageal cancer at our institution between 1998 and 2002, we selected 61 patients for whom complete pulmonary dose-volume histogram (DVH) data were available and analyzed the incidence of pneumonia and acute respiratory distress syndrome (ARDS) in this group. All patients received concurrent chemoradiation therapy, and 39 patients also received induction chemotherapy before concurrent chemoradiation. The median age was 62 years, and the median radiotherapy dose was 45 Gy. The percentage of lung volume receiving at least 10 Gy (V10), 15 Gy (V15), and 20 Gy (V20) were recorded from each pulmonary DVH.Eleven (18%) of the 61 patients had pulmonary complications, 2 of whom died after progression of pneumonia. Pulmonary complications were noted more often (35% vs. 8%, p = 0.014) when the pulmonary V10 was > or =40% vs. <40% and when the V15 was > or /=30% vs. < 30% (33% vs. 10%, p = 0.036). An apparent increase in pulmonary complication rate when V20 was > or =20% vs. <20% (32% vs. 10%, p = 0.079) was not significant. None of the other factors analyzed (surgical procedure, tumor location, use of induction chemotherapy, use of concurrent taxane-based chemoradiation, or smoking history) was associated with the occurrence of pulmonary complications. The median hospital stay was 17 days for patients who had pulmonary complications vs. 12 days for patients who did not (p = 0.08).The use of multimodality therapy may require minimization of lung volume irradiation to levels lower than previously expected. Radiotherapy techniques that decrease the volume of lung receiving low radiation doses may significantly reduce the risk of this potentially life-threatening complication.

Although metastatic breast cancer is widely believed to carry a grim prognosis, treatment developments over the past 25 years have greatly improved survival outcomes in these patients. In selected cases, aggressive treatment approaches may occasionally result in long-term survival of 15 years or more. This review considers the role of surgery in the treatment of single or multiple metastatic lesions restricted to one site. For each site, available literature from 1992-2002 was assessed to determine the role of surgery on survival outcomes and to determine appropriate criteria for selecting the best candidates for surgery. For lung, liver, brain, and sternum metastases, the use of surgery with or without adjuvant therapy resulted in greater median survival times and 5-year survival rates. The best candidate for surgery had no evidence of additional metastatic disease, good performance status, and a long disease-free interval after treatment of the primary tumor. Current treatment standards for breast cancer follow-up do not include imaging studies other than mammography. The addition of chest x-rays as part of routine follow-up should be considered as a cost-effective approach for early assessment of metastases to the lung or sternum that may be appropriate for surgical excision.

✓ Although radical resection is the best treatment for malignant sacral tumors, total sacrectomy for such tumors has been performed in only a few instances. Total sacral resection requires reconstruction of the pelvic ring plus establishment of a bilateral union between the lumbar spine and iliac bone. This technique is illustrated in two patients harboring large, painful, sacral giant-cell tumors that were unresponsive to prior treatment. These patients were treated with complete en bloc resection of the sacrum and complex iliolumbar reconstruction/stabilization and fusion. Surgery was performed in two stages, the first consisting of a midline celiotomy, dissection of visceral/neural structures, and ligation of internal iliac vessels, followed by an anterior L5—S1 discectomy. The second stage consisted of mobilization of an inferiorly based myocutaneous rectus abdominis pedicle flap for wound closure, followed by an L-5 laminectomy, bilateral L-5 foraminotomy, ligation of the thecal sac, division of sacral nerve roots, and transection of the ilia lateral to the tumor and sacroiliac joints. Placement of the instrumentation required segmental fixation of the lumbar spine from L-3 down by means of pedicle screws and the establishment of a bilateral liaison between the lumbar spine and the ilia by using the Galveston L-rod technique. The pelvic ring was then reestablished by means of a threaded rod connecting left and right ilia. Both autologous (posterior iliac crest) and allograft bone were used for fusion, and a tibial allograft strut was placed between the remaining ilia. The patients were immobilized for 8 weeks postoperatively and underwent progressive rehabilitation. At the 1-year follow-up review, one patient could walk unassisted, and the other ambulated independently using a cane. Both patients controlled bowel function satisfactorily with laxatives and diet and could maintain continence but required self-catheterization for bladder emptying. The authors conclude that in selected patients, total sacrectomy represents an acceptable surgical procedure that can offer not only effective local pain control, but also a potential cure, while preserving satisfactory ambulatory capacity and neurological function.

To determine the impact of pathologic response following preoperative chemoradiation (CRT) on the AJCC esophageal cancer staging system.Increasing numbers of locoregionally advanced esophageal cancer patients are treated with preoperative CRT prior to surgical resection.Five hundred ninety-three pts from 1985 to 2003 with esophageal cancer who underwent surgery with (n = 239) or without CRT (n = 354) were reviewed. Resected esophageal tumors were assessed for pathologic response by determining extent of residual tumor following CRT (P0, 0% residual; P1, 1%-50% residual; P2, >50% residual).After CRT down-staging, pTNM specific survival was similar, irrespective of treatment group (P = 0.98). The pTNM stage distribution was more favorable in the CRT group (P < 0.001) despite a more advanced initial cTNM stage distribution (P < 0.001). Following CRT, the pathologic response (pP) at the primary tumor as defined by extent of residual tumor predicted overall survival (3 years: P0, 0% residual = 74%; P1, 1%-50% residual = 54%; P2, >50% residual = 24%, P < 0.001) and stage specific survival with greater accuracy than pTNM stage alone.Our analyses demonstrate that following CRT, pTNM continues to predict survival. The extent of pathologic response following CRT is an independent risk factor for survival (pP) and should be incorporated in the pTNM esophageal cancer staging system to better predict patient outcome in esophageal cancer.

Background: The therapeutic outcome for unresectable, locally advanced, malignant thymoma has been poor. Objective: To improve tumor resectability and patient survival rates by studying a multimodal approach to therapy for unresectable malignant thymoma. Design: Prospective cohort study. Setting: Tertiary care cancer center. Participants: All eligible patients had newly diagnosed, histologically proven, unresectable malignant thymoma. Intervention: The treatment regimen consisted of induction chemotherapy (three courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone), surgical resection, postoperative radiation therapy, and consolidation chemotherapy (three courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone). Tissue samples were taken at the time of surgical resection for assessment of tumor necrosis and Ki-67 expression. Measurements: Tumor response and resectability (both overall and after induction chemotherapy) and disease-free survival rate in patients who received multimodal therapy. Results: 13 patients were consecutively enrolled from February 1990 to December 1996, and 12 evaluable patients were assessed for response. Disease responded to induction chemotherapy completely in 3 patients (25%) and partially in 8 patients (67%); 1 patient had a minor response (8%). Eleven patients had surgical resection; 1 refused surgery. Tumors were removed completely in 9 (82%) and incompletely in 2 (18%) of 11 patients who had been receiving radiation therapy and consolidation chemotherapy. All 12 patients are alive (100% at 7 years), with a median follow-up of 43 months, and 10 patients are disease free (73% disease-free survival at 7 years). A high correlation was seen between tumor necrosis after induction chemotherapy and Ki-67 expression (r = −0.88). Conclusions: Aggressive multimodal treatment is highly effective and may cure locally advanced, unresectable malignant thymoma.

Although rarely curative, chemotherapy remains the mainstay of treatment for metastatic urothelial cancer. The role of surgery for metastatic disease is not well established for urothelial cancer, but is sometimes undertaken in the face of persistent or recurrent disease that can be surgically resected.We identified 31 patients with metastatic urothelial cancer undergoing metastasectomy with the intent of rendering them free of disease. All gross disease was completely resected in 30 patients (97%). The most frequently resected location was lung in 24 cases (77%), followed by distant lymph nodes in 4 (13%), brain in 2 (7%) and a subcutaneous metastasis in 1 (3%).Median survival from diagnosis of metastases and from time of metastasectomy was 31 and 23 months, respectively. The 5-year survival from metastasectomy was 33%. Median time to progression following metastasectomy was 7 months. Five patients were alive and free of disease for more than 3 years after metastasectomy.The results in this highly selected cohort, with 33% alive at 5 years after metastasectomy, suggest that resection of metastatic disease is feasible and may contribute to long-term disease control especially when integrated with chemotherapy. Further prospective studies should be undertaken to better characterize the selection criteria and benefit from this intervention.

Background. Multidisciplinary surgical teams enable an aggressive approach to tumors involving the thoracic spine.Methods. From February 1994 to July 1996, 61 patients underwent anterior resections of thoracic spine tumors. Their median age was 56 years. The indications for operation were curative in intent in 7 of 61 and palliative in 54 of 61 (to relieve intractable metastatic bone pain with neurologic compromise [n = 38] and pain alone [n = 16]). Sixteen patients came to our institution unable to ambulate with impending paraplegia.Results. Anterior approaches included combined left side of the neck and median sternotomy for lesions involving vertebrae T-1 through T-3 (n = 9), posterolateral thoracotomy for T-3 through T-10 (n = 39), and thoracoabdominal approach at T-11 and T-12 (n = 13). Median hospital stay was 9.0 days (range, 4 to 57 days). Complications occurred in 18 of 61 (29.5%). In 55 of 61 (90%), pain was significantly improved after the operation. Twelve of the 16 patients who initially presented in wheelchairs regained ambulatory function. There were five perioperative deaths (8.2%). The 1-year cumulative survival for the entire group was 60%.Conclusions. An aggressive surgical approach in cancer patients with locally advanced or metastatic disease in the thoracic spine was associated with acceptable morbidity and mortality. There was significant improvement in their quality of life by control of intractable pain in 90% and recovery of ambulatory function in 75% of patients who presented with critical spinal cord compromise.

In Brief Objectives: Assess outcomes following intrathoracic leaks after esophagectomy from 1970 to 2004 to evaluate the impact of evolving surgical and perioperative techniques on leak-associated mortality (LAM). Summary Background Data: An intrathoracic leak following esophagectomy has historically been considered a catastrophic event, with mortality as high as 71%. Concerns about this complication often affect choice of surgical approach for esophagectomy. Methods: A retrospective review of all esophagectomies for cancer from 1970 to 2004 (n = 1223) was performed. Outcomes following intrathoracic anastomoses (n = 621) were analyzed by era: historical 1970–1986 (n = 145) and modern 1987–2004 (n = 476). Results: There was no difference in the frequency of leak between the time intervals (4.8% versus 6.3%, P = 0.5). Despite a significant increase in the use of preoperative chemoradiation (1% versus 42%, P < 0.001) in the historical versus modern era, the overall mortality decreased from 11% to 2.5% (P < 0.001). The LAM was markedly reduced from 43% to 3.3% (P = 0.016). Factors associated with LAM included failure to use enteral nutrition (HR 13.22, CI 1.8–96.8) and era in which the surgery was performed (HR 18.3, 1.9–180). Other differences included an increased proportion of successful reoperations for leak control (11/30 versus 0/7, P = 0.08) and use of reinforcing muscle flaps (7/11). In the modern era, perioperative mortality is not significantly different for patients with or without intrathoracic leaks (3.3% versus 2.5%, P = 0.55), nor is long-term survival (P = 0.16). Conclusions: Modern surgical management of intrathoracic leaks results in no increased mortality and has no impact on long-term survival. Clinical decisions regarding the use of intrathoracic anastomoses should not be affected by concerns of increased mortality from leak. An intrathoracic leak following esophagectomy has historically been considered a catastrophic event, with mortality as high as 71%. This retrospective review of 621 intrathoracic esophagectomies shows a decrease in leak-associated mortality from 43% to 3.3%. Clinical decisions regarding the use of intrathoracic anastomoses should not be affected by concerns of increased mortality from leak.

The prevention of major pulmonary events (MPEs) after pneumonectomy may minimize postoperative mortality rates. The purpose of this study was to identify preoperative and perioperative factors associated with the development of MPEs after pneumonectomy to help predict which patients are at increased risk for MPEs.We retrospectively reviewed the medical records of all patients (n = 261) who underwent pneumonectomies between January 1990 and May 1999. We analyzed preoperative and perioperative risk factors, the primary end point of an MPE and the secondary end points of mortality (in-hospital or 30 days postprocedure), length of stay, and hospital charges. A postoperative MPE included only pneumonia or acute respiratory distress syndrome as defined by the Centers for Disease Control and the American and European Consensus Conference's established criteria. Simple atelectasis that did not progress to pneumonia or a documented aspiration was not included.Four patients died within 12 hours of operation; the records of the remaining 257 patients were analyzed. An MPE occurred in 33 (12.8%) of 257 patients; 16 (6.2%) of 257 patients died. A multivariate analysis performed on relevant variables showed that only the timing of smoking cessation (1 month or sooner before operation) was a significant predictor of an MPE. Age, side of pneumonectomy, and the use of preoperative chemotherapy or combined chemotherapy and radiation therapy were not significant predictors of an MPE. An MPE significantly increased the mortality rate 2.1% versus 39.3%, p < 0.001).Mortality after pneumonectomy increased significantly with the development of an MPE. Patients who continue to smoke within 1 month of operation are at an increased risk for developing an MPE. Interventions to minimize MPEs may minimize the mortality rate after pneumonectomy.

Vertebral body invasion by superior sulcus tumor has traditionally been considered a contraindication to surgical resection. Attempts at definitive radiation or chemoradiation have not been successful. Recent advances in spinal instrumentation have allowed more complete resection of vertebral body tumors. We, therefore, reviewed our recent experience with vertebral resection of superior sulcus tumors.All patients (n = 17) undergoing resection of superior sulcus tumors with T4 involvement of the vertebrae from October 18, 1990 to September 21, 1998 at the University of Texas M.D. Anderson Cancer Center (MDACC) were evaluated. Their clinical and pathologic data were reviewed and analyzed for short- and long-term outcomes.Total vertebrectomy was performed in 7 patients (42%), partial vertebrectomy in 7 (42%), and 3 (18%) underwent neural foramina or transverse process resection. The median hospital stay was 11 days. Postoperative complications occurred in 7 patients (42%) and included pneumonia (6, 36%), arrhythmia (2, 12%), cerebrospinal fluid leak (2, 12%), wound breakdown (1, 6%), and reoperation for bleeding (1, 6%). Sixteen out of 17 patients received preoperative or postoperative radiation therapy. No perioperative mortality occurred. All patients remained ambulatory after spinal reconstruction. Overall actuarial survival at 2 years was 54%, with 11 patients still alive 2 to 50 months after resection. Locoregional tumor recurrence was noted in all 6 patients who had positive surgical margins, as opposed to 1 out of 11 patients (9%) with negative margins (p < 0.006). Additionally, the 2-year actuarial survival of patients with negative microscopic margins was 80% versus 0% for positive margins (p < 0.0006).An aggressive multidisciplinary approach to superior sulcus tumors with vertebral invasion can lead to long-term survival with acceptable morbidity if negative margins can be obtained. Vertebral body invasion should no longer be considered a contraindication for resection of superior sulcus tumors.

Patients with locoregional carcinoma of the esophagus or gastroesophageal junction have a poor survival rate after surgery. Preoperative chemotherapy or chemoradiotherapy has not improved the outcome for these patients. Our study was designed to assess the feasibility of preoperative induction combination chemotherapy in addition to chemoradiotherapy to improve the curative resection rate, local control, and survival. PATIENTS AND METHODS Patients having histologic proof of localized carcinoma (either squamous cell carcinoma or adenocarcinoma) of the esophagus or gastroesophageal junction underwent full classification including endoscopic ultrasonography (EUS). Patients first received up to two courses of induction chemotherapy consisting of 5-fluorouracil at 750 mg/m(2)/day as continuous infusion on Days 1--5, cisplatin at 15 mg/m(2)/day as an intravenous bolus on Days 1--5, and paclitaxel at 200 mg/m(2) as a 24-hour intravenous infusion on Day 1. The second course was repeated on Day 29. This was followed by radiotherapy (45 grays in 25 fractions) and concurrent admission of 5-fluorouracil (300 mg/m(2)/day as a continuous infusion 5 days/week) and cisplatin (20 mg/m(2) on Days 1--5 of radiotherapy). After chemoradiotherapy, patients underwent surgery. The feasibility of this approach, curative resection rates, patient survival, and patterns of failure were assessed.Thirty-seven of 38 patients enrolled were evaluable for toxicity and survival. Adenocarcinoma and distal esophageal location of carcinoma were observed frequently. Thirty-five (95%) of the 37 patients underwent surgery, all of whom had an R0 (curative) resection. A pathologic complete response was noted in 11 (30%) of the 37 total patients. In addition, 5 patients (14%) had only microscopic carcinoma. According to EUS classification, 31 (89%) of the 35 patients who underwent surgery had a T3 carcinoma whereas according to pathologic classification only 3 (9%) had a T3 carcinoma (P </= 0.01). Similarly, according to EUS classification, 23 patients (66%) had an N1 carcinoma, whereas according to pathologic classification only 7 patients (20%) had an N1 carcinoma (P < or = 0.01). At a median follow-up of 20 months (minimum follow-up, 13+ months; maximum follow-up, 36+ months), the median survival duration for the 37 patients had not yet been reached. In addition, there were two deaths related to surgery.These data show that the three-step strategy of preoperative paclitaxel-based induction chemotherapy then chemoradiotherapy followed by surgery is feasible and appears quite active in patients having locoregional carcinoma of the esophagus or gastroesophageal junction. Future investigations should focus on substituting cisplatin with less toxic agents and including more systemic therapy with newer classes of agents.

Malignant pleural mesothelioma often recurs locally in spite of aggressive resection by extrapleural pneumonectomy and conventional radiotherapy. This may be due to failure to recognize the extent of clinical target volume (CTV) or suboptimal dose delivery to a target that abuts the heart, esophagus, liver, lung, kidney, and spinal cord. We report how these geometric/dosimetric constraints were overcome by exploiting intensity-modulated radiotherapy in the first cohort patient.Twenty-eight patients who had undergone extrapleural pneumonectomy were treated with intensity-modulated radiotherapy. The CTV included the surgically violated inner chest wall, insertion of diaphragm, pleural reflections, and deep margin of the incision. CTV delineation was facilitated by intraoperative radio-opaque marking. Motion was assessed. CTV doses were 45-50 Gy with boosts taken to 60 Gy.Despite the large, irregular CTV (median, 4151 cc; range, 2667-7286 cc), an average of 97% of the CTV was covered to the target dose (range, 92%-100%). Respiratory motion was minimal because of immobility of the prosthetic diaphragm. Normal tissue dose constraints were met. The commonest effects were nausea/vomiting (89%) and dyspnea (80%). Esophagitis was absent (59% of patients) or mild (34% grade 1/2). At median follow-up of 9 months (range, 5-27 months), local control within the contoured target was 100%. One-year survival, disease-specific survival, and disease-free survival are 65%, 91%, and 88%, respectively.Intensity-modulated radiotherapy after extrapleural pneumonectomy is tolerable and seems effective, at least at this early point. As local control improves, systemic metastases become more common, and it may be appropriate to add novel agents to further improve the therapeutic ratio.

The incidence of second primary lung cancers (SPLC) after resection of nonsmall cell lung cancer (NSCLC) is estimated to be 1% to 4% per patient year. The overall effect of SPLC on survival after resection of stage I NSCLC is unknown. Here we report the incidence, management, and outcome of SPLC in a large prospective cohort of patients who underwent careful follow-up.National Cancer Institute Intergroup Trial NCI #I91-0001 examined the effectiveness of isotretinoin A for chemoprevention of second primary tumors, the primary endpoint in that trial. Prospective data from patients randomly assigned to the placebo arm were analyzed.Five hundred sixty-nine patients underwent complete resection of pathologic stage I NSCLC. The median follow-up was 5.9 years. Second primary tumors developed in 88 (15%) patients. Of these, 49 (56%) were SPLC (incidence = 1.99/100 patient-years), with a median interval from initial surgery of 4.2 years. Second primary lung cancer never developed in patients who had never smoked (n = 44, p = 0.046; never versus ever smokers). Current smokers had a higher incidence of SPLC than former smokers (hazard ratio = 1.91, p = 0.03). Age, sex, stage, histology, tumor location and initial surgery had no effect on SPLC development. Despite semiannual follow-up with chest radiographs, 12 (24%) patients had metastatic disease at the time of diagnosis of SPLC. Surgical resection was performed in 31 (63%) SPLC patients. Median survival was 4.1 years in those who underwent surgery and 1.4 years in those who did not (p = 0.003). Overall SPLC-related mortality in the original cohort was 3.7%.Patients who undergo surgery for SPLC can achieve prolonged survival. Despite close follow-up however many patients with SPLC present with advanced disease. That indicates a need for continued lifelong postoperative surveillance.

Primary malignant neoplasms of the trachea are very rare and data relating to them are limited. This study was conducted to review the presentation, management, and outcomes of primary tracheal cancers at our institution, a large multidisciplinary cancer center.Retrospective chart review was conducted for all patients found to have a pathologic diagnosis of primary tracheal malignancy.Since 1945, 74 patients were diagnosed with primary tracheal cancers. Among these, 34 (45.9%) were squamous cell carcinomas, 19 (25.7%) were adenoid cystic carcinomas, and 21 (28.4%) were of other histologic types. Presenting symptoms were most frequently dyspnea (55.4%), hemoptysis (48.6%), cough (41.9%), and hoarseness (35.1%). Most patients (77.3%) were former or current smokers, particularly those with squamous cell carcinoma (93.3%). For the entire group of 74 patients, the 5-year disease-specific mortality rate was 72.9% and the 5-year all-cause mortality rate was 79.3%. Patients who had adenoid cystic carcinoma and those with cervical primaries had better rates of disease-specific and overall survival than others (p = 0.036 and 0.006 for the former patient group and p = 0.006 and 0.030 for the latter patient group). Among patients with incident disease treated at our institution (n = 45), those undergoing primary operation with adjuvant radiotherapy appeared to have better disease-specific and overall survival rates compared with those undergoing primary radiotherapy with or without chemotherapy (p = 0.0002 and 0.0003, respectively). Although those undergoing operation and receiving radiotherapy did better than those undergoing operation alone, the difference was not statistically significant.Primary tracheal cancers are very rare, and our results should be viewed with caution, given that our population comprised a small heterogeneous group treated over a 60-year period. Although squamous cell carcinoma was the most common pathology in smokers, adenoid cystic carcinoma was more prevalent among nonsmokers. Operation with adjuvant postoperative radiotherapy is recommended for most patients.

The purpose of the current study was to test the hypothesis that a lower clinical TNM stage is associated with a higher rate of pathologic complete response (pathCR) in patients with esophageal carcinoma receiving preoperative chemoradiotherapy and to determine whether outcome after pathCR is related to clinical stage or treatment.Clinical parameters and surgical specimens of patients with esophageal carcinoma undergoing preoperative chemoradiotherapy were analyzed to identify predictors of pathCR. In patients with pathCR, predictors of overall survival (OS), disease-free survival (DFS), and distant recurrence were studied.Sixty-nine (29%) of 235 patients achieved pathCR. In patients with American Joint Committee on Cancer (AJCC) Stage II carcinoma, the proportion achieving pathCR was significantly larger than that achieving <pathCR (65% vs. 35%; P = 0.03). The proportion of patients who received induction chemotherapy was higher in the pathCR group than in the <pathCR group (54% vs. 46%; P = 0.05). However, neither TNM classification, primary tumor location, histologic type, gender, therapy sequence, or radiation dose (45 grays [Gy] vs. 50.4 Gy) were found to have any influence on OS or DFS. The median OS from pathCR was significantly longer than that from <pathCR (133 mos vs. 34 mos; P = 0.002). Similarly, DFS was longer in the pathCR group than in the <pathCR (P = 0.001).Patients with clinical AJCC Stage II esophageal carcinoma are more likely to achieve a pathCR after preoperative chemoradiotherapy than are those with Stage III carcinoma. Chemoradiotherapy as primary therapy for patients with Stage I esophageal carcinoma warrants investigation as a means to preserve their esophagus.

Abstract BACKGROUND The current study was conducted to test the hypothesis that patterns of failure are correlated with the degree of residual carcinoma after preoperative chemoradiotherapy (CRT) in patients with esophageal carcinoma. METHODS The authors analyzed the clinical characteristics of patients with carcinoma of the esophagus who underwent preoperative CRT. The residual carcinoma in the resected specimen was categorized into 3 groups (0%, 1–50%, and &gt; 50%). The initial patterns of failure were analyzed according to these categories. RESULTS Of the 235 patients who underwent CRT, 69 (29%) achieved a pathologic complete response (pathCR; Group A), 109 patients (46%) achieved a response but it was less than a pathCR (1–50% residual carcinoma; Group B), and 57 (24%) had no response (&gt; 50% residual carcinoma; Group C). The time to locoregional recurrence was significantly longer for Group A compared with Group C ( P = 0.05). The rate of distant metastases was significantly lower in Groups A and B compared with Group C (14% in Group A, 29% in Group B, and 33% in Group C; P = 0.03). The distant metastases‐free survival was found to be significantly longer in Groups A and B compared with Group C (Group A vs. Group B, P = 0.01; Group A vs. Group C, P &lt; 0.0001; and Group B vs. Group C, P = 0.03). A significantly higher proportion of patients in the responding groups (Groups A and B) had no disease recurrence compared with Group C (81% in Group A, 67% in Group B, and 61% in Group C; P = 0.04). The overall survival and disease‐free survival were found to be significantly longer in Groups A and B compared with Group C. CONCLUSIONS Data from the current study demonstrate that the proportion of residual carcinoma after preoperative CRT is significantly correlated with patterns of locoregional and distant failure. Future investigations should focus on reducing the proportion of residual carcinoma and metastatic disease progression in patients with esophageal carcinoma. Cancer 2005. © 2005 American Cancer Society.

A cervical side-to-side stapled esophagogastric anastomosis appears to decrease morbidity compared with traditional hand-sewn techniques. We evaluated our experience with this novel technique in intrathoracic anastomoses and compared the outcome with circular-stapled or hand-sewn techniques.All patients undergoing transthoracic esophagectomy from 1999 to 2005 for esophageal cancer with gastric replacement were reviewed. A prospective quality improvement database, telephone interview, and chart review were used to collect data. A side-to-side stapled anastomosis was done in 44 patients, circular-stapled anastomosis in 147, and hand-sewn anastomosis in 23. Propensity scores were generated from 14 variables, which were then used to generate 23 patient triplets. End points included leak, dysphagia, stricture, other major complications, and overall survival. Follow-up was available on all patients.For matched triplet comparison, no significant difference was noted in anastomotic leaks (8.7% with side-to-side stapled, 4.3% with circular-stapled, and 4.3% with hand-sewn; p = 0.78). Postoperative dysphagia was significantly higher in hand-sewn anastomoses at 56.5% versus 26.1% with side-to-side stapled and 21.7% with circular-stapled (p = 0.04). Stricture requiring esophageal dilation was also increased in hand-sewn at 34.8% versus 8.7% with side-to-side stapled and 8.7% with circular-stapled (p = 0.04). No difference was noted in perioperative mortality, long-term survival, or locoregional recurrences between techniques.In this carefully matched group of patients, intrathoracic use of the side-to-side stapled esophagogastric anastomosis in esophageal cancer patients is safe and effective. Postoperative dysphagia and need for stricture dilation may be decreased using a stapled compared with a traditional hand-sewn anastomosis.

The current American Joint Committee on Cancer (AJCC) esophageal cancer staging for nodal status is difficult to interpret and is based solely on lymph node location relative to the primary tumor's esophageal location. Recent reports suggest that the number of lymph nodes involved is also an important factor. We reviewed our esophageal experience to propose an improved nodal staging system.In all, 1,027 patients with resected esophageal cancer from 1970 to 2005 were reviewed. Lymph nodes stations were assigned according to AJCC criteria. Overall survival was assessed by Kaplan-Meier analysis. The impact of location, number of involved lymph nodes, and use of preoperative chemotherapy or radiation therapy, or both, was assessed.Nonregional nodal involvement (n = 17) was associated with decreased survival compared with regional (n = 441) or celiac nodal (n = 73) involvement (3-year: 0% versus 24% and 23%; p < 0.001). The number of involved lymph nodes was strongly associated with survival (3-year: 0 nodes = 63%, 1 to 3 nodes = 31%, more than 3 nodes = 13%; p < 0.001), and multivariable Cox proportional-hazards analysis suggested that the location and number of involved lymph nodes were independent predictors of survival (p < 0.001). We propose a modified nodal staging system that designates celiac nodes as regional and includes number of involved nodes: pN0, no nodes (3 years = 63%, n = 496); pN1-regional, 1 to 3 nodes (3 years = 32%, n = 292); pN2-regional, more than 3 nodes (3 years = 14%, n = 222); pN3-nonregional node (3 years = 0%, n = 17 [p < 0.0001]). This modified nodal staging system better predicts survival than the current AJCC nodal staging system in which survival for pN1 (3 years = 24%) and pM1a (3 years = 23%) do not differ (p = 0.67). The use of induction before surgical resection did not alter the predictive effect of the new nodal staging system.Modification of the AJCC nodal classification system to incorporate the number of involved lymph nodes with regional and nonregional node location simplifies and better predicts long-term survival than does the current AJCC nodal system.

Background Lung metastases are considered a poor prognostic factor in patients with resectable colorectal liver metastases. Study Design We reviewed records of 1,260 consecutive patients with liver-only or liver-plus-lung (L+L) metastases from colorectal cancer who underwent resection with curative intent (1995 to 2009). Survival and prognostic factors were analyzed. Results There were 112 patients who underwent resection of L+L (mean 2 liver, 2 lung metastases). Mean tumor sizes were 3 cm and 1 cm, respectively. Thirty-four (31%) had bilateral lung metastases. Ten (9%) had synchronous L+L metastases, 60 (54%) had diagnosis of lung metastases within 1 year of liver resection. Most (108 of 112, 96%) had resection of liver before or at the same time as lung. Preoperative chemotherapy was used in 77 (69%) before liver resection and 56 (50%) before lung resection. Among L+L patients, no postoperative deaths occurred; postoperative morbidity rates were 26% after liver resection and 4% after lung resection. After a median of 49 months follow-up, L+L patients (n = 112) had better survival than liver only (n = 1,148) (5-year overall survival, L+L, 50% vs liver only, 40%; p = 0.01). CEA level > 5 ng/dL (hazard ratio [HR] 2.1, 95% CI 1.1 to 4.4, p = 0.04) and rectal primary (HR 2.9, 95% CI 1.4 to 6, p = 0.004) were associated with worse survival in L+L patients. Conclusions The survival rate for patients who undergo resection of L+L metastases from colorectal cancer is greater than the survival rate of the general population of patients who undergo resection of liver metastases only. The presence of resectable lung metastases is neither a poor prognostic factor nor a contraindication to resection of liver metastases.

BackgroundAfter neoadjuvant chemoradiation (CXRT) for esophageal cancer, surgery has traditionally been recommended to be performed within 8 weeks. However, surgery is often delayed for various reasons. Data from other cancers suggest that delaying surgery may increase the pathologic complete response rate. However, there are theoretical concerns that waiting longer after radiation may lead to a more difficult operation and more complications. The optimal timing of esophagectomy after CXRT is unknown.MethodsFrom a prospective database, we analyzed 266 patients with resected esophageal cancer who were treated with neoadjuvant CXRT from 2002 to 2008. Salvage resections were excluded from this analysis. We compared patients who had surgery within 8 weeks of CXRT and those who had surgery after 8 weeks. We used multivariable analysis to determine whether increased interval between chemoradiation and surgery was independently associated with perioperative complication, pathologic response, or overall survival.ResultsOne hundred fifty patients were resected within 8 weeks and 116 were resected greater than 8 weeks after completing CXRT. Mean length of operation, intraoperative blood loss, anastomotic leak rate, and perioperative complication rate were similar for the two groups. Pathologic complete response rate and overall survival were also similar for the two groups (p = not significant). In multivariable analysis, timing of surgery was not an independent predictor of perioperative complication, pathologic complete response, or overall survival.ConclusionsThe timing of esophagectomy after neoadjuvant CXRT is not associated with perioperative complication, pathologic response, or overall survival. It may be reasonable to delay esophagectomy beyond 8 weeks for patients who have not yet recovered from chemoradiation. After neoadjuvant chemoradiation (CXRT) for esophageal cancer, surgery has traditionally been recommended to be performed within 8 weeks. However, surgery is often delayed for various reasons. Data from other cancers suggest that delaying surgery may increase the pathologic complete response rate. However, there are theoretical concerns that waiting longer after radiation may lead to a more difficult operation and more complications. The optimal timing of esophagectomy after CXRT is unknown. From a prospective database, we analyzed 266 patients with resected esophageal cancer who were treated with neoadjuvant CXRT from 2002 to 2008. Salvage resections were excluded from this analysis. We compared patients who had surgery within 8 weeks of CXRT and those who had surgery after 8 weeks. We used multivariable analysis to determine whether increased interval between chemoradiation and surgery was independently associated with perioperative complication, pathologic response, or overall survival. One hundred fifty patients were resected within 8 weeks and 116 were resected greater than 8 weeks after completing CXRT. Mean length of operation, intraoperative blood loss, anastomotic leak rate, and perioperative complication rate were similar for the two groups. Pathologic complete response rate and overall survival were also similar for the two groups (p = not significant). In multivariable analysis, timing of surgery was not an independent predictor of perioperative complication, pathologic complete response, or overall survival. The timing of esophagectomy after neoadjuvant CXRT is not associated with perioperative complication, pathologic response, or overall survival. It may be reasonable to delay esophagectomy beyond 8 weeks for patients who have not yet recovered from chemoradiation.

Outcomes of salvage esophagectomy after definitive chemoradiation (CRT) for squamous cell carcinoma are well defined. Previous reports of salvage esophagectomy in patients with recurrent adenocarcinoma after definitive CRT are limited by small numbers and high morbidity and mortality rates.We reviewed our experience of 65 patients with esophageal adenocarcinoma treated from 1997 to 2010 who underwent salvage esophagectomy after failed definitive CRT. We then compared this group to 65 matched patients of 521 total patients with esophageal adenocarcinoma who received preoperative CRT followed by planned esophagectomy. Propensity matching and multivariable analysis were performed.Median time to surgery from completion of therapy for the salvage group was 216 days. Major postoperative events (major pulmonary event, conduit loss, leak, readmission to intensive care unit) occurred in 35% (23 of 65) of salvage patients and 31% (20 of 65) of the planned resection matched group. Anastomotic leak occurred in 18.5% (12 of 65) and 11.3 (59 of 521) of salvage and planned groups, respectively. Thirty-day mortality was 3.1% (2 of 65) after salvage resection and 4.6% (3 of 65) after planned resection. There was no difference in 3-year overall or median survival between the two groups of patients (32 months, 48% salvage, versus 40 months, 57% planned resection). Multivariable analysis did not identify salvage strategy or time from completion of therapy to resection as a predictor of major event or death.Postoperative morbidity, mortality, and overall survival of patients after salvage esophagectomy are comparable to matched patients after planned resection. These results suggest that patients with esophageal adenocarcinoma who fail definitive CRT and recur locoregionally should be considered for salvage esophagectomy at experienced esophageal centers.

Esophageal continuity after esophagectomy can be established without a viable stomach conduit by using the colon or jejunum. The current study evaluated the technical outcomes of the long-segment supercharged jejunal (SPJ) interposition.A database was developed to capture patient characteristics, operative technique, and outcomes for patients with an SPJ interposition at 2 institutions from 2000 to 2010. A multivariable analysis was performed to determine predictors of leak and graft loss. A selective prospective manometric analysis was performed to describe peristalsis of the SPJ.Of the 60 patients undergoing SPJ reconstruction, 44 (73%) were men, and the median age was 57 years (range, 28 to 76 years). The operation in 23 patients (38%) was performed to reverse esophageal discontinuity, and 57 (95%) patients underwent reconstruction for cancer. Early complications included 18 instances (30%) of pneumonia, 19 anastomotic leaks (32%), and 5 instances of graft loss with diversion (8%). Three patients (5%) died in the hospital or within 30 days. After jejunal reconstruction, 50 patients (83%) were able to return to a regular diet. The 90-day mortality rate was 10% (n=6). Characteristic postoperative manometric findings included segmental peristalsis, as is typical for in situ jejunum. Median survival was 28 months and the 5-year survival rate was 30%.An SPJ conduit can reestablish or maintain gastrointestinal continuity in high-risk patients when the stomach is unavailable. This is our preferred conduit for reconstruction of the esophagus over the colon.

Resection of pulmonary colorectal carcinoma metastases may provide long-term benefit, but patient selection remains controversial. The objective of this study was to identify preoperative predictors of survival and lung recurrence for patients undergoing resection of such lesions.A prospectively collected database was retrospectively reviewed to identify patients who underwent their first colorectal carcinoma pulmonary metastasectomy. Two multivariate logistic analyses were performed to identify preoperative predictors of survival and lung recurrence. Preoperative factors, pathologic colorectal carcinoma stage, additional sites of metastases, timing of metastatic occurrence, and premetastasectomy disease-free interval were included in the univariate analyses.From January 2000 to December 2010, 229 patients met inclusion criteria. The mean age was 60 years, and 100 patients (43.7%) were women. The overall median time and 5-year survival rate were 70.1 months and 55.4%, respectively, after the first pulmonary metastasectomy. Median follow-up was 37.2 months. Age older than 60 years (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.005 to 1.052; p=0.016), male sex (HR, 1.84; 95% CI, 1.089 to 3.094; p=0.023), and more than three lung metastases (HR, 1.15; 95% CI, 1.024 to 1.282; p=0.018) predicted survival at 5 years in one multivariate analysis. In the second, more than three lung metastases present at first metastasectomy (HR, 1.19; 95% CI, 1.071 to 1.321; p=0.001) and the preoperative disease-free interval of less than 3 years (HR, 0.99; 95% CI, 0.973 to 0.997; p=0.013) predicted lung recurrence.Older age, male sex, and more lung metastases predict poorer survival after resection of pulmonary colorectal cancer metastases. The number of lung metastases present at the first metastasectomy and the preoperative disease-free interval predicted recurrence in the lung.

BackgroundIt is unclear whether the enhanced dexterity and visualization of the surgical robot lessens morbidity and influences staging or survival. We compared outcomes of robotic-assisted lobectomy (RAL) with thoracoscopic video-assisted lobectomy (VAL) or open lobectomy (OL) of non-small cell lung cancer.MethodsUsing a prospective surgical database, perioperative and cancer-related outcomes of patients who received a lobectomy for non-small cell lung cancer from 2011 to 2017 were analyzed. Outcomes between each surgical approach were compared using inverse probability of treatment weighting generated from the inverse of the propensity score.ResultsThere were 831 patients: 106 RAL, 301 VAL, and 424 OL. More RAL patients than VAL received neoadjuvant therapy (16% vs 6%, P = .001), but less than OL (28% vs 16%, P = .014). After adjustment, RAL was associated with longer operative times, less blood loss, and improved nodal harvest (all P < .02). There were no differences in morbidity, nodal upstaging, or mortality between surgical approaches. Length of stay was shorter with RAL vs OL (P < .01). Unadjusted cost was higher after RAL vs VAL (P = .003), but after adjustment, cost differences disappeared.ConclusionsRobotic-assisted lobectomy was associated with improved nodal harvest and less blood loss as compared with VAL or OL. Length of stay was shorter with RAL as opposed to OL. Unexpectedly, cost was not higher with RAL. The profile of patients who received RAL more closely approximated OL, suggesting RAL may allow typical thoracotomy patients to receive minimally invasive surgery after adequate training and experience. It is unclear whether the enhanced dexterity and visualization of the surgical robot lessens morbidity and influences staging or survival. We compared outcomes of robotic-assisted lobectomy (RAL) with thoracoscopic video-assisted lobectomy (VAL) or open lobectomy (OL) of non-small cell lung cancer. Using a prospective surgical database, perioperative and cancer-related outcomes of patients who received a lobectomy for non-small cell lung cancer from 2011 to 2017 were analyzed. Outcomes between each surgical approach were compared using inverse probability of treatment weighting generated from the inverse of the propensity score. There were 831 patients: 106 RAL, 301 VAL, and 424 OL. More RAL patients than VAL received neoadjuvant therapy (16% vs 6%, P = .001), but less than OL (28% vs 16%, P = .014). After adjustment, RAL was associated with longer operative times, less blood loss, and improved nodal harvest (all P < .02). There were no differences in morbidity, nodal upstaging, or mortality between surgical approaches. Length of stay was shorter with RAL vs OL (P < .01). Unadjusted cost was higher after RAL vs VAL (P = .003), but after adjustment, cost differences disappeared. Robotic-assisted lobectomy was associated with improved nodal harvest and less blood loss as compared with VAL or OL. Length of stay was shorter with RAL as opposed to OL. Unexpectedly, cost was not higher with RAL. The profile of patients who received RAL more closely approximated OL, suggesting RAL may allow typical thoracotomy patients to receive minimally invasive surgery after adequate training and experience.

We present 1470 surgical resections for thymoma identified in the pathology files of 14 institutions from 11 countries with the purpose of determining and correlating a simplified histological classification of thymoma and pathological staging with clinical outcome. The study population was composed of 720 men and 750 women between the ages of 12 and 86 years (average, 54.8 years). Clinically, 137 patients (17%) had a history of myasthenia gravis, 31 patients (3.8%) of other autoimmune disease, and 55 (6.8%) patients of another neoplastic process. Surgical resection was performed in all patients. Histologically, 1284 (87.13%) cases were thymomas (World Health Organization types A, B1, and B2, and mixed histologies), and 186 (12.7%) were atypical thymomas (World Health Organization type B3). Of the entire group, 630 (42.9%) were encapsulated thymomas, and 840 (57.9%) were invasive thymomas in different stages. Follow-up information was obtained in 1339 (91%) patients, who subsequently were analyzed by univariate and multivariate statistical analysis. Follow-up ranging from 1 to 384 months was obtained (mean, 69.2 months) showing tumor recurrence in 136 patients (10.1%), whereas 227 died: 64 (28.2%) due to tumor and 163 (71.8%) due to other causes. Statistical analysis shows that separation of these tumors into thymoma and atypical thymoma is statistically significant (P = .001), whereas tumor staging into categories of encapsulated, minimally invasive, and invasion into adjacent organs offers a meaningful clinical assessment with a P = .038. Our findings suggest that our simplified histological schema and pathological staging system are excellent predictors of clinical outcome.

Lobectomy is a standard treatment for stage I non-small cell lung cancer, but a significant proportion of patients are considered at high risk for complications, including mortality, after lobectomy and might not be candidates. Identifying who is at risk is important and in evolution. The objective of The American Association for Thoracic Surgery Clinical Practice Standards Committee expert panel was to review important considerations and factors in assessing who is at high risk among patients considered for lobectomy.The American Association for Thoracic Surgery Clinical Practice Standards Committee assembled an expert panel that developed an expert consensus document after systematic review of the literature. The expert panel generated a priori a list of important risk factors in the determination of high risk for lobectomy. A survey was administered, and the expert panel was asked to grade the relative importance of each risk factor. Recommendations were developed using discussion and a modified Delphi method.The expert panel survey identified the most important factors in the determination of high risk, which included the need for supplemental oxygen because of severe underlying lung disease, low diffusion capacity, the presence of frailty, and the overall assessment of daily activity and functional status. The panel determined that factors, such as age (as a sole factor), were less important in risk assessment.Defining who is at high risk for lobectomy for stage I non-small cell lung cancer is challenging, but remains critical. There was impressive strong consensus on identification of important factors and their hierarchical ranking of perceived risk. The panel identified several key factors that can be incorporated in risk assessment. The factors are evolving and as the population ages, factors such as neurocognitive function and frailty become more important. A minimally invasive approach becomes even more critical in this older population to mitigate risk. The determination of risk is a clinical decision and judgement, which should also take into consideration patient perspectives, values, preferences, and quality of life.

Whether extrapleural pneumonectomy (EPP) or extended pleurectomy/decortication (P/D) is the optimal resection for malignant pleural mesothelioma remains controversial. We therefore compared perioperative outcomes and long-term survival of patients who underwent EPP versus P/D.Patients with the diagnosis of malignant pleural mesothelioma who underwent either EPP or P/D from 2000 to 2019 were identified from our departmental database. Propensity score matching was performed to minimize potential confounders for EPP or P/D. Survival analysis was performed by the Kaplan-Meier method and Cox multivariable analysis.Of 282 patients, 187 (66%) underwent EPP and 95 (34%) P/D. Even with propensity score matching, perioperative mortality was significantly higher for EPP than for P/D (11% vs 0%; P = .031); when adjusted for perioperative mortality, median overall survival between EPP and P/D was 15 versus 22 months, respectively (P = .276). Cox multivariable analysis for the matched cohort identified epithelioid histology (hazard ratio [HR], 0.56; P = .029), macroscopic complete resection (HR, 0.41; P = .004), adjuvant radiation therapy (HR, 0.57; P = .019), and more recent operative years (HR, 0.93; P = .011)-but not P/D-to be associated with better survival. Asbestos exposure (HR, 2.35; P = .003) and pathologic nodal disease (HR, 1.61; P = .048) were associated with worse survival.In a multimodality treatment setting, P/D and EPP had comparable long-term oncologic outcomes, although P/D had much lower perioperative mortality. The goal of surgical cytoreduction should be macroscopic complete resection achieved by the safest operation a patient can tolerate.

Background For extrathoracic malignant neoplasms that have metastasized to the lungs, previous investigations have demonstrated both oncologic and survival benefits after pulmonary and repeated metastasectomy. Little is known about the feasibility of incrementally increasing numbers of subsequent metastasectomy procedures. Methods We conducted a retrospective review of patients who underwent ≥3 pulmonary resection procedures for recurrent, metachronous metastatic disease of nonlung primary malignant neoplasms at a single institution between 1992 and 2020. Primary outcomes collected pertained to safety and feasibility, including estimated blood loss (EBL), hospital length of stay, and details of postoperative complications. Results There were 117 patients who met inclusion criteria, having undergone at least 3 metastasectomy operations, with 55 (47.1%) undergoing a fourth operation and 20 (17.1%) undergoing a fifth operation. EBL did not differ between first and second operations (106.6 mL vs 102.5 mL; P = .76). It was, however, significantly greater at third operations (102.5 mL vs 238.7 mL; P = .000016). We noted an increase in wound complications between the second and third operations (0.9% vs 6.8%; P = .02) and incremental increases in likelihood of prolonged air leak with each subsequent operation. The need for reoperation was low for all and similar between operations. Importantly, hospital length of stay was similar for all procedures, as were the frequencies of hospital readmission. Conclusions Third-time redo pulmonary metastasectomy can be performed safely and feasibly in select patients. Further repeated resection should remain a therapeutic option for patients, although risks for potentially longer operating time, greater EBL, and prolonged air leaks may be anticipated.

Background: New methods are needed to detect precancerous lesions in lung tissue. We conducted a study to determine the utility of LIFE™ (laserinduced fluorescence emission) autofluorescence bronchoscopy for the detection of squamous metaplasia and dysplasia in current and former smokers. Methods: In this prospective, single-center study, 53 participants underwent standard white-light bronchoscopy and 39 underwent both white-light and LIFE bronchoscopy Bronchial biopsy specimens were obtained from all participants at six predetermined sites using white-light bronchoscopy and from all other sites that appeared to be abnormal in participants who underwent LIFE bronchoscopy. Relationships between LIFE imaging and histologic findings were examined for 245 biopsy specimens obtained from those participants who had undergone LIFE bronchoscopy. Results: LIFE imaging revealed abnormalities designated as either class II or class III in 89 (36.3 %) and 16 (6.5 %) of the 245 sites examined, respectively, and histopathologic examination showed dysplasia and metaplasia in eight (3.3%) and in 52 (21.2%) of the 245 specimens, respectively. Among the 105 biopsy specimens obtained from sites with abnormal LIFE imaging, only 26 (24.8%) exhibited squamous metaplasia and/or dysplasia, similar to the findings for sites with normal LIFE imaging (34 [24.3%] of 140). Comparison of individuals examined by LIFE imaging with those who underwent white-light bronchoscopy alone revealed no increase in the detection of dysplasia or metaplasia with LIFE bronchoscopy. Conclusion: In this population of current and former smokers, abnormalities detected by LIFE bronchoscopy did not improve the detection of squamous metaplasia or dysplasia. [J Nall Cancer Inst 1998; 90:991–5]

We designed a prospective single arm Phase II study to evaluate the feasibility and mechanisms of apoptosis induction after Ad-p53 (INGN 201) gene transfer and radiation therapy in patients with non-small cell lung cancer.Nineteen patients with nonmetastatic non-small cell lung cancer who were not eligible for chemoradiation or surgery were treated as outpatients with radiation therapy to 60 Gy over 6 weeks in conjunction with three intratumoral injections of Ad-p53 (INGN 201) on days 1, 18, and 32.Seventeen of 19 patients completed all planned radiation and Ad-p53 (INGN 201) gene therapy as outpatients. The most common adverse events were grade 1 or 2 fevers (79%) and chills (53%). Three months after completion of therapy, pathologic biopsies of the primary tumor revealed no viable tumor (12 of 19 patients, 63%), viable tumor (3 of 19 patients, 16%), and not assessed (4 of 19 patients, 21%). Computed tomography and bronchoscopic findings at the primary injected tumor revealed complete response (1 of 19 patients, 5%), partial response (11 of 19 patients, 58%), stable disease (3 of 19 patients, 16%), progressive disease (2 of 19 patients, 11%), and not evaluable (2 of 19 patients, 11%). Quantitative reverse transcription-PCR analysis of the four p53 related genes [p21 (CDKN1A), FAS, BAK, and MDM2] revealed that Bak expression was increased significantly 24 h after Ad-p53 (INGN 201) injection and levels of CDKN1A and MDM2 expression were increased over the course of treatment.Intratumoral injection of Ad-p53 (INGN 201) in combination with radiation therapy is well tolerated and demonstrates evidence of tumor regression at the primary injected tumor. Serial biopsies of the tumor suggest that BAK gene expression is most closely related to Ad-p53 (INGN 201) gene transfer.

To evaluate the safety and effectiveness of a new biodegradable polymeric sealant to close intraoperative air leaks after pulmonary resection.In a multicenter prospective randomized trial, 161 patients with a median age of 67 years old (range 18-85 years old), were randomized in a 2:1 ratio to receive sealant or control for at least one significant air leak (> or = 2.0 mm in size) after pulmonary resection. In the sealant group, all significant air leaks underwent attempted repair by standard methods (sutures, staples, or cautery) prior to the application of sealant. The control group underwent only standard methods. Blood was analyzed for immunologic response. Patients were followed up 1 month after surgery.Intraoperative air leaks were sealed in 77% of the sealant group compared with 16% in the control group (p < 0.001). The sealant group had significantly fewer patients with postoperative air leaks compared with the control group (65% vs 86%, p = 0.005). Median length of hospitalization was 6 days (range, 3-23 days) for the sealant group compared with 7 days (range 4-38 days) for controls (p = 0.028). There was no difference in mortality, morbidity, duration of chest tubes, or immune responses between the two groups.This study demonstrates the effectiveness of a biodegradable polymer when used as an adjunct to standard closure methods for sealing significant intraoperative air leaks that develop from pulmonary surgery. Use of the sealant led to a reduction in postoperative air leaks, which may have decreased the length of hospitalization.

Preoperative chemotherapy (C+S) for non-small cell lung cancer (NSCLC) has increased in an attempt to improve survival. Patients receiving C+S potentially may have an increase in postoperative morbidity and mortality compared with surgery alone (S). We reviewed our experience with C+S and S in a tertiary referral center.Three hundred eighty consecutive patients underwent lobectomy or greater resection for NSCLC between August 1, 1996, and April 30, 1999: 335 patients (259 S; 76 C+S) were analyzed; 45 additional patients were excluded for prior NSCLC, other chemotherapy for other malignancy, or radiation. We compared morbidity and mortality overall, and by subset analysis (clinical stage, pathological stage, procedure, and by protocol use) for both C+S and S patients.Demographics, comorbidities, and spirometry were similar. We noted no significant difference in overall or subset mortality or morbidity including pneumonia, acute respiratory distress syndrome, reintubation, tracheostomy, wound complications, or length of hospitalization.C+S did not significantly affect morbidity or mortality overall, based on clinical stage, postoperative stage, or extent of resection. The potential for enhanced survival in resectable NSCLC justifies continued study of C+S.

The medical criteria for inoperability have been difficult to define in patients with lung cancer.Sixty-six patients with non-small cell lung cancer and radiographically resectable lesions were evaluated prospectively in a clinical trial.The patients were considered by cardiac or pulmonary criteria to be high risk for pulmonary resection.If exercise testing revealed a peak oxygen uptake of 15 mL .kg-1• min-lor greater, the patient was offered surgical treatment.Of the 20 procedures performed, nine were lobectomies, two were bilobectomies, and nine were wedge or segmental resections.All patients were extubated within 24 hours and discharged within 22 days after operation (median time to discharge, 8 days).There were no deaths, and complications occurred in 8 (40%) of the 20 patients.Five patients whose peak oxygen uptake was lower than 15 mL• kg-1• min-1 also underwent sur-C arcinom a of the lung is a fatal disease that, in the United States, contributes to more than 30% of cancer-related deaths in men and is now the most common cause of cancer-related deaths in women.Of the 170,000 patients who will be diagnosed with lung cancer this year, more than half will be seen with advanced-stage IIIb or IV disease.Fewer than one third will have resectable tumors confined to the thorax.Surgical resection is the patient's best chance for cure, but many patients are considered inoperable on medical grounds because of inadequate cardiopulmonary functional reserve.The lower limit at which the operative mortality exceeds the benefit of operative intervention has been difficult to define.Although some authors [1] have found a 5-year survival rate of up to 35% for patients with stage I disease who are treated with radiation therapy, the overall survival rates in most series of patients who received radiation therapy with or without chemotherapy are low [2,3].This study was undertaken to evaluate the effects of surgical and nonsurgical treatments on duration of survival of patients with resectable lung cancer who, because of marginal cardiopulmonary function, would by tradi-

Residency training programs commonly emphasize a single technique of esophagectomy, as the safety and the efficacy of teaching or performing more than one type of esophagectomy are unclear. Between 1986 and 1992, 248 patients were explored for possible esophageal resection. Thoracic surgical residents or fellows performed major components of all resections. Two hundred twenty-one patients (adenocarcinoma, 146; squamous cell carcinoma, 72; and other, 3) underwent transthoracic esophagectomy (n = 134), transhiatal esophagectomy (n = 42), or total thoracic esophagectomy (n = 45), a resectability rate of 89.1% (221/248). Complications occurred in 75% of patients with transthoracic esophagectomy, in 69% with transhiatal esophagectomy, and in 80% with total thoracic esophagectomy. The overall operative mortality rate was 6.8% (15/221). Patients with a cervical anastomosis had a higher leak rate (13%) than those with an intrathoracic anastomosis (6%). Median survival was 22 months (19% 5-year survival) and did not differ by operation type or stage. No patient with unresectable disease (n = 27) survived longer than 10 months. Survival for patients with adenocarcinoma stages 3 and 2a suggested a trend toward improved survival after transthoracic esophagectomy despite similar rates of local and distant recurrence. Transthoracic esophagectomy, transhiatal esophagectomy, and total thoracic esophagectomy performed within a residency training program have similar morbidity, mortality, and recurrence rates as those in other modern series. A specific technique of esophagectomy can be selected for individual patients. Survival and sites of recurrence primarily reflect disease stage, not the technique of esophagectomy used.

Retinoids, including retinol and retinoic acid derivatives, maintain the normal growth and differentiation of human bronchial epithelial cells. The signaling pathways through which retinoids mediate these effects have not been defined. Insulin-like growth factor binding protein-3 (IGFBP-3) and the transforming growth factor-β (TGF-β) gene family (β1–3) were examined as potential components of the retinoid signaling pathway in normal human bronchial epithelial cells. All-trans-retinoic acid (t-RA) increased the levels of TGF-β2 and IGFBP-3 mRNA and of secreted TGF-β and IGFBP-3 proteins. An antagonist of retinoic acid receptor-α, LG100629, abrogated the increase in TGF-β2 and IGFBP-3 mRNA levels induced by t-RA. t-RA increased IGFBP-3 mRNA levels transiently from 1 to 6 h, and subsequently a sustained increase began at 72 h, which coincided with the appearance of active TGF-β in the media. Treatment with TGF-β2 increased IGFBP-3 mRNA levels, but treatment with latency-associated peptide, which inactivates secreted TGF-β, did not abrogate the effect of t-RA on IGFBP-3 expression. These findings provide evidence that t-RA increased TGF-β2 and IGFBP-3 expression through an retinoic acid receptor-α-dependent pathway, and the increase in IGFBP-3 expression by t-RA did not require activation of the TGF-β pathway by autocrine or paracrine mechanisms. Retinoids, including retinol and retinoic acid derivatives, maintain the normal growth and differentiation of human bronchial epithelial cells. The signaling pathways through which retinoids mediate these effects have not been defined. Insulin-like growth factor binding protein-3 (IGFBP-3) and the transforming growth factor-β (TGF-β) gene family (β1–3) were examined as potential components of the retinoid signaling pathway in normal human bronchial epithelial cells. All-trans-retinoic acid (t-RA) increased the levels of TGF-β2 and IGFBP-3 mRNA and of secreted TGF-β and IGFBP-3 proteins. An antagonist of retinoic acid receptor-α, LG100629, abrogated the increase in TGF-β2 and IGFBP-3 mRNA levels induced by t-RA. t-RA increased IGFBP-3 mRNA levels transiently from 1 to 6 h, and subsequently a sustained increase began at 72 h, which coincided with the appearance of active TGF-β in the media. Treatment with TGF-β2 increased IGFBP-3 mRNA levels, but treatment with latency-associated peptide, which inactivates secreted TGF-β, did not abrogate the effect of t-RA on IGFBP-3 expression. These findings provide evidence that t-RA increased TGF-β2 and IGFBP-3 expression through an retinoic acid receptor-α-dependent pathway, and the increase in IGFBP-3 expression by t-RA did not require activation of the TGF-β pathway by autocrine or paracrine mechanisms. Retinoids control normal tracheobronchial epithelial growth and differentiation. Rodents that are deprived of vitamin A develop squamous metaplasia in the tracheobronchial epithelium, and normal epithelial differentiation is restored by vitamin A supplementation (1Wolbach S.B. Howe P.T. J. Exp. Med. 1925; 42: 753-778Google Scholar,2Chopra D.P. J. Natl. Cancer Inst. 1982; 69: 895-901Google Scholar). In tissue culture, human bronchial epithelial (HBE) 1The abbreviations used are: HBE, human bronchial epithelial; t-RA, all-trans-retinoic acid; TGF-β, transforming growth factor-β; MLEC, mink lung epithelial cells; IGFBP-3, insulin-like growth factor binding protein-3; BPE, bovine pituitary extract; LAP, latency-associated peptide; WLB, Western ligand blot; RAR, retinoic acid receptor; RXR, retinoid X receptors. cells undergo squamous differentiation with a variety of agents, and all-trans-retinoic acid (t-RA) inhibits this process (3Jetten A.M. Rearick J.I. Smits H.L. Biochem. Soc. Trans. 1986; 14: 930-933Google Scholar, 4Jetten A.M. Shirley J.E. Stoner G. Exp. Cell Res. 1986; 167: 539-549Google Scholar, 5Masui T. Wakefield L.M. Lechner J.F. LaVeck M.A. Sporn M.B. Harris C.C. Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 2438-2442Google Scholar, 6Willey J.C. Moser Jr., C.E. Lechner J.F. Harris C.C. Cancer Res. 1984; 44: 5124-5126Google Scholar, 7Saunders N.A. Jetten A.M. J. Biol. Chem. 1994; 269: 2016-2022Google Scholar). HBE cells treated with t-RA develop mucociliary features in collagen gels (3Jetten A.M. Rearick J.I. Smits H.L. Biochem. Soc. Trans. 1986; 14: 930-933Google Scholar, 8Jetten A.M. Brody A.R. Deas M.A. Hook G.E.R. Rearick J.I. Thacher S.M. Lab. Invest. 1987; 56: 654-664Google Scholar). Grown in monolayer cultures, retinol-treated HBE cells undergo growth arrest with no evidence of morphologic differentiation (9Miller L.A. Cheng L.Z. Wu R. Cancer Res. 1993; 53: 2527-2533Google Scholar). Retinoids are ligands for the retinoic acid receptors (RAR-α, -β, and -γ) and retinoid X receptors (RXR-α, -β, and -γ), which form RAR-RXR heterodimers and RXR homodimers and are transcriptionally activated by ligand binding (reviewed in Ref. 10Mangelsdorf D.J. Evans R.M. Cell. 1995; 83: 841-850Google Scholar). In bronchial epithelial cells, RAR-α is expressed at high levels and has been shown to activate growth inhibitory pathways (11Kim Y.-H. Dohi D.F. Han G.R. Zou C.-P. Oridate N. Walsh G.L. Nesbitt J.C. Xu X.-C. Hong W.K. Lotan R. Kurie J.M. Cancer Res. 1995; 55: 5603-5610Google Scholar, 12Zhang L.-X. Mills K.J. Dawson M.I. Collins S.J. Jetten A.M. J. Biol. Chem. 1994; 270: 6022-6029Google Scholar). The signaling pathways activated by RAR-α that mediate growth inhibition in normal HBE cells have not been defined. Retinoids increase the expression of transforming growth factor-β (TGF-β) family members (13Glick A.B. Flanders K.C. Danielpour D. Yuspa S.H. Sporn M.B. Cell. Regul. 1989; 1: 87-97Google Scholar, 14Niles R.M. Thompson N.L. Fenton F. In Vitro Cell. Dev. Biol. Anim. 1994; 30: 256-262Google Scholar, 15Glick A.B. McCune B.K. Abdulkarem N. Flanders K.C. Lumadue J.A. Smith J.M. Sporn M.B. Development. 1991; 111: 1081-1086Google Scholar, 16Nunes I. Kojima S. Rifkin D.B. Cancer Res. 1996; 56: 495-499Google Scholar, 17Danielpour D. J. Cell. Physiol. 1996; 166: 231-239Google Scholar, 18Turley J.M. Funakoshi S. Ruscetti F.W. Kasper J. Murphy W.J. Longo D.L. Birchenall-Roberts M.C. Cell Growth & Differ. 1995; 6: 655-663Google Scholar, 19Nugent P. Potchinsky M. Lafferty C. Greene R.M. Exp. Cell Res. 1995; 220: 495-500Google Scholar, 20Cohen P.S. Letterio J.J. Gaetano C. Chan J. Matsumoto K. Sporn M.B. Thiele C.J. Cancer Res. 1995; 55: 2386-2830Google Scholar, 21Kojima S. Rifkin D.B. J. Cell. Physiol. 1993; 155: 323-332Google Scholar, 22Batova A. Danielpour D. Pirisi L. Creek K.E. Cell Growth & Differ. 1992; 3: 763-772Google Scholar). TGF-β is secreted as a latent complex and converted to an active form, and it signals through a heteromeric complex of the type I and type II receptors (23Wrana J.L. Attisano L. Wieser R. Ventura F. Massagué J. Nature. 1994; 370: 341-347Google Scholar). Activation of the TGF-β pathway has been implicated in the effects of retinoids on cellular growth and differentiation (13Glick A.B. Flanders K.C. Danielpour D. Yuspa S.H. Sporn M.B. Cell. Regul. 1989; 1: 87-97Google Scholar, 14Niles R.M. Thompson N.L. Fenton F. In Vitro Cell. Dev. Biol. Anim. 1994; 30: 256-262Google Scholar, 15Glick A.B. McCune B.K. Abdulkarem N. Flanders K.C. Lumadue J.A. Smith J.M. Sporn M.B. Development. 1991; 111: 1081-1086Google Scholar, 16Nunes I. Kojima S. Rifkin D.B. Cancer Res. 1996; 56: 495-499Google Scholar, 17Danielpour D. J. Cell. Physiol. 1996; 166: 231-239Google Scholar, 18Turley J.M. Funakoshi S. Ruscetti F.W. Kasper J. Murphy W.J. Longo D.L. Birchenall-Roberts M.C. Cell Growth & Differ. 1995; 6: 655-663Google Scholar, 19Nugent P. Potchinsky M. Lafferty C. Greene R.M. Exp. Cell Res. 1995; 220: 495-500Google Scholar, 20Cohen P.S. Letterio J.J. Gaetano C. Chan J. Matsumoto K. Sporn M.B. Thiele C.J. Cancer Res. 1995; 55: 2386-2830Google Scholar, 21Kojima S. Rifkin D.B. J. Cell. Physiol. 1993; 155: 323-332Google Scholar, 22Batova A. Danielpour D. Pirisi L. Creek K.E. Cell Growth & Differ. 1992; 3: 763-772Google Scholar). In addition, the secretion of insulin-like growth factor binding protein-3 (IGFBP-3) is enhanced by retinoid treatment (24Gucev Z.S. Oh Y. Kelly K.M. Rosenfeld R.G. Cancer Res. 1996; 56: 1545-1550Google Scholar, 25Zhou Y. Mohan S. Linkhart T.A. Baylink D.J. Strong D.D. Endocrinology. 1996; 137: 975-983Google Scholar, 26Sheikh M.S. Shao Z.-M. Chen J.-C. Clemmons D.R. Roberts Jr., C.T. Leroith D. Fontana J.A. Biochem. Biophys. Res. Commun. 1992; 188: 1122-1130Google Scholar, 27Sheikh M.S. Shao A.-M. Hussain A. Clemmons D.R. Chen J.-C. Roberts Jr., C.T. LeRoith D. Fontana J.A. J. Cell. Physiol. 1993; 155: 556-567Google Scholar, 28Leyen S.A.-V. Hembree J.R. Eckert R.L. J. Cell. Physiol. 1994; 160: 265-274Google Scholar, 29Adamo M.L. Shao Z.-M Lanau F. Chen J.C. Clemmons D.R. Roberts Jr., C.T. LeRoith D. Fontana J.A. Endocrinology. 1992; 131: 1858-1866Google Scholar, 30Martin J.L. Coverley J.A. Pattison S.T. Baxter R.C. Endocrinology. 1995; 136: 1219-1226Google Scholar, 31Katz J. Weiss H. Goldman B. Kanety H. Stannard B. LeRoith D. Shemer J. J. Cell. Physiol. 1995; 165: 223-227Google Scholar, 32Hembree J.R. Agarwal C. Beard R.L. Chandraratna R.A.S. Eckert R.L. Cancer Res. 1996; 56: 1794-1799Google Scholar, 33Sheikh M.S. Shao Z.-M. Hussain A. Clemmons D.R. Chen J.-C. Roberts Jr., C.T. LeRoith D. Fontana J.A. J. Cell. Physiol. 1993; 155: 556-567Google Scholar, 35Fontana J.A. Burrows-Mezu A. Clemmons D.R. LeRoith D. Endocrinology. 1991; 128: 1115-1122Google Scholar). IGFBP-3 is one of a family of seven IGFBPs (36Cohen P. Fielder P.J. Hasegawa Y. Frisch H. Giudice L.C. Rosenfeld R.G. Acta Endocrinol. 1991; 124: 74-85Google Scholar, 37Holly J.M.P. Martin J.L. Growth Regul. 1994; 4: 20-30Google Scholar, 38Drop S.L.S. Schuller A.G.P. Lindenbergh-Kortelve D.J. Groffen C. Brinkman A. Zwarthoff E.C. Growth Regul. 1992; 2: 69-79Google Scholar, 39Swisshelm K. Ryan K. Tsuchiya K. Sager R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4472-4476Google Scholar). IGFBP-3 has been proposed to inhibit cell growth by reducing IGF bioavailability, by altering the responsiveness of the IGF-I receptor to IGF-I, and by mechanisms independent of the IGF-I receptor (40Valentinis B. Bhala A. DeAngelis T. Baserga R. Cohen P. Mol. Endocrinol. 1995; 9: 361-367Google Scholar, 41Conover C.A. Endocrinology. 1992; 130: 3191-3199Google Scholar). IGFBP-3 expression is also increased by TGF-β2 treatment in breast cancer cells and has been implicated in the growth inhibitory effects of TGF-β2 (42Oh Y. Muller H.M. Ng L. Rosenfeld R.G. J. Biol. Chem. 1995; 270: 13589-13592Google Scholar). These findings support the notion that TGF-β and IGFBP-3 actions are connected through a common retinoid signal transduction pathway. In this study, we examined the regulation of IGFBP-3 and TGF-β gene family expression by t-RA in normal HBE cells. We demonstrated that t-RA increased the levels of TGF-β2 and IGFBP-3 mRNA and of secreted TGF-β and IGFBP-3 proteins. These events were inhibited by a retinoid that functions as an RAR-α antagonist. Treatment with TGF-β2 increased IGFBP-3 mRNA levels, demonstrating a linkage of IGFBP-3 with TGF-β2 signaling pathways. However, the addition of latency-associated peptide (LAP), which inactivates secreted TGF-β, did not abrogate the effect of t-RA on IGFBP-3 expression. These findings provide evidence that t-RA increased TGF-β2 and IGFBP-3 expression through an RAR-α-dependent pathway, and the increase in IGFBP-3 expression by t-RA did not require activation of the TGF-β pathway by autocrine or paracrine mechanisms. Normal HBE cells were cultured from bronchial mucosal biopsy samples taken from fresh surgical specimens as monolayer cultures on standard plasticware in keratinocyte serum-free medium (Life Technologies, Inc.) containing bovine pituitary extract (BPE) and epidermal growth factor as described previously (11Kim Y.-H. Dohi D.F. Han G.R. Zou C.-P. Oridate N. Walsh G.L. Nesbitt J.C. Xu X.-C. Hong W.K. Lotan R. Kurie J.M. Cancer Res. 1995; 55: 5603-5610Google Scholar). Mink lung epithelial cells (MLECs) stably transfected with a luciferase reporter plasmid containing a truncated plasminogen activator inhibitor type I promoter (16Nunes I. Kojima S. Rifkin D.B. Cancer Res. 1996; 56: 495-499Google Scholar) were a gift from Drs. Irene Nunes and Daniel Rifkin (Department of Cell Biology and Kaplan Cancer Center, New York University Medical Center, New York, NY). MLECs were cultured in Dulbecco's modified Eagle's medium (Life Technologies, Inc.) containing 10% fetal calf serum as described previously (16Nunes I. Kojima S. Rifkin D.B. Cancer Res. 1996; 56: 495-499Google Scholar). t-RA was purchased from Sigma. The RAR-α antagonist LG100629 (43Apfel C. Bauer F. Crettaz M. Forni L. Kamber M. Kaufmann F. LeMotte P. Pirson W. Klaus M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7129-7133Google Scholar) was obtained from Ligand Pharmaceuticals, Inc. (La Jolla, CA), and LAP was provided by R & D Systems, Inc. (Minneapolis, MN). Recombinant TGF-β2 was purchased from Genzyme, Inc. (Cambridge, MA). Actinomycin D and cycloheximide were purchased from Sigma. Total cellular RNA was prepared from normal HBE cells, electrophoresed (20 μg/lane) on a 1% agarose gel containing 2% formaldehyde, transferred to a nylon membrane (Zetaprobe, Bio-Rad), hybridized to an [α-32P]dCTP-labeled cDNA probe, washed, and autoradiographed as described previously (11Kim Y.-H. Dohi D.F. Han G.R. Zou C.-P. Oridate N. Walsh G.L. Nesbitt J.C. Xu X.-C. Hong W.K. Lotan R. Kurie J.M. Cancer Res. 1995; 55: 5603-5610Google Scholar). cDNAs for TGF-β1, -β2, and -β3 (44Derynck R. Jarrett J.A. Chen E.Y. Eaton D.H. Bell J.R. Assoian R.K. Roberts A.B. Sporn M.B. Goeddel D.V. Nature. 1985; 316: 701-705Google Scholar, 45De Martin R. Haendler B. Hofer-Warbinek R. Gaugitsch H. Wrann M. Schlusner H. Seifert J.M. Bodmer S. Fontana A. Hofer E. EMBO J. 1987; 6: 3673-3677Google Scholar, 46Derynck R. Lindquist P.B. Lee A. Wen D. Tamm J. Graycar J.L. Rhee L. Mason A.J. Miller D.A. Coffey R.J. Moses H.L. Chen E.Y. EMBO J. 1988; 7: 3737-3743Google Scholar) were obtained from Dr. Rik Derynck (University of California, San Francisco, CA), and the IGFBP-3 cDNA (47Wood W.I. Cachianes G. Henzel W.J. Winslow G.A. Spencer S.A. Hellmiss R. Martin J.L. Baxter R.C. Mol. Endocrinol. 1988; 2: 1176-1185Google Scholar) was obtained from Dr. William Wood (Genentech, Inc., San Francisco, CA). Normal HBE cells were seeded on 10-cm plates (105 cells/plate), treated with t-RA for different time periods or with medium alone, and conditioned medium samples were collected simultaneously 144 h after cell seeding. For the medium sample that represents the 0–24-h time point, treatment with 10−6m t-RA in BPE-free medium (to eliminate exogenous TGF-β) was begun 120 h after cell seeding, and an aliquot was collected at 144 h. For the sample that represents 24–48 h, treatment was begun 96 h after cell seeding, replaced at 120 h with BPE-free medium containing t-RA, and an aliquot was collected at 144 h. For the sample that represents 48–72 h, treatment was begun 72 h after cell seeding and replaced at 120 h with BPE-free medium containing t-RA, and an aliquot was collected at 144 h. For the sample that represents 72–96 h, treatment was begun 48 h after cell seeding and replaced at 120 h with BPE-free medium containing t-RA, and an aliquot was collected at 144 h. For the sample that represents 96–120 h, treatment was begun 24 h after cell seeding and replaced at 120 h with BPE-free medium containing t-RA, and an aliquot was collected at 144 h. For the control (untreated) medium sample, no t-RA was added, the medium was changed to BPE-free medium at 120 h, and an aliquot was collected at 144 h. Conditioned medium samples were transferred to three separate wells on a six-well plate seeded with MLECs that were stably transfected with the TGF-β-responsive luciferase vector (105 cells/well). MLECs were treated for 16 h, and then cytosolic luciferase activity was measured as described previously (11Kim Y.-H. Dohi D.F. Han G.R. Zou C.-P. Oridate N. Walsh G.L. Nesbitt J.C. Xu X.-C. Hong W.K. Lotan R. Kurie J.M. Cancer Res. 1995; 55: 5603-5610Google Scholar). Luciferase values reflect TGF-β bioactivity in the conditioned medium. To examine bioactivity that reflects total (active plus latent) TGF-β levels, MLECs were treated with conditioned medium previously heated to 80 °C for 5 min, which activates latent TGF-β (21Kojima S. Rifkin D.B. J. Cell. Physiol. 1993; 155: 323-332Google Scholar). The results represent the means and standard deviations of luciferase activities from three identical wells, and luciferase activities were corrected for normal HBE cell numbers determined at the end of t-RA treatment. The presence of t-RA in the conditioned medium did not appreciably alter luciferase activity in MLECs (data not shown). Conditioned medium samples were collected from t-RA-treated normal HBE cells as described for the TGF-β bioactivity assay. Aliquots determined on the basis of equal cell number were concentrated 1:10 with Centriprep 10 filters (Amicon, Inc., Beverly, MA), loaded on a 1% SDS, 12% polyacrylamide gel, blotted to a nitrocellulose membrane (BAS-83, Schleicher & Schuell, Inc., Burlingame, VT), incubated for 1 h at room temperature with an anti-IGFBP-3 affinity purified monoclonal antibody (Diagnostic Systems Laboratories, Webster, TX), and detected with the enzyme-linked chemiluminesence assay (ECL kit, Amersham Corp.). For WLB, the membrane was incubated with a 2 × 106 cpm mixture of125I-labeled IGF-I and IGF-II and exposed to film as described previously (48Cohen P. Peehl D.M. Lamson G. Rosenfeld R.G. J. Clin. Endocrinol. Metab. 1991; 73: 407-491Google Scholar). Normal HBE cells were seeded at a density of 105 cells/10-cm plate and treated for 120 h with media alone, 10−6m t-RA alone, and 10−6m t-RA in combination with LAP at concentrations of 1, 10, 100, 200, and 500 ng/ml. At 120 h, the cells were trypsinized and stained with trypan blue, and the total viable cell number was counted by using an hemocytometer. We examined the regulation of IGFBP-3 and TGF-β1, -β2, and -β3 mRNA levels in normal HBE cells during 10−6m t-RA treatment by Northern analysis (Fig.1). An increase in TGF-β2 mRNA levels was detected between 6 and 12 h; this increase continued through 120 h. TGF-β1 was expressed constitutively with no change during treatment. TGF-β3 mRNA was not detected (data not shown). IGFBP-3 mRNA was expressed in a bimodal pattern. A transient increase was observed at 6 h, and a sustained increase appeared at 72 h of treatment. Examination of earlier time points revealed that increased IGFBP-3 mRNA was detectable at 1 h of 10−6m t-RA treatment (Fig. 2 A). The increase in IGFBP-3 mRNA at 6 h was inhibited by treatment with actinomycin D or cycloheximide (Fig. 2 B), demonstrating the necessity of both gene transcription and protein synthesis for activation of this retinoid signaling event.Figure 2Northern analysis of IGFBP-3 expression was performed on total cellular RNA prepared from normal HBE cells.Expression was examined in cells treated with 10−6m t-RA for different time periods (0.5, 1, 2, 3, 4, 5, or 6 h) (A). The effect of 10−6mt-RA treatment on IGFBP-3 expression was examined in the presence of 1 μg/ml actinomycin D (Act D) or 10 μg/ml cycloheximide (CHX) (B). Photographs of ethidium bromide-stained gels illustrate the relative amount of RNA loaded per lane. The absence (−) and the presence (+) of an agent are indicated.View Large Image Figure ViewerDownload (PPT) We investigated the contribution of RAR-α-dependent signaling pathways to the increased TGF-β2 and IGFBP-3 mRNA levels induced by t-RA. Normal HBE cells were treated for 120 h with 10−8m t-RA and different doses of LG100629 (43Apfel C. Bauer F. Crettaz M. Forni L. Kamber M. Kaufmann F. LeMotte P. Pirson W. Klaus M. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7129-7133Google Scholar), which is a synthetic retinoid that functions as an RAR-α antagonist, and total cellular RNA was prepared for Northern analysis. In combination with 10−6m t-RA, LG100629, which must be in molar excess to inhibit t-RA-induced activation of RAR-α, was toxic to normal HBE cells (data not shown). LG100629 abrogated the increase in TGF-β2 and IGFBP-3 expression induced by 10−8m t-RA (Fig.3). TGF-β1 mRNA levels, which did not change with t-RA treatment, were not altered by LG100629. LG100629 also inhibited the increase in IGFBP-3 expression observed at 6 h of t-RA treatment (data not shown). The effect of t-RA on TGF-β bioactivity in conditioned medium was investigated. Normal HBE cells were treated with 10−6m t-RA, and conditioned medium samples that reflect defined 24-h periods (0–24, 24–48, 48–72 h, etc.) of t-RA treatment were collected as described under “Experimental Procedures.” MLECs that are stably transfected with a reporter plasmid containing a truncated plasminogen activator inhibitor type I promoter (16Nunes I. Kojima S. Rifkin D.B. Cancer Res. 1996; 56: 495-499Google Scholar) were treated with conditioned medium samples for 16 h and subjected to luciferase assays to determine relative levels of TGF-β bioactivity in the conditioned media. Total TGF-β (active plus latent) bioactivity was measured by heating the conditioned medium samples to convert latent TGF-β into its active form. Luciferase activities increased during t-RA treatment (Fig. 4), demonstrating increases in total and active TGF-β. The increase in active TGF-β occurred between 48 and 72 h of treatment. The effect of t-RA on IGFBP-3 protein secretion was examined in conditioned medium samples collected at 24-h intervals (as described for the MLEC luciferase assay) by performing immunoblot and WLB (Fig.5). IGFBP-3 was detected in the media of untreated cells (t = 0) by WLB, and increased IGFBP-3 levels, first detected by immunoblot at 24 h, occurred with t-RA treatment. Because the increase in active TGF-β protein in the media coincided with the increase in IGFBP-3 mRNA levels at 72 h, we examined whether IGFBP-3 expression is responsive to activation of TGF-β2 signaling pathways. Normal HBE cells were treated with 5 ng/ml TGF-β2, which has been shown to increase IGFBP-3 expression in human breast cancer cells (42Oh Y. Muller H.M. Ng L. Rosenfeld R.G. J. Biol. Chem. 1995; 270: 13589-13592Google Scholar), and Northern analysis was performed at 72 h, revealing increased IGFBP-3 mRNA (Fig.6). The contribution of TGF-β signaling pathways to the t-RA-induced increase in IGFBP-3 mRNA was explored by treatment with 10−6m t-RA combined with varying doses of LAP, which noncovalently associates with active TGF-β in the extracellular space, converting TGF-β into its inactive form. Examination of conditioned medium samples collected on day 5 revealed that LAP abrogated the increase in TGF-β activity induced by 10−6m t-RA (Fig. 7), confirming its inhibitory effect on extracellular TGF-β activity. However, LAP did not measurably alter the effects of t-RA on IGFBP-3 mRNA or secreted protein levels (Fig. 8).Figure 7Luciferase assays were performed on MLECs stably transfected with a reporter plasmid containing a TGF-β response element (as described under “Experimental Procedures”). For these studies, normal HBE cells were treated for 120 h with media alone, 10−6m t-RA alone, or 10−6m t-RA combined with different doses of LAP. Fresh medium (containing BPE) was added at 72 h, and conditioned medium samples were collected at 120 h. MLECs seeded onto six-well plates were treated with the conditioned medium samples for 16 h and subjected to luciferase assays. The results represent the means and standard deviations of luciferase activities from three identical wells, and luciferase activities were corrected for normal HBE cell numbers determined at the end of t-RA treatment.RA, retinoic acid.View Large Image Figure ViewerDownload (PPT)Figure 8Northern (A) and immunoblot analysis (B) were performed using total cellular RNA and conditioned medium samples, respectively, prepared from normal HBE cells treated for 120 h with media alone, 10−6m t-RA, or 10−6m t-RA combined with different doses of LAP. A photograph of the ethidium bromide-stained gel illustrates the relative amounts of RNA loaded per lane. Media were replaced at 72 h, and conditioned medium samples were collected at 120 h. Sample aliquots for loading were determined on the basis of equal cell number. The positions of molecular size markers are indicated for the immunoblot.View Large Image Figure ViewerDownload (PPT) In this study, we demonstrated that t-RA increased IGFBP-3 and TGF-β2 mRNA and protein levels in normal HBE cells. t-RA increases the expression of IGFBP-3 and TGF-β family members in a variety of transformed and nontransformed cell lines (13Glick A.B. Flanders K.C. Danielpour D. Yuspa S.H. Sporn M.B. Cell. Regul. 1989; 1: 87-97Google Scholar, 14Niles R.M. Thompson N.L. Fenton F. In Vitro Cell. Dev. Biol. Anim. 1994; 30: 256-262Google Scholar, 15Glick A.B. McCune B.K. Abdulkarem N. Flanders K.C. Lumadue J.A. Smith J.M. Sporn M.B. Development. 1991; 111: 1081-1086Google Scholar, 16Nunes I. Kojima S. Rifkin D.B. Cancer Res. 1996; 56: 495-499Google Scholar, 17Danielpour D. J. Cell. Physiol. 1996; 166: 231-239Google Scholar, 18Turley J.M. Funakoshi S. Ruscetti F.W. Kasper J. Murphy W.J. Longo D.L. Birchenall-Roberts M.C. Cell Growth & Differ. 1995; 6: 655-663Google Scholar, 19Nugent P. Potchinsky M. Lafferty C. Greene R.M. Exp. Cell Res. 1995; 220: 495-500Google Scholar, 20Cohen P.S. Letterio J.J. Gaetano C. Chan J. Matsumoto K. Sporn M.B. Thiele C.J. Cancer Res. 1995; 55: 2386-2830Google Scholar, 21Kojima S. Rifkin D.B. J. Cell. Physiol. 1993; 155: 323-332Google Scholar, 22Batova A. Danielpour D. Pirisi L. Creek K.E. Cell Growth & Differ. 1992; 3: 763-772Google Scholar, 23Wrana J.L. Attisano L. Wieser R. Ventura F. Massagué J. Nature. 1994; 370: 341-347Google Scholar, 24Gucev Z.S. Oh Y. Kelly K.M. Rosenfeld R.G. Cancer Res. 1996; 56: 1545-1550Google Scholar, 25Zhou Y. Mohan S. Linkhart T.A. Baylink D.J. Strong D.D. Endocrinology. 1996; 137: 975-983Google Scholar, 26Sheikh M.S. Shao Z.-M. Chen J.-C. Clemmons D.R. Roberts Jr., C.T. Leroith D. Fontana J.A. Biochem. Biophys. Res. Commun. 1992; 188: 1122-1130Google Scholar, 27Sheikh M.S. Shao A.-M. Hussain A. Clemmons D.R. Chen J.-C. Roberts Jr., C.T. LeRoith D. Fontana J.A. J. Cell. Physiol. 1993; 155: 556-567Google Scholar, 28Leyen S.A.-V. Hembree J.R. Eckert R.L. J. Cell. Physiol. 1994; 160: 265-274Google Scholar, 29Adamo M.L. Shao Z.-M Lanau F. Chen J.C. Clemmons D.R. Roberts Jr., C.T. LeRoith D. Fontana J.A. Endocrinology. 1992; 131: 1858-1866Google Scholar, 30Martin J.L. Coverley J.A. Pattison S.T. Baxter R.C. Endocrinology. 1995; 136: 1219-1226Google Scholar, 31Katz J. Weiss H. Goldman B. Kanety H. Stannard B. LeRoith D. Shemer J. J. Cell. Physiol. 1995; 165: 223-227Google Scholar, 32Hembree J.R. Agarwal C. Beard R.L. Chandraratna R.A.S. Eckert R.L. Cancer Res. 1996; 56: 1794-1799Google Scholar, 33Sheikh M.S. Shao Z.-M. Hussain A. Clemmons D.R. Chen J.-C. Roberts Jr., C.T. LeRoith D. Fontana J.A. J. Cell. Physiol. 1993; 155: 556-567Google Scholar, 34Kordon E.C. McKnight R.A. Jhappan C. Henninghausen L. Merlino G. Smith G.H. Dev. Biol. 1995; 168: 47-61Google Scholar, 35Fontana J.A. Burrows-Mezu A. Clemmons D.R. LeRoith D. Endocrinology. 1991; 128: 1115-1122Google Scholar). In contrast to our findings in normal HBE cells, the levels of TGF-β1 and -β2 both increase in t-RA-treated hamster tracheal epithelial cells grown in collagen gels (14Niles R.M. Thompson N.L. Fenton F. In Vitro Cell. Dev. Biol. Anim. 1994; 30: 256-262Google Scholar), providing evidence that retinoid signaling in bronchial epithelial cells depends upon the culture conditions and is species-specific. Further, we found that t-RA stimulated the conversion of latent TGF-β into its active form, suggesting that t-RA activated a protease that cleaves latent TGF-β in normal HBE cells. This TGF-β activity accounted for a relatively small fraction of total TGF-β, suggesting that protease activity is tightly regulated. In bovine epithelial cells, t-RA activates latent TGF-β through enhanced cell-associated plasmin activity (21Kojima S. Rifkin D.B. J. Cell. Physiol. 1993; 155: 323-332Google Scholar), whereas in HL-60 cells, activation of TGF-β by t-RA occurs through plasmin-independent mechanisms (16Nunes I. Kojima S. Rifkin D.B. Cancer Res. 1996; 56: 495-499Google Scholar). We examined the role of RAR-α, which is expressed constitutively and activates growth inhibitory pathways in normal HBE cells (11Kim Y.-H. Dohi D.F. Han G.R. Zou C.-P. Oridate N. Walsh G.L. Nesbitt J.C. Xu X.-C. Hong W.K. Lotan R. Kurie J.M. Cancer Res. 1995; 55: 5603-5610Google Scholar), in these retinoid signaling events. An RAR-α antagonist inhibited the effects of t-RA on TGF-β2 and IGFBP-3 expression. Normal HBE cells exhibited a bimodal pattern of IGFBP-3 mRNA expression, and the antagonist inhibited the increase at both time points. Treatment with an RAR-α antagonist also blocked the increase in transglutaminase type II expression induced by t-RA in rat tracheobronchial epithelial cells (12Zhang L.-X. Mills K.J. Dawson M.I. Collins S.J. Jetten A.M. J. Biol. Chem. 1994; 270: 6022-6029Google Scholar). Further, RAR activation increases lGFBP-3 expression in human ectocervical epithelial cell lines (32Hembree J.R. Agarwal C. Beard R.L. Chandraratna R.A.S. Eckert R.L. Cancer Res. 1996; 56: 1794-1799Google Scholar). These studies support a role for RARs in specific retinoid signaling events. Retinoid receptors regulate gene expression directly by binding to gene promoters or indirectly by protein-protein interactions with other transcription factors. We found that transcriptional mechanisms contribute to the increase in IGFBP-3 expression, and t-RA induced this effect rapidly (1 h). Based on these findings, we will investigate direct binding of retinoid receptors to the IGFBP-3 gene promoter and its role in the activation of IGFBP-3 expression by t-RA. We found increased TGF-β bioactivity in the media at 72 h of t-RA treatment, which was coincident with the increase in IGFBP-3 mRNA levels, and TGF-β2 treatment increased IGFBP-3 expression. Similarly, TGF-β2 treatment increases IGFBP-3 expression in breast cancer cells (42Oh Y. Muller H.M. Ng L. Rosenfeld R.G. J. Biol. Chem. 1995; 270: 13589-13592Google Scholar). Based on these findings, we investigated whether t-RA-induced IGFBP-3 expression was TGF-β-dependent. Supporting this possibility, retinoid signaling events such as increased expression of thrombospondin and fibronectin are TGF-β-dependent in rat prostatic epithelial cells (17Danielpour D. J. Cell. Physiol. 1996; 166: 231-239Google Scholar). We found that LAP did not abrogate the increase in IGFBP-3 expression induced by t-RA, suggesting that the increase in IGFBP-3 mRNA levels by t-RA did not require activation of the TGF-β2 signaling pathway through autocrine or paracrine mechanisms. It is possible that multiple retinoid signaling pathways, including TGF-β-dependent ones, activate IGFBP-3 expression, and blocking one retinoid signaling pathway is not sufficient to alter the effects of t-RA on IGFBP-3 expression. Further, TGF-β may activate IGFBP-3 expression through intracrine mechanisms, which LAP cannot inhibit. Supporting this possibility, intracrine signaling has been reported to be a mechanism of TGF-β1 actions in mammary epithelial differentiation (34Kordon E.C. McKnight R.A. Jhappan C. Henninghausen L. Merlino G. Smith G.H. Dev. Biol. 1995; 168: 47-61Google Scholar). Prior work in a variety of cell types has demonstrated the importance of the TGF-β and IGFBP-3 signaling pathways in the biologic effects of t-RA. Blocking antibodies to TGF-β inhibit the mucous differentiation of hamster tracheal epithelial cells by t-RA and partially abrogate the growth inhibitory effects of t-RA in lymphoma cells, rat prostatic epithelial cells, and keratinocytes (13Glick A.B. Flanders K.C. Danielpour D. Yuspa S.H. Sporn M.B. Cell. Regul. 1989; 1: 87-97Google Scholar, 14Niles R.M. Thompson N.L. Fenton F. In Vitro Cell. Dev. Biol. Anim. 1994; 30: 256-262Google Scholar, 17Danielpour D. J. Cell. Physiol. 1996; 166: 231-239Google Scholar,18Turley J.M. Funakoshi S. Ruscetti F.W. Kasper J. Murphy W.J. Longo D.L. Birchenall-Roberts M.C. Cell Growth & Differ. 1995; 6: 655-663Google Scholar). In breast cancer cells, t-RA increases IGFBP-3 expression, and antisense IGFBP-3 oligonucleotides abrogate the growth inhibitory effects of t-RA (24Gucev Z.S. Oh Y. Kelly K.M. Rosenfeld R.G. Cancer Res. 1996; 56: 1545-1550Google Scholar). In contrast, LAP did not alter the growth inhibitory effects of t-RA on normal HBE cells (data not shown). These findings suggest that the role of the TGF-β pathway in cell growth and differentiation depends on the tissue of origin, culture conditions, and transformation state of the cells examined. Additional investigations into the roles of the TGF-β and IGFBP-3 signaling pathways in the biologic effects of retinoid treatment are warranted.

Lung cancer risk remains elevated for many years after quitting smoking. To assess using proliferation indices in bronchial tissues as an intermediate endpoint biomarker in lung cancer chemoprevention trials, we determined the relationship between the extent, intensity, and cessation of tobacco smoking and proliferative changes in bronchial epithelial biopsy specimens.Bronchial biopsy specimens were obtained from up to six epithelial sites in 120 current smokers (median pack-years, 42) and 207 former smokers (median pack-years, 40; median quit-years, 8.1). Sections from the paraffin-embedded specimens were stained with hematoxylin--eosin to determine the metaplasia index and with an antibody to Ki-67 to determine the proliferative (labeling) index for the basal and parabasal (Ki-67 PLI) layers. All statistical tests were two-sided.Biopsy sites with metaplasia had statistically significantly higher Ki-67-labeling indices than those without metaplasia (P<.001) in both current and former smokers. Increased proliferation was observed in multiple biopsy sites, with the average Ki-67 PLI of the subject strongly correlating with the metaplasia index (r =.72 for current smokers; P<.001), even in sites without metaplasia (r =.23 for current smokers; P<.001). In current smokers, the Ki-67 PLI was associated with the number of packs smoked/day (P =.02) but not with smoking years or pack-years. In subjects who had quit smoking, the Ki-67 PLI dropped statistically significantly within 1 year (P =.008) but remained detectable for more than 20 years, even in the absence of squamous metaplasia.Smoking appears to elicit a dose-related proliferative response in the bronchial epithelia of active smokers. Although the proliferative response decreased gradually in former smokers, a subset of individuals had detectable proliferation for many years and may benefit from targeted chemoprevention. Bronchial epithelial proliferation, measured by Ki-67, may provide a useful biomarker in the assessment of lung cancer risk and in the response to chemopreventive interventions.

The records of 101 patients who had undergone chest wall reconstruction both with and without stabilization of the chest wall by Marlex mesh were reviewed to see if Marlex reduced ventilator dependence and hospital stay, and to determine whether the use of Marlex was associated with any increased risk of infection. In 40 patients in whom Marlex was used, the mean number of days on postoperative ventilator support was 0.8, and mean hospital stay was 9.7 days. In 61 patients in whom Marlex was not used, the mean number of days on ventilator support was 4.9, and mean hospital stay was 17.5 days. These differences were statistically significant (p = 0.03, p = 0.006). Two patients in the Marlex-stabilized group (5%) developed wound infections, but these were preceded by ischemic necrosis of overlying flaps. None of the patients without Marlex developed wound infections. That difference was not statistically significant. We conclude that the use of Marlex in chest wall reconstruction does not significantly increase the risk of wound infection, provided that overlying tissues are properly vascularized and remain viable, and that synthetic mesh does improve chest wall stability and reduce ventilator dependence and overall hospital stay.

Loss of retinoic acid receptor beta (RAR-beta) expression in the bronchial epithelium is considered a biomarker of preneoplasia. Retinoids can restore expression of this receptor and, presumably, halt the progression of carcinogenesis. This study was designed to investigate whether either of two retinoid-based regimens, 9-cis-retinoic acid (RA) or 13-cis-RA plus alpha-tocopherol (AT), could reverse RAR-beta expression loss in former smokers after 3 months of treatment.Individuals (n = 226) who had smoked at least 20 pack-years and had ceased smoking for at least 12 months were randomly assigned to receive 3 months of daily oral 9-cis-RA (100 mg), 13-cis-RA (1 mg/kg) + AT (1200 IU), or placebo. Bronchoscopy and biopsy at six predetermined sites of the bronchial tree were performed before treatment and at 3 and 6 months thereafter. Specimens were evaluated for squamous metaplasia, dysplasia, and RAR-beta expression. McNemar's test was used to test changes in RAR-beta expression and squamous metaplasia within each treatment group, and a generalized estimating equations model was applied to model the treatment effect, adjusting for covariates. All statistical tests were two-sided.A total of 177 assessable subjects completed at least 3 months of therapy and underwent at least the baseline and 3-month bronchoscopic evaluations with biopsies. RAR-beta was detected in 69.7% of all baseline biopsy samples, and metaplasia was evident in 6.9% of all baseline samples from 240 subjects. Restoration of RAR-beta expression (P =.03) and reduction of metaplasia (P =.01) were found in the 9-cis-RA group. After adjustment for years of smoking, packs/day smoked, and metaplasia, treatment with 9-cis-RA, but not with 13-cis-RA + AT, led to a statistically significant increase in RAR-beta expression compared with placebo (P =.03).9-cis-RA treatment can restore RAR-beta expression in the bronchial epithelium of former smokers, raising the possibility that this retinoid has potential chemopreventive properties in former smokers.

Many patients with cancer have limited esophageal reconstruction options when the stomach is unavailable as a replacement conduit or when long-segment discontinuity exists. Jejunum has been used as an alternative conduit, both as a pedicled or free flap interposition; however, reports of this are usually limited to short-segment repairs. Microvascular augmentation of a pedicled jejunal flap allows creation of a longer conduit, making it possible to replace the entire esophagus with jejunum. Few reports describe this technique in patients with cancer. We report our initial experience with "supercharged" pedicled jejunum as an alternative conduit for total esophageal reconstruction.Review of a prospectively collected departmental database was performed to identify those patients who underwent total esophageal reconstruction with supercharged pedicled jejunum. Data regarding their perioperative course and postoperative function were gathered from the prospectively collected clinical data, review of hospital records, and patient interviews.Total esophageal reconstruction with supercharged pedicled jejunum was attempted in 26 patients (age range, 37-74 years) between March 2000 and April 2004. Twenty-four of 26 patients were ultimately discharged with an intact supercharged pedicled jejunum flap, for an overall success rate of 92.3%. One patient experienced intraoperative flap loss caused by technical difficulties harvesting the flap and never had the flap interposed. One other flap loss occurred in the early postoperative period in a patient who had multisystem organ failure after a prolonged reconstruction. Cervical anastomotic leaks occurred in 19.2% (5/26) of the patients. Two midconduit leaks occurred that were suspicious for iatrogenic perforation from nasogastric tube placement; one required reoperation. One additional early reoperation was performed for cecal ischemia. There were no mortalities. Functional results were available in 95.4% (21/22) of the patients receiving supercharged pedicled jejunum who survived at least 6 months after reconstruction. At the time of follow-up, 95% (20/21) of the patients were tolerating regular diet, and 76.2% (16/21) did not require any supplemental alimentation. Ninety-five percent (20/21) of the patients were free from reflux symptoms, and 80.9% (17/21) had no dumping symptoms. Only 1 patient required dilation of a midconduit stricture. One patient required late reoperation for conduit redundancy.Supercharged pedicled jejunum is a suitable alternative conduit for total esophageal replacement in patients with cancer with otherwise limited reconstructive options. Functional outcomes are excellent, despite the severity of disease and technical challenges in this patient population.

BackgroundExtrapleural pneumonectomy for malignant pleural mesothelioma (MPM) is a high-risk procedure, and patients require careful preoperative staging to exclude advanced disease. Computed tomography, magnetic resonance imaging, and positron emission tomography are useful staging modalities, but do not reliably identify contralateral mediastinal involvement or transdiaphragmatic invasion. We evaluated the role of extended surgical staging procedures, which generally includes a combination of laparoscopy, peritoneal lavage, and mediastinoscopy, to more precisely stage patients with MPM.MethodsOne hundred eighteen patients with MPM, deemed clinically and radiologically resectable, underwent extended surgical staging. Mediastinoscopy was performed in 111 patients, laparoscopy in 109 patients, and peritoneal lavage in 78 patients.ResultsTen (9.2%) patients had gross evidence of transdiaphragmatic or peritoneal involvement. Peritoneal lavage was positive for metastatic MPM in 2 (2.6%) patients, neither of whom had obvious transdiaphragmatic invasion. Ipsilateral mediastinal nodes contained metastatic tumor in 10 of 62 (16.1%) patients. Contralateral nodes were positive in 4 of 111 (3.6%) patients. Of the patients who underwent biopsy of both ipsilateral and contralateral mediastinal nodes, and who had complete pathologic staging after extrapleural pneumonectomy (n = 46), 14 (30.4%) had N2-positive nodes. Only 5 of these patients were correctly identified by mediastinoscopy (sensitivity 36%, accuracy 80%). Extended surgical staging identified 16 (13.6%) patients who had contralateral nodal involvement, transdiaphragmatic invasion, or positive peritoneal cytology.ConclusionsExtended surgical staging defines an important subset of patients with unresectable MPM not identified by imaging. Because of the potential morbidity associated with extrapleural pneumonectomy, we advocate that extended surgical staging be performed in all patients with MPM before resection. Extrapleural pneumonectomy for malignant pleural mesothelioma (MPM) is a high-risk procedure, and patients require careful preoperative staging to exclude advanced disease. Computed tomography, magnetic resonance imaging, and positron emission tomography are useful staging modalities, but do not reliably identify contralateral mediastinal involvement or transdiaphragmatic invasion. We evaluated the role of extended surgical staging procedures, which generally includes a combination of laparoscopy, peritoneal lavage, and mediastinoscopy, to more precisely stage patients with MPM. One hundred eighteen patients with MPM, deemed clinically and radiologically resectable, underwent extended surgical staging. Mediastinoscopy was performed in 111 patients, laparoscopy in 109 patients, and peritoneal lavage in 78 patients. Ten (9.2%) patients had gross evidence of transdiaphragmatic or peritoneal involvement. Peritoneal lavage was positive for metastatic MPM in 2 (2.6%) patients, neither of whom had obvious transdiaphragmatic invasion. Ipsilateral mediastinal nodes contained metastatic tumor in 10 of 62 (16.1%) patients. Contralateral nodes were positive in 4 of 111 (3.6%) patients. Of the patients who underwent biopsy of both ipsilateral and contralateral mediastinal nodes, and who had complete pathologic staging after extrapleural pneumonectomy (n = 46), 14 (30.4%) had N2-positive nodes. Only 5 of these patients were correctly identified by mediastinoscopy (sensitivity 36%, accuracy 80%). Extended surgical staging identified 16 (13.6%) patients who had contralateral nodal involvement, transdiaphragmatic invasion, or positive peritoneal cytology. Extended surgical staging defines an important subset of patients with unresectable MPM not identified by imaging. Because of the potential morbidity associated with extrapleural pneumonectomy, we advocate that extended surgical staging be performed in all patients with MPM before resection.

Imaging plays a crucial role in the diagnosis and staging of superior sulcus tumors, assessment of their resectability, determination of the optimal approach to disease management, and evaluation of the response to therapy. Computed tomography (CT), magnetic resonance (MR) imaging, and positron emission tomography (PET)/CT contribute important and complementary information. Whereas CT is optimal for depicting bone erosion and for staging of intrathoracic disease, MR imaging is superior for evaluating tumor extension to the intervertebral neural foramina, the spinal cord, and the brachial plexus, primarily because of the higher contrast resolution and multiplanar capability available with MR imaging technology. Use of PET/CT enables the detection of unsuspected nodal and distant metastases. However, imaging has only limited usefulness for evaluating the response of a tumor to induction therapy and detecting local recurrence, and surgical biopsy often is necessary to verify the results of therapy.

Radical surgery for malignant pleural mesothelioma does not improve survival in patients with nodal metastases. Imaging is poor at predicting nodal involvement and mediastinoscopy, though frequently used, is of low sensitivity. As endobronchial ultrasound (EBUS) and esophageal endoscopic ultrasound (EUS) are accurate for nodal staging of lung cancer, we hypothesized that they would be at least as sensitive as cervical video-mediastinoscopy for nodal staging of mesothelioma.Eighty-five patients with mesothelioma who were potential candidates for radical surgery underwent preoperative staging with mediastinoscopy (n = 50) or EBUS (n = 38). Eleven patients also underwent EUS.Diagnostic yield (specimens containing lymphocytes or tumor cells) was 100% for mediastinoscopy and 84% for EBUS (p < 0.001). Mediastinoscopy identified 7 of 50 (14%) patients with nodal metastases. Thirty-eight (76%) mediastinoscopy-negative patients underwent surgery with nodal sampling and there were 18 false negatives. Endobronchial ultrasound identified 13 of 38 (34%) patients with nodal metastases. Twenty-two (58%) EBUS-negative patients underwent surgery with nodal sampling and there were 10 false negatives. Sensitivity and negative predictive value for mediastinoscopy were 28% and 49%, and 59% and 57% for EBUS. Eleven patients had EUS preoperatively, which revealed infradiaphragmatic nodal metastases in 5 patients.Although this study is retrospective, EBUS had higher sensitivity than either mediastinoscopy or imaging studies for detection of nodal metastases. Nevertheless, the ability to accurately identify nodal involvement preoperatively in patients with mesothelioma remains suboptimal. Esophageal ultrasound may complement EBUS particularly in cases where infradiaphragmatic nodal metastases are suspected.

Esophageal cancer staging uses tumor depth as the sole criterion for assessment of the primary tumor (pT). To the authors' knowledge the impact of esophageal tumor length on long-term outcome and the esophageal cancer staging system has not been fully evaluated in the current era.All esophageal cancer patients (n = 209) undergoing surgery from 1995 to 2005 who did not receive preoperative chemotherapy or radiotherapy were reviewed. Maximum esophageal tumor length along a craniocaudal axis was determined pathologically after surgical resection. Univariate and multivariate analyses were used to assess the impact of esophageal tumor length (< or = 3 cm vs >3 cm) on long-term survival.Esophageal tumor length was closely associated with long-term survival (hazards ratio [HR] of 6.14 [95% confidence interval (95% CI), 4.1-9.25]; 5-year survival: < or = 3 cm = 68%, >3 cm = 10% [P < .001]). Multivariate Cox regression analyses demonstrated tumor length (HR of 2.13 [95% CI, 1.26-3.63]) was found to be a significant independent predictor of long-term survival even when controlled for sex, age, tumor location, histology, margin positivity, surgical procedure, and current pTNM criteria. The incorporation of tumor length in pTNM staging significantly improves the ability to predict the long-term survival of patients (5-year survival for patients with tumors < or = 3 cm and stages I, IIA, IIB, and III disease = 86%, 62%, 49%, and 22%, respectively; survival for patients with tumors measuring >3 cm and stages I, IIA, IIB, and III disease = 27%, 22%, 0%, and 8%, respectively [P < .1]).Esophageal tumor length is an independent predictor of long-term survival in the current era and should be considered for incorporation into the current esophageal cancer staging system to better predict long-term survival and identify high-risk patients for postoperative therapy.

Postesophagectomy diaphragmatic hernia (PDH) is a recognized but severely under-reported and potentially hazardous event. Information regarding the natural course of this condition and guidelines regarding indications for reoperative intervention are lacking. In this study we aim to describe the frequency, predictors of incidence, and indications for repair.Cross-sectional imaging (computed tomography scan) from patients who underwent esophagectomy between January 2001 and December 2007 at a single center were reviewed by two radiologists blinded to previous reports and clinical outcomes. Patients with PDH were compared with a similar cohort who did not have hernia. Patient characteristics, outcomes, and hernia descriptors including longitudinal progression were recorded. Multivariable logistic regression analyses identified predictors of PDH and need for repair.Of a total of 440 patients who underwent esophagectomy, 67 (15%) were radiologically diagnosed with PDH. Of these, only 7 of 67 cases (10%) were prospectively reported by the radiologist. Median time interval from esophagectomy to hernia was 2 years. Type of esophagectomy was an independent predictor for hernia developing (p = 0.027). Patients with high body mass index were less prone to have PDH (p = 0.043). Thus far, 9 patients (2%) have required surgical intervention, all for hernia-related symptoms or progression. Despite mesh repair, 4 of 9 have recurred and 2 were re-repaired. There was 1 PDH-associated death, 8 years after transhiatal resection.Variables contributing to PDH are both technical and patient dependent. Whereas the majority of patients with PDH have not required repair, a small portion who became symptomatic or had large, progressive hernia required remedial surgery. Postesophagectomy patients require long-term surveillance for PDH.

We present 250 cases of thymomas with emphasis on their clinical staging and follow-up. The patients were 120 males and 130 females between the ages of 13 and 92 years. Surgical resection was performed and histopathologic material evaluated in every case. Grossly, the tumors resected varied in size from 3 to 20 cm in greatest diameter. According to our proposed staging system, 31 cases were stage 0, 128 were stage I, 70 stage II, and 21 stage III at the time of resection. Histologically, approximately 53% of thymomas were of mixed histologic types. Follow-up information ranging from 1 to 16 years was obtained, showing significant statistical P values of .044 and .016 for overall and recurrence-free survival, respectively. We consider that our proposed staging system offers better stratification of cases and improved histologic definitions for proper staging of cases of thymoma.

ObjectiveFor inoperable patients with pulmonary malignancy, stereotactic body radiotherapy is a reasonable therapeutic option. Despite good early tumor control, local failure occurs in up to 10% of patients by 3 years. Because management of local recurrence after stereotactic body radiotherapy is unclear, we evaluated use of surgery as a salvage option.MethodsA retrospective review was conducted of consecutive patients from a single institution who underwent salvage resection of primary and metastatic pulmonary malignancies previously treated with stereotactic body radiotherapy. In addition, a literature search was conducted to identify previous reports of pulmonary resection for local stereotactic body radiotherapy failures, to allow cumulative analyses with previously published cases.ResultsA total of 21 patients met inclusion criteria. The median time between stereotactic body radiotherapy and salvage surgery was 16.2 months (range, 6.4-71.5). Postoperative complications occurred in 7 patients (18.9%), in whom atrial arrhythmias and prolonged air leaks (>5 days) were most frequent (n = 2 each, 5.4%). There was no local recurrence after salvage surgery. Distant failure occurred in 5 of 21 patients (23.8%) at a median of 36.2 months, and median disease-free survival was 19.2 months. The 30- and 90-day mortality was 4.8% (1 patient). Cumulative analysis included 37 patients from 4 institutions and comprised 26 (78.8%) primary non–small cell lung cancers and 11 (29.7%) lung metastases. Median overall survival after salvage surgery was 46.9 months, and 3-year survival was 71.8%.ConclusionsAfter local failure of stereotactic body radiotherapy, salvage resection remains a viable option for operable patients, with acceptable morbidity and survival. As use of stereotactic body radiotherapy continues to expand, further studies to evaluate the optimal management for local failure are needed.

Whether robotic segmentectomies are advantageous is unclear. We describe our experience with the robot, comparing patient populations and outcomes with video-assisted thoracoscopic surgery (VATS) and open resection.Patients who underwent anatomic segmentectomy from 2004 to 2019 were reviewed. Resection methods were categorized as robotic, VATS, or open. Segmentectomies were categorized as simple or complex. Baseline characteristics and perioperative outcomes were analyzed from 2015 to 2019 due to implementation of the Enhanced Recovery After Surgery pathway for all thoracic surgery patients and to thus minimize confounders resulting from the Enhanced Recovery After Surgery protocol.Since 2004, an increase has occurred in segmentectomies, including robotic and complex segmentectomies. Of the 222 segmentectomies performed from 2015 to 2019, 77 (35%) were robotic, 40 VATS (18%), and 105 open (47%). More complex segmentectomies were performed in the robotic group compared with VATS and open (45% vs 15% vs 22%; P < .001). Operative time for robotic resections were longer compared with VATS and open (205 vs 147 vs 147 minutes; P < .001) but had lower blood loss (50 vs 75 vs 100 mL; P < .001) and shorter chest tube days (2 vs 2 vs 3 days; P = .004) and lengths of stay (3 vs 3 vs 4 days; P < .001). Perioperative mortality was low in all groups. No robotic segmentectomy was converted to open compared with 7.5% for VATS (P = .038). Prolonged air leak was lower for robotic compared with open (4% vs 13%; P = .038).Robotic segmentectomy has increased in our institution, with a concurrent rise in atypical segmentectomies. Despite performing more complex procedures, there were no conversions and low perioperative morbidity and mortality. Our results suggest that the robotic platform can facilitate performance of complex anatomic segmentectomies.

The melanoma antigen (MAGE)-encoding genes are expressed in various tumor types, including lung, and are thought to be silent in all normal tissues except testis. In search of biomarkers for early lung cancer detection and cancer risk assessment, we investigated frequencies of expressional activation of MAGE-A1, -A3, and -B2 genes in non-small cell lung cancers (NSCLCs). Expression of these genes was evaluated by reverse transcription-PCR (RT-PCR) in 20 primary NSCLC samples and corresponding normal lung tissues as well as in 20 bronchial brush specimens from former smokers without lung cancer. mRNA in situ hybridization was done to confirm the gene expression pattern at the cellular level. Methylation-specific PCR was performed to evaluate the hypomethylation status of CpG sites in the promoter regions of these genes. Among the 20 primary NSCLC samples analyzed, 14 (70%) expressed MAGE-A1 and 17 (85%) each expressed MAGE-A3 and MAGE-B2. A substantial number of normal lung tissues adjacent to NSCLC also had a detectable level of MAGE expression (65, 75, and 80% for MAGE-A1, -A3, and -B2, respectively). We found that 7 (35%), 10 (50%), and 11 (55%) of the adjacent normal lung tissue samples exhibited promoter hypomethylation at MAGE-A1, -A3, and -B2, respectively, compared with 15 (75%), 16 (80%), and 16 (80%) of the NSCLC samples. Among the 20 bronchial epithelium samples from former smokers, 7 (35%), 10 (50%), and 12 (60%) had also detectable -A1, -A3, and -B2 expression, respectively. Activation of MAGE-A1, -A3, and -B2 genes is common not only in NSCLC but also in bronchial epithelium with severe carcinogen insult. These results suggest that MAGE genes may be activated very early in lung carcinogenesis and may be considered as targets for lung cancer prevention.

Retinoids are pivotal in the growth and differentiation of certain epithelial tissues, interacting with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors. RAR-beta mRNA is undetectable by in situ hybridization (ISH) in 50% of non-small-cell lung cancers (NSCLC). RAR-beta may suppress tumorigenicity. Therefore, we hypothesized that loss of expression of RAR-beta gene in stage I NSCLC is a prognostic factor of a poor clinical outcome.We retrospectively analyzed RAR-beta mRNA levels (by ISH using a digoxigenin-labeled antisense riboprobe) in specimens from 185 consecutive patients with completely resected clinical/radiographic stage I NSCLC for whom clinical follow-up data were available.One hundred fifty-six patients who met the criteria of pathologic stage I NSCLC and positivity for RXR-alpha mRNA (used as a control to assess RNA degradation) and who had adequate follow-up could be evaluated. RAR-beta mRNA expression was undetectable in 51 patients, weakly positive in 64 patients, and strongly positive in 41 patients. Overall survival of the 41 patients with strongly positive RAR-beta was significantly worse than for the 115 patients with weak or absent RAR-beta (P =.045).Unexpectedly, strong RAR-beta expression was associated with a significantly worse outcome of early-stage NSCLC. The mechanisms underlying this clinically and biologically important finding should be further explored.

Objective: Primary sarcomas involving the chest wall requiring full-thickness excision are rare.We reviewed our experience with these lesions in a tertiary referral cancer center by using multidisciplinary approaches.Methods: A 10-year retrospective study identified 51 patients referred with primary sarcomas of the chest wall: 40 for initial treatment and 11 after previous unsuccessful surgical excisions elsewhere (secondary referral).Presenting symptoms were pain alone in 23 (45%) of 51 patients, pain with an associated mass in 8 (16%) patients, and an asymptomatic mass alone in 13 (25%) patients.Median symptom duration was 241 days in the primary group and 225 days in the recurrent group.Tumor locations were the sternum (n = 11), the rib alone (n = 36), and the posterior rib with extension into vertebral bodies (n = 4).Histologic types included the following: chondrosarcomas (n = 15), malignant fibrous histiocytomas (n = 9), osteosarcomas (n = 4), Ewing sarcomas (n = 3), desmoid tumors (n = 7), and other types (n = 13).The median tumor volume of those referred initially was 311 cm 3 compared with 84 cm 3 in patients with recurrent lesions.Results: Twenty-six (51%) of 51 patients received treatment before resection, including chemotherapy alone (n = 22), radiation alone (n = 3), and combined chemotherapy and radiation therapy (n = 1).The complete sternum was removed in 6 of 11 patients, and the average number of ribs requiring resection was 3.8.Four patients had vertebral body resections.Prosthetic meshes alone were required in 16 of 51 patients, and meshes with methylmethacrylate were required in 18 of 51 patients.Muscle flap reconstructions by plastic surgery were required in 24 patients.Negative margins were obtained in 47 of 51 patients.There were no perioperative deaths with morbidities occurring in 12 (24%) of 51 patients (wound [n = 3], prolonged air leak [n = 1], prolonged ventilator requirement [n = 1], arrhythmias [n = 3], doxorubicin (Adriamycin)-induced cardiomyopathy [n = 1], and other [n = 3]).Postoperative treatment was administered to 13 patients (chemotherapy alone, n = 9; chemotherapy with radiation therapy, n = 4).The cumulative 5year survival of all patients was 64% (initial referral, 61.3%; secondary referral, 72.7%).The average follow-up is 44.7 months. Conclusions:A combined aggressive multidisciplinary approach to primary sarcomas of the chest wall resulted in no treatment-related deaths and a cumulative 5-year survival of 64% in patients referred to our tertiary care cancer center.(

Cyclin-dependent kinases can be activated by cdc25, which removes inhibitory phosphates from tyrosine and threonine residues. At least three cdc25 genes (cdc25A, cdc25B, and cdc25C) have been identified in humans. Accumulating evidence indicates that cdc25A and cdc25B possess oncogenic properties. Recently, overexpression of cdc25A and of cdc25B was found in many breast and head and neck cancers. To determine potential roles of cdc25s in non-small cell lung cancer (NSCLC), we analyzed primary tumors and corresponding normal lung tissues from 40 patients with NSCLC for relative expression levels of these genes by multiplex reverse transcription PCR (RT-PCR). cdc25A was overexpressed in 60% (24 of 40) of the tumors and cdc25B in 45% (18 of 40) of the tumors, whereas cdc25C was not overexpressed in any of the tumors analyzed. Because c-myc can increase cdc25A and cdc25B expression, it may be a factor in cdc25 overexpression. We found that c-myc was overexpressed in only 18% (7 of 40) of the tumors. We found no association between overexpression of c-myc and cdc25A or cdc25B. We also investigated whether the cdc25B gene was amplified in NSCLC and found this was true in 40% (8 of 20) of the tumors tested. However, this amplification was not correlated with gene expression status. Interestingly, among 24 tumors with cdc25A overexpression and 18 with cdc25B overexpression, 42% (10 of 24) and 44% (8 of 18) were poorly differentiated histological type. In contrast, well or moderately differentiated tumors had lower frequencies of cdc25A and cdc25B overexpression [19% (3 of 16) and 23% (5 of 22), respectively]. These data indicate that overexpression of cdc25A and cdc25B is frequent and that it may play an important role in NSCLC. However, it is unlikely that this overexpression is caused by c-myc stimulation or cdc25B gene amplification.

To evaluate the long-term outcome of chemotherapy, chemoradiotherapy, and surgery for patients with locoregionally advanced esophageal cancer.Thirty-eight patients with locoregionally advanced esophageal cancer were entered into a Phase II study between November 1996 and October 1998 at the University of Texas M. D. Anderson Cancer Center. Patients initially received two cycles of chemotherapy with paclitaxel (200 mg/m(2)), 5-fluorouracil (750 mg/m(2)/d for 5 days), and cisplatin (15 mg/m(2)/d for 5 days), followed by chemoradiotherapy, consisting of radiation (45 Gy during 5 weeks) with 5-fluorouracil (300 mg/m(2)/d during radiation) and cisplatin (15 mg/m(2)/d for 5 days). Surgical resection was performed 4-6 weeks after the completion of the chemoradiotherapy.Most patients had adenocarcinoma (n = 32; 84%). Pretreatment endoscopic ultrasonography revealed T3 tumors in 33 patients (87%) and N1 disease in 25 patients (66%). Thirty-seven patients (97%) completed the planned chemotherapy and chemoradiotherapy, and 35 patients (92%) underwent surgery, with a 30-day mortality rate of 6% (2 of 35 patients). A pathologic complete response or microscopic residual carcinoma (<10% viable) was found in 25 (71%) of 35 patients and was associated with a disease-free survival rate of 72% at 3 years and 51% at 5 years. On the basis of an intention-to-treat analysis and a median potential follow-up of 58 months, the 3- and 5-year overall survival rate for all 38 patients was 63% and 39%, respectively.The long-term results of this study suggest that the strategy of induction chemotherapy followed by chemoradiotherapy and surgery is safe and warrants further evaluation in the treatment of patients with locoregionally advanced esophageal cancer.

Resection of sternal tumors may be tailored to the patient and the location of the malignancy.We reviewed our results of sternectomy (typically 5-cm margins) performed in 30 patients over a 10-year period.Thirteen patients had primary sternal sarcoma (six chondrosarcoma, five osteosarcoma, two other); 10 patients had local recurrence from breast cancer; 4 patients had metastases; 3 patients had other (two osteoradionecrosis, one malignant fibrous histiocytoma). Morbidity occurred in 8 patients (26.7%): wound dehiscence, 2; wound infection, 1; hemorrhage, 1; pneumonia, 1; prolonged air leak, 1; empyema, 1; and bronchopleural fistula, 1. One patient, with multiple metastases, died from adult respiratory distress syndrome on day 25 (overall mortality, 3.3%; 1 of 30). The area of reconstruction ranged from 35 to 264 cm2. The technique of reconstruction included muscle flap alone in 13 patients; muscle flap and mesh, 9; muscle flap and rigid prosthesis (Marlex methylmethacrylate), 7; or other, 1 patient. Nineteen patients (63%) were extubated within 24 hours after operation. Median intensive care unit stay was 2 days; median hospitalization, 6 days. Late local recurrence after resection occurred in 6 patients; 4 from breast cancer (3 patients had concurrent distant metastases). Five-year actuarial survival after primary tumor resection was 73% and 33% after resection of recurrent breast cancer (median, 21 months).Partial sternectomy may be performed for primary sternal tumors with short hospitalization and good local control. Wider local excision or total sternectomy may minimize local re-recurrence of breast carcinoma to the sternum.

Purpose: Superior sulcus tumors (SST) of the lung are uncommon and constitute approximately 3% of non–small cell lung cancer (NSCLC). These tumors cause specific symptoms and signs, and are associated with patterns of failure that differ from those seen for NSCLC tumors in other nonapical locations. Prognostic factors and most effective treatments are controversial. We conducted a retrospective study at The University of Texas M. D. Anderson Cancer Center to identify outcome predictors for patients with SST treated by a multidisciplinary approach. Methods and Materials: This retrospective review of 143 patients without distant metastasis at presentation is a continuation of a previous M. D. Anderson study now updated to 1994. In this study, we examine the 5-year survival rate by pretreatment tumor and patient characteristics and by the treatments received. Strict criteria were used to define SST. Actuarial life-table analyses and Cox proportional hazard models were used to compare survival rates. Results: Overall predictors of 5-year survival were weight loss (p < 0.01), supraclavicular fossa (p = 0.03), or vertebral body (p = 0.05) involvement, stage of the disease (p < 0.01), and surgical treatment (p < 0.01). Five-year survival for patients with Stage IIB disease was 47% compared to 14% for Stage IIIA, and 16% for Stage IIIB. For patients with Stage IIB disease, surgical treatment (p < 0.01) and weight loss (p = 0.01) were significant independent predictors of 5-year survival. Among patients with Stage IIIA disease, the only predictor of survival was Karnofsky performance score (KPS) (p = 0.02). For patients with Stage IIIB disease, the only independent predictor of survival was a right superior sulcus location, which was associated with a worse 5-year survival rate than that for patients with tumors in the left superior sulcus (p = 0.02). More patients with adenocarcinoma than with squamous cell tumors experienced cerebral metastases within 5 years (p < 0.01). Patients without gross residual disease after surgical resection who received postoperative radiation therapy with total doses of 55 to 64 Gy had a 5-year survival rate of 82% as compared with the 5-year survival rate of 56% in patients who received 50 to 54 Gy. Twenty-three patients survived for longer than 3 years. Of these, 4 patients (17%) received radiation therapy alone or in combination with chemotherapy without surgical resection. The other 19 patients (83%) had resection combined with radiation therapy and/or chemotherapy. Conclusions: The findings from this study confirm the importance of the new staging system, separating T3 N0 M0 (Stage IIB) from Stage IIIA, since there was a significant difference in the 5-year survival (p < 0.01). Interestingly, there was no significant 5-year survival difference between Stage IIIA (N2) and Stage IIIB (T4 or N3). This study also suggests that surgery is an important component of the multidisciplinary approach to patients with SST if their nodes were negative. Disease that is minimally invading surrounding normal structures can be resected followed by radiation therapy in doses of 55 to 64 Gy. Further investigation of treatment strategies combining high-dose radiation therapy (≥66 Gy) with chemotherapy is indicated for patients with unresectable and/or node-positive (N2) SST.

Thoracic or lumbar spine malignant tumors involving both the anterior and posterior columns represent a complex surgical problem. The authors review the results of treating patients with these lesions in whom surgery was performed via a simultaneous anterior-posterior approach.The hospital records of 26 patients who underwent surgery via simultaneous combined approach for thoracic and lumbar spinal tumors at our institution from July 1994 to March 2000 were reviewed. Surgery was performed with the patients in the lateral decubitus position for the procedure. The technical details are reported. The mean survival determined by Kaplan-Meier analysis was 43.4 months for the 15 patients with primary malignant tumors and 22.5 months for the 11 patients with metastatic spinal disease. At 1 month after surgery, 23 (96%) of 24 patients who complained of pain preoperatively reported improvements (p < 0.001, Wilcoxon signed-rank test), and eight (62%) of 13 patients with preoperative neurological deficits were functionally improved (p = 0.01). There were nine major complications, five minor complications, and no deaths within 30 days of surgery. Two patients (8%) later underwent surgery for recurrent tumor.The simultaneous anterior-posterior approach is a safe and feasible alternative for the exposure tumors of the thoracic and lumbar spine that involve both the anterior and posterior columns. Advantages of the approach include direct visualization of adjacent neurovascular structures, the ability to achieve complete resection of lesions involving all three columns simultaneously (optimizing hemostasis), and the ability to perform excellent dorsal and ventral stabilization in one operative session.

To determine pathologic response rates to liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) administered intrapleurally in patients with malignant pleural mesothelioma.Thirty-three patients with malignant pleural mesothelioma and free-flowing pleural effusions received intrapleural L-NDDP once every 3 weeks at a dose of 450 mg/m2. Thoracoscopic evaluation with pleural biopsies was performed before therapy and then after every two cycles. The primary end point was pathologic response as determined by thoracoscopic biopsy.After at least two cycles, post-treatment pleural biopsy analysis was negative in 14 patients for a pathologic response rate of 42% (95% CI, 25% to 61%). Median survival was 11.2 months. There were three treatment-related deaths secondary to peritonitis, cellulitis at the thoracoscopy site, and empyema. Grade 3 nonhematologic toxicities included infection, fever, dyspnea, and anorexia, which occurred in five (15%), one (3%), one (3%), and one (3%) patients, respectively. There were no grade 4 nonhematologic toxicities. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in five (15%), three (9%), and two (6%) patients, respectively. Two patients with pathologic responses subsequently underwent pleural decortication. Both surgical specimens revealed residual tumor in regions that were not in direct communication with the pleural space.Intrapleural L-NDDP therapy in this patient population is feasible with significant but manageable toxicity. Although pathologic responses are highly encouraging, areas of mesothelioma that are not in direct communication with the pleural space will evade drug exposure and limit efficacy in some patients. The optimal role of intrapleural L-NDDP therapy currently remains to be determined.

The current study tested the hypothesis that the clinical outcome of patients with localized esophageal carcinoma after preoperative chemoradiotherapy (CTRT) depends on histology.The authors stratified patients by adenocarcinoma (ACA) or squamous cell carcinoma (SCC) and compared the overall survival (OS) and patterns of failure among patients achieving pathologic complete response (pathCR) and <pathCR after preoperative CTRT. A correlation between baseline clinical stage and posttherapy pathologic response was made for ACA and SCC.Of the 235 patients who underwent preoperative CTRT, 42 (18%) had SCC and 193 (82%) had ACA. In the ACA group, 56 patients (29%) achieved a pathCR and in the SCC group 13 patients (31%) achieved a pathCR. In the ACA group, a larger proportion of pathCR patients (n=44; 79%) than <pathCR patients (n=82; 60%) were alive at the time of last follow-up (P=0.01) and pathCR patients had a longer OS than <pathCR patients (P=0.0006). However, in the SCC group OS or proportion alive did not differ significantly between pathCR and <pathCR patients (P>or=0.05). In the ACA group, a greater portion of <pathCR patients (32%) than pathCR patients (16%) had distant metastases (P=0.02) and the distant metastases-free survival of pathCR patients was longer than that of <pathCR patients (P=0.0012). In the SCC group, the proportion or time to distant-metastases did not differ significantly. Pretreatment clinical stage did not correlate with pathologic response for either histology.The results of the current study suggest that the clinical biology of SCC and ACA is different after CTRT. An investigation of molecular and patient genetics is needed to improve therapy.

Patients with localized esophageal carcinoma often develop locoregional and distant disease recurrence. The current study investigated the outcome of a new chemotherapy combination as induction therapy before chemoradiotherapy.Forty-three patients with resectable carcinoma of the esophagus or gastroesophageal junction were enrolled. Most of the tumors were endoscopic ultrasonography (EUS) (EUS)T3 (84%) and (EUS)N1 (63%). The patients received < or = 2 6-week cycles of CPT-11 and cisplatin followed by chemoradiotherapy (45 grays with 5-fluorouracil and paclitaxel). Five to six weeks after chemoradiotherapy, the patients underwent staging and surgery. The feasibility, curative resection rates, overall and disease-free survival rates, rate of significant pathologic response, and patterns of disease recurrence were assessed.Of the 43 patients, 39 (91%) underwent an R0 resection. Two patients (5%) died after surgery. A pathologic complete response (pathCR) was observed in 11 (28%) of the 39 patients (or 26% of the 43 patients). In addition, 16 patients (41% of 39 patients or 37% of 43 patients) had < 10% viable tumor in the surgical specimen (pathPR). A comparison of endoscopic ultrasonograpy T and N classifications with surgical T and N classifications demonstrated significant down-staging (P < 0.01). The median survival period of all 43 patients was 22.1 months. Patients who had achieved a pathCR or pathPR had a longer median survival (25.6 months) than those who achieved less than a pathPR (18.5 months; P = 0.52). None of the clinical parameters examined were found to correlate with survival or pathologic response.CPT-11-based induction chemotherapy resulted in substantial pathCR and pathPR rates, both of which lead to a favorable survival outcome. The three-step strategy needs to be developed further, with the investigation of targeted therapies with chemotherapy and radiotherapy.

The hypothesis tested in this study was whether a skeletal muscle could be transformed to be fatigue resistant, to be used to power an implantable extra-aortic balloon assist device, and therefore to provide dynamically significant cardiac assistance. Eight dogs underwent implantation of an Itrel pacemaker to stimulate the thoracodorsal nerve over 8 to 18 weeks and transform the latissimus dorsi muscle. Biopsies of these muscles confirmed near complete (up to 98%) transformation into fatigue-resistant type I muscle fibers, identified by the adenosinetriphosphatase histochemical stains. Biochemical assays showed conversion of myosin isoforms to that of myocardial V3 phenotype, decreased activity of anaerobic glycolytic marker, and increased activity of aerobic enzyme marker, which indicated greater resemblance of such muscle to the myocardial fibers. In four dogs, the optimal stimulation parameters of such muscles in response to a burst stimulator, which synchronizes and summates the muscle contraction, were studied and compared with the contralateral, nontransformed muscle. Fatigue tests confirmed the marked fatigue resistance of the transformed muscle. In four dogs, a 100 ml balloon was placed beneath the transformed latissimus dorsi muscle and connected to the thoracic aorta with a Dacron graft By means of the optimal burst-stimulating parameters identified above, the latissimus dorsi muscle was stimulated to contract during diastole, compressing the balloon to achieve diastolic augmentation while allowing the balloon to fill during systole. A 39% increase (p < 0.001) in the “subendocardial viability index” (diastolic pressure-time index/tension-time index) was obtained as calculated from the left ventricular and ascending aortic pressure tracings. We conclude that the skeletal muscle can be transformed to resemble myocardium, which can generate sufficient force to provide hemodynamically significant and clinically relevant counterpulsation.

The impact of esophageal tumor length on pT1 esophageal adenocarcinoma has not been well evaluated.Case histories of all patients (n = 133) undergoing esophageal resection from 1979 to 2007 with pT1 adenocarcinoma of the esophagus were reviewed. Univariate and multivariate analyses of esophageal tumor length and other standard prognostic factors were performed.Patients with early-stage pT1 esophageal adenocarcinoma with tumors less than 3 cm demonstrate decreased long-term survival (3 years: >3 cm = 46% vs 93%; P < .001) and higher risk of lymph node involvement (lymph node positive: >3 cm = 47% vs 10%; P < .001). Multivariable analysis shows that esophageal tumor length (>3 cm) is an independent risk factor for survival in patients with pT1 early-stage esophageal cancer (hazard ratio: 4.8, 95% confidence intervals: 1.4-16.5; P < .001) even when controlled for submucosal involvement, lymph node involvement, and lymphatic/vascular invasion status. In combination with submucosal involvement, esophageal tumor length (>3 cm) identifies a high-risk population of pT1 esophageal adenocarcinoma (3 years: group 1 [0 risk factors] = 100%, group 2 [1 risk factor] = 87%, and group 3 [2 risk factors] = 33%; P < .001).This study demonstrates that esophageal tumor length (>3 cm) is a risk factor for long-term survival and lymph node involvement in early-stage pT1 esophageal adenocarcinoma. Esophageal tumor length (>3 cm) in combination with submucosal involvement may help to identify a high-risk group of patients with pT1 esophageal adenocarcinoma.

Controversy currently exists about the optimum preoperative treatment platform for locoregionally advanced esophageal cancer, namely, preoperative chemoradiotherapy (preoperative C/RT) or preoperative chemotherapy alone. We therefore reviewed sequential phase II/III trials performed at a single institution to assess the impact of preoperative chemotherapy versus preoperative C/RT strategies.In all, 157 esophageal cancer patients were sequentially enrolled in phase II/III trials at the University of Texas M.D. Anderson Cancer Center from March 27, 1990, to March 8, 2005. The treatment approaches included preoperative chemotherapy, n = 76 (INT 113 and ID90-01); preoperative C/RT, n = 81 (ID96-189 and DM98-349). Analysis was by intention to treat. Factors evaluated included demographics, preoperative staging, type of surgery, pathology, adjuvant therapies, and long-term outcome.Adenocarcinoma predominated (85%), with cT3 (73%) and cN1 (43%). No significant difference was noted between groups in demographics or perioperative mortality. More patients with preoperative C/RT were staged with endoscopic ultrasound (52% versus 9%, p < 0.001). Preoperative C/RT demonstrated increased pathologic complete response (28% versus 4%, p < 0.001) and overall survival (3 years, 48% versus 29%, p = 0.04). Preoperative C/RT was a significant independent predictor of improved overall survival (hazard ratio 0.58, 95% confidence interval: 0.37 to 0.90, p = 0.015) and disease-free survival (hazard ratio 0.55, 95% confidence interval: 0.35 to 0.85, p = 0.007) in multivariable regression.In sequential phase II/III trials involving locoregionally advanced esophageal cancer patients, preoperative C/RT was associated with improved overall and disease-free survival rates (p = 0.046 and p = 0.015, respectively) and increased pathologic complete response (p < 0.001) compared with preoperative chemotherapy.

Primary mediastinal germ-cell tumors are rare, and the effect of newer drugs and treatment strategies in this disease on overall survival is not known. We retrospectively assessed treatment outcomes at a single institution. We identified men seen at our institution from 1998 through 2005 for mediastinal germ-cell tumors. Medical records were reviewed for patient characteristics, histology, tumor markers, treatment, and survival outcome. Thirty-four patients met study criteria, of whom 27 had nonseminomatous germ-cell tumor (NSGCT) and 7 had pure seminoma. Eleven patients (41%) with NSGCT were alive at last contact with a median overall survival time of 33.5 months. Among 13 patients with NSGCT referred to us at initial diagnosis, 7 (54%) were alive and recurrence-free at a median follow-up of 56.5 months. Progression-free survival was associated with absence of risk factors (any histology other than endodermal sinus tumor, β-hCG > 1000 mIU/mL, or disease outside the mediastinum). For the patients whose disease progressed (n = 5) or who had been referred to us for salvage treatment (n = 14), the 3-year overall survival from the date of first progression was 23%. Conversely, patients with seminoma did uniformly well with platinum-based chemotherapy; most did not undergo radiation or surgery. Chemotherapy given to maximum effect followed by surgical consolidation resulted in long-term progression-free survival for 54% of patients with mediastinal NSGCT. The number of risk factors present at diagnosis may be associated with survival outcome and should be studied in a larger test group.