Rebecca Slack

Reactive intermediates such as reactive nitrogen species play essential roles in the cell as signaling molecules but, in excess, constitute a major source of cellular damage. We found that nitrosative stress induced by steady-state nitric oxide (NO) caused rapid activation of an ATM damage-response pathway leading to downstream signaling by this stress kinase to LKB1 and AMPK kinases, and activation of the TSC tumor suppressor. As a result, in an ATM-, LKB1-, TSC-dependent fashion, mTORC1 was repressed, as evidenced by decreased phosphorylation of S6K, 4E-BP1, and ULK1, direct targets of the mTORC1 kinase. Decreased ULK1 phosphorylation by mTORC1 at S757 and activation of AMPK to phosphorylate ULK1 at S317 in response to nitrosative stress resulted in increased autophagy: the LC3-II/LC3-I ratio increased as did GFP-LC3 puncta and acidic vesicles; p62 levels decreased in a lysosome-dependent manner, confirming an NO-induced increase in autophagic flux. Induction of autophagy by NO correlated with loss of cell viability, suggesting that, in this setting, autophagy was functioning primarily as a cytotoxic response to excess nitrosative stress. These data identify a nitrosative-stress signaling pathway that engages ATM and the LKB1 and TSC2 tumor suppressors to repress mTORC1 and regulate autophagy. As cancer cells are particularly sensitive to nitrosative stress, these data open another path for therapies capitalizing on the ability of reactive nitrogen species to induce autophagy-mediated cell death.

Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor responses in a subset of patients with advanced malignancies, but they may also induce inflammatory responses and toxicities termed immune-related adverse events (irAEs). These irAEs are often low grade and manageable, but severe irAEs may lead to prolonged hospitalizations or fatalities. Early intervention is necessary to minimize morbidities that occur with severe irAEs. However, correlative biomarkers are currently lacking. In a phase II clinical trial that treated 27 patients with metastatic prostate cancer, we aimed to test the safety and efficacy of androgen deprivation therapy plus ipilimumab. In this study, we observed grade 3 toxicities in >40% of treated patients, which led to early closure of the study. Because ipilimumab enhances T-cell responses, we hypothesized that increased clonal T-cell responses in the systemic circulation may contribute to irAEs. Sequencing of the T-cell receptor β-chains in purified T cells revealed clonal expansion of CD8 T cells, which occurred in blood samples collected before the onset of grade 2-3 irAEs. These initial results suggested that expansion of ≥55 CD8 T-cell clones preceded the development of severe irAEs. We further evaluated available blood samples from a second trial and determined that patients who experienced grade 2-3 irAEs also had expansion of ≥55 CD8 T-cell clones in blood samples collected before the onset of irAEs. We propose that CD8 T-cell clonal expansion may be a correlative biomarker to enable close monitoring and early intervention for patients receiving ipilimumab.

Our previous clinical experience with vaccinia and replication-defective avipox recombinant carcinoembryonic antigen (CEA) vaccines has demonstrated safety and clinical activity with a correlation between CEA-specific immune response and survival. Preclinical evidence demonstrated that the addition of the transgenes for three T-cell costimulatory molecules (B7-1, ICAM-1, LFA-3, designated TRICOM) results in a significant improvement in antigen-specific T-cell responses and antitumor activity. We describe here the first trial in humans of the CEA-TRICOM vaccines (also including an enhancer agonist epitope within the CEA gene).Fifty-eight patients with advanced CEA-expressing cancers were accrued to eight cohorts that involved vaccinations with the following: replication-defective fowlpox recombinant (rF)-CEA(6D)-TRICOM; primary vaccination with recombinant vaccinia (rV)-CEA(6D)-TRICOM plus rF-CEA(6D)-TRICOM booster vaccinations; and rV-CEA(6D)-TRICOM and then rF-CEA(6D)-TRICOM, plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with vaccines, or with divided doses of vaccine with GM-CSF. Vaccines were administered every 28 days for six doses and then once every 3 months. Reverting to treatments every 28 days was allowed if patients progressed on the 3-month schedule.In this phase I study, no significant toxicity was observed. Twenty-three patients (40%) had stable disease for at least 4 months, with 14 of these patients having prolonged stable disease (> 6 months). Eleven patients had decreasing or stable serum CEA, and one patient had a pathologic complete response. Enhanced CEA-specific T-cell responses were observed in the majority of patients tested.We demonstrated that the CEA-TRICOM vaccines are safe and can generate significant CEA-specific immune responses, and they seem to have clinical benefit in some patients with advanced cancer.

In an open-label trial we have previously demonstrated that paroxetine reduces hot flashes. We initiated a stratified, randomized, double-blind, cross-over, placebo-controlled trial to investigate the efficacy of paroxetine 10 mg and 20 mg compared to placebo in reducing hot flash frequency and composite score. A secondary objective was to evaluate quality of life (QOL) parameters.Women who suffered at least two hot flashes a day for 1 month or longer were eligible. Women were randomly assigned to 4 weeks of paroxetine 10 mg or 20 mg followed by placebo for 4 weeks, or placebo for 4 weeks followed by paroxetine 10 mg or 20 mg for 4 weeks. Participants completed baseline daily hot flash diaries for one week prior to the start of the study and throughout the study, and QOL questionnaires at baseline, week 5 and week 9.279 women were screened, and 151 were randomly assigned. Paroxetine 10 mg reduced hot flash frequency and composite score by 40.6% and 45.6%, respectively, compared to 13.7% and 13.7% for placebo (P = .0006 and P = .0008, respectively). Paroxetine 20 mg reduced hot flash frequency and composite score by 51.7% and 56.1%, respectively, compared with 26.6% and 28.8% for placebo (P = .002 and P = .004, respectively). Efficacy was similar between the two doses, but women were less likely to discontinue low-dose paroxetine. Paroxetine 10 mg was associated with a significant improvement in sleep compared with placebo (P = .01).Paroxetine is an effective treatment for hot flashes in women with or without a prior breast cancer.

NKX3.1 is a prostate-specific homeobox gene located on chromosome 8p21. In the mouse, Nkx3.1 has growth-suppressive and differentiating effects on prostatic epithelium. Mutations of the coding region of NKX3.1 were not found in human prostate cancer, failing to support the notion that NKX3.1 was a tumor suppressor gene. To study the expression o NKX3.1 protein in human tissues and prostate cancer, we derived a rabbit antiserum against purified recombinant NKX3.1. Among normal human tissues, NKX3.1 expression was seen in testis, in rare pulmonary mucous glands, and in isolated regions of transitional epithelium of the ureter. NKX3.1 was uniformly expressed in nuclei of normal prostate epithelial cells in 61 histological sections from radical prostatectomy specimens. We analyzed 507 samples of neoplastic prostate epithelium, most of which were contained on a tissue microarray that contained samples from different stages of prostatic neoplasia. We observed complete loss of NKX3.1 expression in 5% of benign prostatic hyperplasias, 20% of high-grade prostatic intraepithelial neoplasias, 6% of T1a/b samples, 22% of T3/4 samples, 34% of hormone-refractory prostate cancers, and 78% of metastases. Our data show that NKX3.1 expression is highly, but not exclusively, specific for the prostate. Loss of NKX3.1 expression is strongly associated with hormone-refractory disease and advanced tumor stage in prostate cancer (P < 0.0001).

Invadopodia are filopodia-like projections possessing protease activity that participate in tumor cell invasion. We demonstrate that co-localization of cortactin and phosphotyrosine identifies a subset of cortactin puncta termed “invadopodial complexes” that we find to be closely associated with the plasma membrane at active sites of focal degradation of the extracellular matrix in MDA-MB-231 breast cancer cells. Manipulation of c-Src activity in cells by transfection with kinase activated c-Src(527) or kinase inactive c-Src(295) results in a dramatic increase or decrease, respectively, in the number of these structures associated with changes in the number of sites of active matrix degradation. Overexpression of kinase-inactive c-Src(295) does not prevent localization of cortactin at the membrane; however, co-localized phosphotyrosine staining is decreased. Thus, elevated phosphotyrosine at invadopodial complexes is specifically associated with the proteolytic activity of invadopodia. Further, invadopodial complexes are spatially, morphologically and compositionally distinct from focal adhesions as determined by localization of focal adhesion kinase (FAK), which is not present in invadopodial complexes. Expression of kinase-inactive c-Src(295) blocks invadopodia activity, but does not block filopodia formation. Thus, invadopodia, but not filopodia, are highly correlated with matrix invasion, and sites of invadopodial activity can be identified by the formation of invadopodial complexes.

Nonhormonal treatment options have been investigated as treatments for hot flashes, a major clinical problem in many women. Starting in 2000, a series of 10 individual double-blind placebo-controlled studies has evaluated newer antidepressants and gabapentin for treating hot flashes. This current project was developed to conduct an individual patient pooled analysis of the data from these published clinical trials.Individual patient data were collected from the various study investigators who published their study results between 2000 and 2007. Between-study heterogeneity for study characteristics and patient populations was tested via chi2 tests before a pooled analysis. The primary end point, the change in hot flash activity from baseline to week 4, for each agent was calculated via both weighted and unweighted approaches, using the size of the study as the weight. Basic summary statistics were produced for hot flash score and frequency using the following three statistics: raw change, percent reduction, and whether or not a 50% reduction was achieved.This study included seven trials of newer antidepressants and three trials of gabapentin. The optimal doses (defined by individual study results) of the newer antidepressants paroxetine, venlafaxine, fluoxetine, and sertraline decreased hot flash scores by 41%, 33%, 13%, and 3% to 18% compared with the corresponding placebo arms, respectively. The three gabapentin trials decreased hot flashes by 35% to 38% compared with the corresponding placebo arms.Some newer antidepressants and gabapentin, within 4 weeks of therapy initiation, decrease hot flashes more than placebo.

Purpose Stereotactic radiosurgery (SRS) is an appealing treatment option after previous radiotherapy because of its precision, conformality, and reduced treatment duration. We report our experience with reirradiation using fractionated SRS for head-and-neck cancer. Methods and Materials From 2002 to 2008, 65 patients received SRS to the oropharynx (n = 13), hypopharynx (n = 8), nasopharynx (n = 7), paranasal sinus (n = 7), neck (n = 7), and other sites (n = 23). Thirty-eight patients were treated definitively and 27 patients with metastatic disease and/or untreated local disease were treated palliatively. Nine patients underwent complete macroscopic resection before SRS. Thirty-three patients received concurrent chemoradiation. The median initial radiation dose was 67 Gy, and the median reirradiation SRS dose was 30 Gy (21–35 Gy) in 2–5 fractions. Results Median follow-up for surviving patients was 16 months. Fifty-six patients were evaluable for response: 30 (54%) had complete, 15 (27%) had partial, and 11 (20%) had no response. Median overall survival (OS) for all patients was 12 months. For definitively treated patients, the 2-year OS and locoregional control (LRC) rates were 41% and 30%, respectively. Multivariate analysis demonstrated that higher total dose, surgical resection, and nasopharynx site were significantly associated with improved LRC; surgical resection and nonsquamous histology were associated with improved OS. Seven patients (11%) experienced severe reirradiation-related toxicity, including one treatment-attributed death. Conclusion SRS reirradiation for head-and-neck cancer is feasible. This study demonstrates encouraging response rates with acceptable toxicity. Fractionated SRS reirradiation with concurrent chemotherapy in select patients warrants further study. Stereotactic radiosurgery (SRS) is an appealing treatment option after previous radiotherapy because of its precision, conformality, and reduced treatment duration. We report our experience with reirradiation using fractionated SRS for head-and-neck cancer. From 2002 to 2008, 65 patients received SRS to the oropharynx (n = 13), hypopharynx (n = 8), nasopharynx (n = 7), paranasal sinus (n = 7), neck (n = 7), and other sites (n = 23). Thirty-eight patients were treated definitively and 27 patients with metastatic disease and/or untreated local disease were treated palliatively. Nine patients underwent complete macroscopic resection before SRS. Thirty-three patients received concurrent chemoradiation. The median initial radiation dose was 67 Gy, and the median reirradiation SRS dose was 30 Gy (21–35 Gy) in 2–5 fractions. Median follow-up for surviving patients was 16 months. Fifty-six patients were evaluable for response: 30 (54%) had complete, 15 (27%) had partial, and 11 (20%) had no response. Median overall survival (OS) for all patients was 12 months. For definitively treated patients, the 2-year OS and locoregional control (LRC) rates were 41% and 30%, respectively. Multivariate analysis demonstrated that higher total dose, surgical resection, and nasopharynx site were significantly associated with improved LRC; surgical resection and nonsquamous histology were associated with improved OS. Seven patients (11%) experienced severe reirradiation-related toxicity, including one treatment-attributed death. SRS reirradiation for head-and-neck cancer is feasible. This study demonstrates encouraging response rates with acceptable toxicity. Fractionated SRS reirradiation with concurrent chemotherapy in select patients warrants further study.

Concurrent chemoradiation is a standard option for locally advanced pancreatic cancer (LAPC). Concurrent conventional radiation with full-dose gemcitabine has significant toxicity. Stereotactic body radiation therapy (SBRT) may provide the opportunity to administer radiation in a shorter time frame with similar efficacy and reduced toxicity. This Pilot study assessed the safety of concurrent full-dose gemcitabine with SBRT for LAPC.Patients received gemcitabine, 1000 mg/m2 for 6 cycles. During week 4 of cycle 1, patients received SBRT (25 Gy delivered in five consecutive daily fractions of 5 Gy prescribed to the 75-83% isodose line). Acute and late toxicities were assessed using NIH CTCAE v3. Tumor response was assessed by RECIST. Patients underwent an esophagogastroduodenoscopy at baseline, 2, and 6 months to assess the duodenal mucosa. Quality of life (QoL) data was collected before and after treatment using the QLQ-C30 and QLQ-PAN26 questionnaires.Between September 2009 and February 2011, 11 patients enrolled with one withdrawal during radiation therapy. Patients had grade 1 to 2 gastrointestinal toxicity from the start of SBRT to 2 weeks after treatment. There were no grade 3 or greater radiation-related toxicities or delays for cycle 2 of gemcitabine. On endoscopy, there were no grade 2 or higher mucosal toxicities. Two patients had a partial response. The median progression free and overall survival were 6.8 and 12.2 months, respectively. Global QoL did not change between baseline and immediately after radiation treatment.SBRT with concurrent full dose gemcitabine is safe when administered to patients with LAPC. There is no delay in administration of radiation or chemotherapy, and radiation is completed with minimal toxicity.

Self-expandable metal stents (SEMSs) are used to relieve malignant biliary obstruction.To compare outcomes between covered self-expandable metal stents (CSEMSs) and uncovered self-expandable metal stents (USEMSs) in malignant biliary obstruction.Retrospective cohort study.Tertiary cancer center.Patients with malignant biliary obstruction.Placement of CSEMS or USEMS.Time to recurrent biliary obstruction (TRO), overall survival (OS), and adverse events.From January 2000 to June 2011, 749 patients received SEMSs: 171 CSEMSs and 578 USEMSs. At 1 year, there was no significant difference in the percentage of patients with recurrent obstruction (CSEMSs, 35% vs USEMSs, 38%) and survival (CSEMSs, 45% vs USEMSs, 49%). There was no significant difference in the median OS (CSEMSs, 10.4 months vs USEMSs, 11.8 months; P = .84) and the median TRO (CSEMSs, 15.4 months vs USEMSs, 26.3 months; P = .61). The adverse event rate was 27.5% for the CSEMS group and 27.7% for the USEMS group. Although tumor ingrowth with recurrent obstruction was more common in the USEMS group (76% vs 9%, P < .001), stent migration (36% vs 2%, P < .001) and acute pancreatitis (6% vs 1%, P < .001) were more common in the CSEMS group.Retrospective study.There was no significant difference in the patency rate or overall survival between CSEMSs and USEMSs for malignant distal biliary strictures. The CSEMS group had a significantly higher rate of migration and pancreatitis than the USEMS group. No significant SEMS-related adverse events were observed in patients undergoing neoadjuvant chemoradiation or surgical resection.

<h3>Background and aim</h3> Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any. <h3>Methods</h3> The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria. <h3>Results</h3> 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was −13.0% for CXB+DFMO and −1.0% for CXB (p=0.69). Mean % change in adenoma burden was −40% (CXB+DFMO) vs −27% (CXB) (p=0.13). Video-based global polyp change was −0.80 for CXB+DFMO vs −0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02). <h3>Conclusions</h3> CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves. <h3>Trial registration number</h3> ClinicalTrials.gov number N01-CN95040.

Direct DNA sequencing was used to determine the frequency of alleles within the HLA-A2 family in five US population groups. The most frequently detected HLA-A2 allele in all groups was HLA-A*02011. Caucasian and Native American populations appear to be the most homogeneous exhibiting 95.7% and 94.3% A*02011, respectively. Hispanic and Asian/Pacific Islander populations were the most allelicly diverse populations with 9 and 7 different HLA-A2 alleles present, respectively, but the majority of the populations were HLA-A*02011. African-Americans were also diverse, not in the number of alleles seen, but in the percentage of non-A*02011 alleles in the population. HLA-A*0202 (25.8%) and A*0205 (12.9%) were present in a large percentage of African-Americans. Only 13 of the 31 known HLA-A2 alleles were observed in the study. The allelic distributions reflected statistically significant differences among population groups.

High levels of peripheral‐type benzodiazepine receptor (PBR), the alternative‐binding site for diazepam, are part of the aggressive human breast cancer cell phenotype in vitro. We examined PBR levels and distribution in normal tissue and tumors from multiple cancer types by immunohistochemistry. Among normal breast tissues, fibroadenomas, primary and metastatic adenocarcinomas, there is a progressive increase in PBR levels parallel to the invasive and metastatic ability of the tumor (p < 0.0001). In colorectal and prostate carcinomas, PBR levels were also higher in tumor than in the corresponding non‐tumoral tissues and benign lesions (p < 0.0001). In contrast, PBR was highly concentrated in normal adrenal cortical cells and hepatocytes, whereas in adrenocortical tumors and hepatomas PBR levels were decreased. Moreover, malignant skin tumors showed decreased PBR expression compared with normal skin. These results indicate that elevated PBR expression is not a common feature of aggressive tumors, but rather may be limited to certain cancers, such as those of breast, colon‐rectum and prostate tissues, where elevated PBR expression is associated with tumor progression. Thus, we propose that PBR overexpression could serve as a novel prognostic indicator of an aggressive phenotype in breast, colorectal and prostate cancers.

Background and Aims The adenoma detection rate (ADR) is a quality metric tied to interval colon cancer occurrence. However, manual extraction of data to calculate and track the ADR in clinical practice is labor-intensive. To overcome this difficulty, we developed a natural language processing (NLP) method to identify adenomas and sessile serrated adenomas (SSAs) in patients undergoing their first screening colonoscopy. We compared the NLP-generated results with that of manual data extraction to test the accuracy of NLP and report on colonoscopy quality metrics using NLP. Methods Identification of screening colonoscopies using NLP was compared with that using the manual method for 12,748 patients who underwent colonoscopies from July 2010 to February 2013. Also, identification of adenomas and SSAs using NLP was compared with that using the manual method with 2259 matched patient records. Colonoscopy ADRs using these methods were generated for each physician. Results NLP correctly identified 91.3% of the screening examinations, whereas the manual method identified 87.8% of them. Both the manual method and NLP correctly identified examinations of patients with adenomas and SSAs in the matched records almost perfectly. Both NLP and the manual method produced comparable values for ADRs for each endoscopist and for the group as a whole. Conclusions NLP can correctly identify screening colonoscopies, accurately identify adenomas and SSAs in a pathology database, and provide real-time quality metrics for colonoscopy. The adenoma detection rate (ADR) is a quality metric tied to interval colon cancer occurrence. However, manual extraction of data to calculate and track the ADR in clinical practice is labor-intensive. To overcome this difficulty, we developed a natural language processing (NLP) method to identify adenomas and sessile serrated adenomas (SSAs) in patients undergoing their first screening colonoscopy. We compared the NLP-generated results with that of manual data extraction to test the accuracy of NLP and report on colonoscopy quality metrics using NLP. Identification of screening colonoscopies using NLP was compared with that using the manual method for 12,748 patients who underwent colonoscopies from July 2010 to February 2013. Also, identification of adenomas and SSAs using NLP was compared with that using the manual method with 2259 matched patient records. Colonoscopy ADRs using these methods were generated for each physician. NLP correctly identified 91.3% of the screening examinations, whereas the manual method identified 87.8% of them. Both the manual method and NLP correctly identified examinations of patients with adenomas and SSAs in the matched records almost perfectly. Both NLP and the manual method produced comparable values for ADRs for each endoscopist and for the group as a whole. NLP can correctly identify screening colonoscopies, accurately identify adenomas and SSAs in a pathology database, and provide real-time quality metrics for colonoscopy.

Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies. LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m2 IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis. Twenty-four patients were treated for 1–30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m2. Two out of two patients experienced grade 4 neutropenia at the 132 mg/m2 dose level. When an additional three patients were treated at the expanded 110 mg/m2 dose level, two experienced grade 4 neutropenia. The 85 mg/m2 dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m2 with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %. LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m2 without G-CSF or 110 mg/m2 with G-CSF.

BACKGROUND Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA‐damaging agents such as temozolomide. The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects. METHODS A single‐arm, open‐label, phase 2 study was performed to investigate the disease control rate (DCR) after 2 cycles of veliparib plus temozolomide in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies. Fifty patients received temozolomide (150 mg/m 2 /d) on days 1 to 5 and veliparib (40 mg twice daily) on days 1 to 7 of each 28‐day cycle. Another 5 patients with mismatch repair–deficient (dMMR) tumors were also enrolled. Twenty additional patients were then treated with temozolomide at 200 mg/m 2 /d. Archived tumor specimens were used for immunohistochemistry to assess mismatch repair, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O(6)‐methylguanine‐DNA methyltransferase (MGMT) protein expression levels. RESULTS The combination was well tolerated, although some patients required dose reductions for myelosuppression. The primary endpoint was successfully met with a DCR of 24% and 2 confirmed partial responses. The median progression‐free survival was 1.8 months, and the median overall survival was 6.6 months. PTEN protein expression and MGMT protein expression were not predictors of DCR. There was also a suggestion of worse outcomes for patients with dMMR tumors. CONCLUSIONS In this heavily pretreated mCRC population, a combination of veliparib and temozolomide was well tolerated with temozolomide doses up to 200 mg/m 2 /d, and it was clinically active. PARP inhibitor–based therapy merits further exploration in patients with mCRC. Cancer 2018;124:2337‐46 . © 2018 American Cancer Society .

BackgroundThe outcome of children with relapsed Wilms’ tumor is poor, especially with poor-risk factors such as unfavorable histology, early recurrence, previous three-drug therapy, relapse not confined to lungs and abdominal relapse following abdominal radiotherapy. We report the overall response rate, progression-free survival and overall survival of 11 children with relapsed and poor-risk Wilms’ tumor following ifosfamide/carboplatin/etoposide (ICE) chemotherapy.Patients and methodsICE therapy consisted of ifosfamide 1800 mg/m2/day (on day 0–4), carboplatin 400 mg/m2/day (on day 0–1) and etoposide 100 mg/m2/day (on day 0–4). The median age at diagnosis was 39 months (range from 13 months to 16 years) and the median time to relapse after initial diagnosis was 9 months (range 4–72 months). All but one patient had at least one poor prognostic feature, with eight patients showing three or four.ResultsAfter ICE chemotherapy the number of patients showing a complete response (CR) was three (27%) and a partial response (PR) was six (55%). The overall response rate (CR+PR) was 82%. Five of the six patients with a PR subsequently achieved a CR with further therapy. The 3-year event-free survival and overall survival were 63.6 ± 14.5%.ConclusionsThe response rate in children with relapsed and poor-risk Wilms’ tumor is >80% with ICE re-induction chemotherapy followed by post-ICE therapy. The optimal approach for post-ICE consolidation therapy has yet to be determined.

Allogeneic HSCT is highly effective for treating ALL. However, many ALL patients relapse after HSCT. There has been a continuing effort to improve identification of patients at high risk of relapse, with the goal of early intervention to improve outcome.In this retrospective analysis, we examined the effect of MRD on the risk of hematologic relapse in 149 adult patients with ALL in morphologic remission undergoing allogeneic HSCT. MRD was assessed at the time of HSCT and after HSCT.Patients with pretransplant MRD had a trend for shorter progression-free survival (PFS) at 2 years compared with patients without MRD, nearing statistical significance; 28% versus 47%, P = .08, on univariate analysis. This trend remained on multivariate analysis with better PFS in patients without MRD at the time of HSCT, hazard ratio (HR), 0.62 (95% confidence interval, 0.37-1.04); P = .07. Additionally, emergence of MRD after HSCT was a strong predictor for overt hematologic relapse (HR, 4; P < .001) with a median latency interval of 3.8 months.These findings demonstrate the predictive value of monitoring for MRD around the time of transplant in adult patients with ALL.

Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. An institutional review board–approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. OS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size. Long-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted.

Clinical data suggest that large radiation fractions are biologically superior to smaller fraction sizes in prostate cancer radiotherapy. The CyberKnife is an appealing delivery system for hypofractionated radiosurgery due to its ability to deliver highly conformal radiation and to track and adjust for prostate motion in real-time. We report our early experience using the CyberKnife to deliver a hypofractionated stereotactic body radiation therapy (SBRT) boost to patients with intermediate- to high-risk prostate cancer. Twenty-four patients were treated with hypofractionated SBRT and supplemental external radiation therapy plus or minus androgen deprivation therapy (ADT). Patients were treated with SBRT to a dose of 19.5 Gy in 3 fractions followed by intensity modulated radiation therapy (IMRT) to a dose of 50.4 Gy in 28 fractions. Quality of life data were collected with American Urological Association (AUA) symptom score and Expanded Prostate Cancer Index Composite (EPIC) questionnaires before and after treatment. PSA responses were monitored; acute urinary and rectal toxicities were assessed using Common Toxicity Criteria (CTC) v3. All 24 patients completed the planned treatment with an average follow-up of 9.3 months. For patients who did not receive ADT, the median pre-treatment PSA was 10.6 ng/ml and decreased in all patients to a median of 1.5 ng/ml by 6 months post-treatment. Acute effects associated with treatment included Grade 2 urinary and gastrointestinal toxicity but no patient experienced acute Grade 3 or greater toxicity. AUA and EPIC scores returned to baseline by six months post-treatment. Hypofractionated SBRT combined with IMRT offers radiobiological benefits of a large fraction boost for dose escalation and is a well tolerated treatment option for men with intermediate- to high-risk prostate cancer. Early results are encouraging with biochemical response and acceptable toxicity. These data provide a basis for the design of a phase II clinical trial.

BACKGROUND: Local excision, alone or in combination with chemoradiation, is increasingly considered for rectal cancer. Higher risks of disease recurrence have been demonstrated after local excision. OBJECTIVE: The aim of this study was to examine the outcomes of current-era multimodality salvage for recurrent rectal cancer after local excision. DESIGN: This was a single-institutional retrospective study. SETTINGS: This study was conducted at a tertiary-referral cancer center between 1993 and 2011. PATIENTS: Forty-six patients with recurrent rectal cancer after initial local excision were included. INTERVENTION: Multimodality salvage treatment was performed as appropriate. MAIN OUTCOME MEASURES: The primary outcomes measured were the pattern of disease recurrence, salvage treatments, and resultant overall and re-recurrence-free survival. RESULTS: After the initial local excision, recurrent disease was diagnosed after a median interval of 1.9 years: local/regionally in 67%, distantly in 18%, and both in 15%. Four patients (9%) had recurrence that was unsalvageable, 2 (4%) declined treatment, and 40 (87%) underwent surgical salvage. Preoperative chemoradiation was given in 30 (75%) patients. The R0 resection rate was 80%, requiring multivisceral resection (33%), total pelvic exenteration (5%), and metastasectomy (25%). The rate of sphincter preservation was 33%, and perioperative morbidity was 50%. The first site of failure after salvage was distant in 38% and was local only in 10%. The 5-year overall and 3-year re-recurrence-free survival were 63% and 43%. Pathologic stage at initial local excision, receipt of neoadjuvant chemoradiation before local excision, recurrence pattern after local excision, pathologic stage at salvage, and R0 resection at salvage influenced re-recurrence-free survival. LIMITATIONS: This study was limited by the referral and selection biases inherent in a small study cohort. CONCLUSIONS: Failure after local excision for rectal cancer may not be salvageable. When feasible, multimodality treatment, including multivisceral resection, pelvic irradiation, and chemotherapy, was associated with potentially lasting treatment-related morbidities and only modest success in long-term disease control. These findings should be compared with the expected stage-specific outcomes of standard proctectomy for early-stage rectal cancer, when local excision is being considered.

Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with higher stage of presentation and worse survival. The objective of this study was to examine the clinicopathologic characteristics associated with overall survival (OS), specifically examining the percentage of sarcomatoid component (PSC).We reviewed clinicopathologic data for all nephrectomized patients with confirmed sRCC. Histologic slides were rereviewed by dedicated genitourinary pathologists to ascertain PSC. Patient characteristics were tabulated overall and by disease stage. Cutpoints in the PSC providing a meaningful difference in OS were identified by recursive partitioning analysis (RPA). Factors selected included age group, gender, race, clinical stage, tumor histology, presurgical systemic therapy, lymphovascular invasion, and tumor size. The Kaplan-Meier method and log-rank test were used to assess differences in OS.Among 186 patients with sRCC, 64 (34%) had localized, and 122 (66%) had metastatic disease at presentation. Patients had primarily clear cell histology (73%). Median follow-up was 12.1 months (range: 0.1-242.2mo). Median OS was 12.6 months (95% CI: 10.7-14.9mo). Univariate RPA identified a PSC cutpoint of 10% as prognostically significant. Patients with PSC>10% were at higher risk of death when compared with patients with PSC≤10% (45% vs. 61% 1-y OS; P = 0.04). Multivariate RPA revealed that tumor size, presence of metastatic disease, and PSC were significantly associated with OS. Among 4 identified groups, patients with localized disease and tumor size≤10cm were most likely to be alive at 1 year (89%), and patients with metastatic disease and PSC>40% were least likely to be alive at 1 year (28%; P<0.001).PSC appears to be a prognostic factor in patients with sRCC, with larger percentage of involvement portending a worse survival, especially in patients with metastatic disease.

Peritoneal metastases (PM) in patients with gastric adenocarcinoma (GAC) may be identified by diagnostic laparoscopy (DL) or imaging (I). Although prognosis is poor, some patients have excellent outcome. We compared the overall survival (OS) of patients in 3 groups: those with positive cytology (CY+) by DL (DL-CY+), those with gross PM (GPM) by DL (DL-GPM+) and with GPM obvious on I (I-GPM+).146 GAC patients were identified. The Kaplan-Meier analysis, univariate, and multivariate Cox proportional hazards regression models were employed.Patients were primarily men (67%), with good ECOG scores (0-1; 89%), had DL (84%), had poorly differentiated GAC (92%), and had received chemotherapy (89%). The median OS for all patients was 15 months (5% CI, 12.9-18.2 months). The DL-CY+ group had median OS of 22.5 months (95% CI, 15-29.3 months). Patients with I-GPM+ had four times the risk of death than those with DL-CY+ (P < 0.001) and patients with DL-GPM+ had two times the risk of death than those with DL-CY+ (P = 0.001). At 36 months, all DL-GPM+ and I-GPM+ had died but 8 patients with DL-CY+ remained alive.Some GAC patients with DL-CY+ have long OS; therefore, novel strategies to further prolong their OS are needed.

To analyse survival in patients with clinically localised, surgically resectable micropapillary bladder cancer (MPBC) undergoing radical cystectomy (RC) with and without neoadjuvant chemotherapy (NAC) and develop risk strata based on outcome data.A review of our database identified 103 patients with surgically resectable (≤cT4acN0 cM0) MPBC who underwent RC. Survival estimates were calculated using Kaplan-Meier method and compared using log-rank tests. Classification and regression tree (CART) analysis was performed to identify risk groups for survival.For the entire cohort, estimated 5-year overall survival and disease-specific survival (DSS) rates were 52% and 58%, respectively. CART analysis identified three risk subgroups: low-risk: cT1, no hydronephrosis; high-risk: ≥cT2, no hydronephrosis; and highest-risk: cTany with tumour-associated hydronephrosis. The 5-year DSS for the low-, high-, and highest-risk groups were 92%, 51%, and 17%, respectively (P < 0.001). Patients down-staged at RC <pT1 regardless of the use of NAC had the best survival (5-year DSS of 96% vs 45% for those not down-staged; P < 0.001), while those who were not down-staged despite NAC had 5-year DSS of only 17%.In patients with surgically resectable MPBC, NAC appears to confer benefit to patients with muscle-invasive disease without hydronephrosis, while patients with cT1 disease can proceed to upfront RC. Patients with hydronephrosis do not appear to respond well to NAC and have poor prognosis regardless of treatment paradigm. However, further external validation studies are needed to support the proposed risk stratification before treatment recommendations can be made.

Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy-General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.

Response to neoadjuvant chemotherapy for locally advanced breast cancer can be correlated with long-term outcomes. Surrogate end-point biomarkers may be used to assess response to the treatment. Most reported studies assessed the effects of combination chemotherapy. We assessed the feasibility of obtaining serial core breast biopsies, and correlated rates of apoptosis, proliferation, and expression of related proteins at baseline, during, and after neoadjuvant single agent chemotherapy for locally advanced breast cancer with response.Women with a histologically confirmed unresected T(3) or T(4) infiltrating carcinoma of the breast were eligible. The first 20 patients received three cycles of doxorubicin 90 mg/m(2) followed by three cycles of paclitaxel 250 mg/m(2), or the reverse. Nine women received four cycles of each (doxorubicin 60 mg/m(2) and paclitaxel 175 mg/m(2)). Cycles were administered 14 days apart with filgastrim. End points included: (a). clinical and pathological response; (b). serial apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling] and proliferation (immunohistochemistry, IHC) rates; and (c). expression (IHC) of estrogen receptor, HER2, bcl2, and p53.From April 1997 to June 2001, 29 women were randomized. Twelve patients (42%) had a clinical complete response (cCR), and 16 (55%) had a clinical partial response. Five women (17%) had a pathological complete response, 7 (24%) had microscopic residual disease, and 17 (58%) had macroscopic residual disease. Higher baseline apoptosis and proliferation were associated with an improved pathological response (P = 0.006 and 0.003, respectively). Among 14 evaluable patients, apoptosis increased in women who had a cCR to the first agent but not in women without a cCR. Estrogen receptor-positive patients had a worse pathological response (P = 0.004).The selected regimen is efficacious. It is feasible to obtain serial core biopsies that are informative for studies of apoptosis and IHC. This clinical design can serve as a model for combining standard chemotherapy and novel agents.

Ileostomies are a routine part of the care of patients with rectal cancer, but are associated with significant risk for dehydration, readmission, and acute kidney injury. Telemedicine has proven beneficial in decreasing readmission in chronic medical illnesses, but its utility in patients with an ileostomy is not well studied.The purpose of this study was to evaluate the feasibility of televideoconferencing in the assessment of ileostomy output.An institutional review board-approved, prospective clinical trial was conducted at a single institution from November 2014 through December 2015.The study was conducted in a single, large academic medical center.Patients >18 years of age undergoing surgery with plans for ileostomy were eligible.Televideoconference assessments of ileostomy output and the need for medical intervention were conducted during the postoperative stay and compared with in-person assessment.The primary end point of the trial was the feasibility of using teleconferencing to assess the need for medical intervention, defined as 90% agreement between telemedicine and in-person assessments. Secondary end points included patient/provider satisfaction, and correlative studies examined dehydration events and readmission.Twenty-seven patients underwent 44 teleconferencing assessments of ileostomy output. Compared with in-person treatment decisions, there was a 95% match (95% CI, 85%-99%). The readmission rate for the study participants was 31%, and 18% experienced dehydration events. Both patients and faculty responded favorably to surveys regarding the use of telemedicine in the perioperative period.The study is limited by its in-hospital use of technology and small sample size.Televideoconference evaluation is a feasible, reliable means of assessing ileostomy output with high patient and physician acceptance. Our pilot study provides rationale for further study in the postdischarge setting for patients with ileostomies. The incorporation of televideoconference assessment within a teledischarge program may enable early intervention to improve patient outcomes. See Video Abstract at http://links.lww.com/DCR/A455.

KAI1 is a metastasis suppressor gene for human prostate cancer and is also involved in the progression of a variety of other human cancers. Previously, we have demonstrated that KAI1 expression was down-regulated in metastatic breast cancer cell lines as well as in highly aggressive breast cancer specimens. To determine whether KAI1 expression is responsible for the metastasis suppression in breast cancer, we transfected the human KAI1 cDNA into two highly malignant breast cancer cell lines, LCC6 and MDA-MB-231, which both have low levels of endogenous KAI1 expression. Parental, vector-only transfectants and KAI1 transfectant clones were injected into the mammary fat pads and tail veins, respectively, of athymic nude mice and assessed for both spontaneous and experimental lung metastasis. High KAI1 expression significantly suppressed the metastatic potential of KAI1-transfected LCC6 cells. Metastasis suppression correlated with the reduced rate of tumor growth and a decreased clonogenicity in soft agar. Furthermore, KAI1 expression significantly suppressed the in vitro cell invasion in KAI1-transfected MDA-MB-231 cells. Our results suggested that KAI1 may function as a negative regulator of breast cancer metastasis.

Purpose: To retrospectively determine the sensitivity of ovarian artery (OA) visualization at aortography performed after uterine fibroid embolization (UFE) and, using OA arteriography as the reference standard, compare the extent of arterial flow to the uterus at aortography with selective ovarian arteriography, to establish the utility of aortography and ovarian arteriography in the routine practice of UFE. Materials and Methods: This study received institutional review board approval with waiver of informed consent and was HIPAA compliant. Retrospective review of 1129 consecutive UFE patients (1072 with aortograms, 57 excluded; mean age, 44 years; range, 21–60 years) was performed to identify all visible OAs. Visible OAs were independently graded by two interventional radiologists according to extent of pelvic arterial flow. If selective arteriography was performed, a second grade was assigned based on assessment of the selective study. Descriptive and summary statistics were used for assessment by the senior observer, and interobserver variability was determined. Results: Of 1072 UFE patients, 184 (17.2%) had at least one visible OA. Ten (0.8%) patients were identified at aortography with collateral OA supply to more than 10% of the uterus. In total, 251 OAs were visualized, and 157 of these were further evaluated with selective study. Sixty-two (5.8%) patients were identified at selective arteriography as having collateral OA supply. The sensitivity of aortography was approximately 18%. Interobserver concordance was high (κ values of 0.81 and 0.90 for aortography and selective study, respectively), but not perfect. Conclusion: Aortography rarely helps identify patients with substantial residual OA supply to the uterus and is a poor predictor of the extent of that supply, and thus may be of limited utility in routine UFE. © RSNA, 2007

We evaluated the use of sorafenib to overcome resistance to aromatase inhibitors (AIs) in patients with metastatic breast cancer who had disease recurrence or progression while on AIs. We performed a multi-institution phase I/II study of sorafenib and anastrozole 1 mg daily in 35 postmenopausal females with hormone receptor positive metastatic breast cancer resistant to AIs. Primary objectives were to determine the dose of sorafenib in conjunction with anastrozole and the clinical benefit rate (CBR) (complete response [CR], partial response [PR], or stable disease [SD] ≥ 24 weeks). Secondary objectives were to determine toxicity and to evaluate if response was associated with change in number of circulating endothelial cells or circulating endothelial progenitor cells. Based on the phase I portion, sorafenib 400 mg twice daily was selected as the phase II dose. Among 35 patients, 7 had SD ≥ 24 weeks, 1 had PR ≥ 24 weeks, and 14 had progressive disease (PD) ≤ 24 weeks, corresponding to a CBR of 23%. The most common adverse events (all; Grade 3/4) were fatigue (66%; 17%), diarrhea (63%; 6%), nausea (60%; 9%), and hand-foot syndrome (57%; 34%). Dose reduction occurred in 77% of the patients and 31% came off study due to toxicity. The combination of sorafenib and anastrozole demonstrated a 23% CBR in patients with hormone receptor positive, AI-resistant metastatic breast cancer, which may be attributable to the restoration of sensitivity to AIs. Toxicities occurred frequently resulting in a high rate of discontinuation.

Predictive factors for efficacy of vascular endothelial growth factor pathway-targeted therapies have not been identified or confirmed. Hypertension has been observed as a side effect to anti-vascular endothelial growth factor therapy. The goal of our study was to retrospectively assess if hypertension induced during treatment with bevacizumab was associated with clinical outcome in metastatic colorectal cancer patients treated with bevacizumab. We conducted a retrospective chart review of patients with colorectal cancer treated with bevacizumab at Lombardi Comprehensive Cancer Center from 2004 to 2008. Eighty-four patients with metastatic colorectal cancer were eligible. Eighteen patients (21%) developed grades 3 hypertension. Twelve patients (14%) developed grade 2 hypertension. Six patients (7%) developed grade 1 hypertension. Median overall survival (OS) was 29 months and progression-free survival (PFS) was 10 months. Patients with any grade hypertension while on bevacizumab had an adjusted hazard ratio for death of 0.32 (p = 0.03) and adjusted risk of progression of 51% (p = 0.02) compared to those without hypertension (HTN). When stratified by metastatic disease, patients presenting with metastases who developed HTN had better OS and PFS (p = 0.03 and 0.01.) Among patients without metastases at diagnosis, those with HTN on bevacizumab had better OS and PFS but results were not statistically significant (p = 0.60 and 0.62, respectively). Our data indicate that bevacizumab-induced hypertension may represent an interesting prognostic factor for clinical outcome in advanced colorectal cancer patients receiving bevacizumab.

Abstract Measures shown to improve the adenoma detection during colonoscopy (excellent bowel preparation, cecal intubation, cap fitted colonoscope to examine behind folds, patient position change to optimize colon distention, trained endoscopy team focusing on detection of subtle flat lesions, and incorporation of optimum endoscopic examination with adequate withdrawal time) are applicable to clinical practice and, if incorporated are projected to facilitate comprehensive colonoscopy screening program for colon cancer prevention. To determine adenoma and serrated polyp detection rate under conditions designed to optimize quality parameters for comprehensive screening colonoscopy. Retrospective analysis of data obtained from a comprehensive colon cancer screening program designed to optimize quality parameters. Academic medical center. Three hundred and forty‐three patients between the ages of 50 years and 75 years who underwent first screening colonoscopy between 2009 and 2011 among 535 consecutive patients undergoing colonoscopy. Comprehensive colonoscopy screening program was utilized to screen all patients. Cecal intubation was successful in 98.8% of patients. The Boston Bowel Preparation Scale for quality of colonoscopy was 8.97 (95% confidence interval [ CI ]; 8.94, 9.00). The rate of adenoma detection was 60% and serrated lesion (defined as serrated adenomas or hyperplastic polyps proximal to the splenic flexure) detection was 23%. The rate of precancerous lesion detection (adenomas and serrated lesions) was 66%. The mean number of adenomas per screening procedure was 1.4 (1.2, 1.6) and the mean number of precancerous lesions (adenomas or serrated lesions) per screening procedure was 1.6 (1.4, 1.8). Retrospective study and single endoscopist experience. A comprehensive colonoscopy screening program results in high‐quality screening with high detection of adenomas, advanced adenomas, serrated adenomas, and multiple adenomas.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibrotic reaction or desmoplasia and complex involvement of the surrounding tumor microenvironment. Pancreatic stellate cells are a key mediator of the pancreatic matrix and they promote progression and invasion of pancreatic cancer by increasing cell proliferation and offering protection against therapeutic interventions. Our study utilizes human tumor-derived pancreatic stellate cells (HTPSCs) isolated from fine needle aspirates of pancreatic cancer tissue from patients with locally advanced, unresectable pancreatic adenocarcinoma before and after treatment with full dose gemcitabine plus concurrent hypo-fractionated stereotactic radiosurgery. We show that HTPSCs survive in vivo chemotherapy and radiotherapy treatment and display a more activated phenotype post therapy. These data support the idea that stellate cells play an essential role in supporting and promoting pancreatic cancer and further research is needed to develop novel treatments targeting the pancreatic tumor microenvironment.

No AccessJournal of UrologyAdult Urology1 Sep 2016The Role of Metastasectomy in Patients with Renal Cell Carcinoma with Sarcomatoid Dedifferentiation: A Matched Controlled Analysis Arun Z. Thomas, Mehrad Adibi, Rebecca S. Slack, Leonardo D. Borregales, Megan M. Merrill, Pheroze Tamboli, Kanishka Sircar, Eric Jonasch, Nizar M. Tannir, Surena F. Matin, Christopher G. Wood, and Jose A. Karam Arun Z. ThomasArun Z. Thomas Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Mehrad AdibiMehrad Adibi Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Rebecca S. SlackRebecca S. Slack Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Leonardo D. BorregalesLeonardo D. Borregales Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Megan M. MerrillMegan M. Merrill Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Pheroze TamboliPheroze Tamboli Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Kanishka SircarKanishka Sircar Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Eric JonaschEric Jonasch Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Nizar M. TannirNizar M. Tannir Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Financial interest and/or other relationship with Novartis, BMS, Exelixis, GlaxoSmithKline, Pfizer, Nektar and Epizyme. More articles by this author , Surena F. MatinSurena F. Matin Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author , Christopher G. WoodChristopher G. Wood Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Financial interest and/or other relationship with Pfizer, Ono Pharma, GlaxoSmithKline and Boehringer Ingelheim. More articles by this author , and Jose A. KaramJose A. Karam Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.03.144AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: Management of metastatic renal cell carcinoma with sarcomatoid dedifferentiation remains a therapeutic challenge with no standard treatment strategies. We evaluated whether metastasectomy has any survival benefit in patients with metastatic sarcomatoid dedifferentiation treated with radical nephrectomy. Materials and Methods: From an institutional database of 273 patients with sarcomatoid dedifferentiation treated with nephrectomy we matched 80 with synchronous and asynchronous metastases for age, ECOG (Eastern Cooperative Oncology Group) performance status, histology and lymph node status. Matched pairs were then retained only if patients who did not undergo metastasectomy were alive at metastasectomy comparable to matched surgical patients to decrease the bias of survival outcomes. Overall survival from nephrectomy was studied using univariable and multivariable proportional hazards regression. Results: Median overall survival was 8.3 (95% CI 6.5–10.5) and 18.5 months (95% CI 11.5–42.9) in patients with synchronous and asynchronous metastases, respectively. Overall survival in patients who underwent metastasectomy for synchronous metastasis compared to nonsurgical patients was 8.4 and 8.0 months (p = 0.35), respectively. Similarly, overall survival in patients with asynchronous metastases treated with metastasectomy compared to the nonsurgical group was 36.2 and 13.7 months, respectively (p = 0.29). On multivariable analysis positive lymph nodes at nephrectomy were associated with an increased risk of death in the synchronous and asynchronous patient subgroups (HR 2.1, 95% CI 1.1–4.0, p = 0.03 and HR 3.3, 95% CI 1.2–9.2, p = 0.02, respectively). Conclusions: In the current study there was no clear evidence of benefit in patients with sarcomatoid dedifferentiation who underwent metastasectomy after nephrectomy. Particularly, the group of patients with pathological lymph node positive disease at nephrectomy had considerably worse survival. References 1 : Cytoreductive nephrectomy in metastatic renal cancer. Curr Urol Rep2003; 4: 36. Google Scholar 2 : The changing natural history of renal cell carcinoma. J Urol2001; 166: 1611. Link, Google Scholar 3 : Surgery for metastases of renal cell carcinoma. Scand J Surg2004; 93: 150. Google Scholar 4 : Metastasectomy after targeted therapy in patients with advanced renal cell carcinoma. J Urol2011; 185: 439. 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Google Scholar 30 : Prognostic factors of patients with metastatic renal cell carcinoma with removed metastases: a multicenter study of 556 patients. Urology2013; 82: 846. Google Scholar © 2016 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 196Issue 3September 2016Page: 678-684Supplementary Materials Advertisement Copyright & Permissions© 2016 by American Urological Association Education and Research, Inc.Keywordsnephrectomycarcinoma, renal cellmortalitykidneyneoplasm metastasisMetricsAuthor Information Arun Z. Thomas Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Mehrad Adibi Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Rebecca S. Slack Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Leonardo D. Borregales Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Megan M. Merrill Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Pheroze Tamboli Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Kanishka Sircar Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Eric Jonasch Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Nizar M. Tannir Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Financial interest and/or other relationship with Novartis, BMS, Exelixis, GlaxoSmithKline, Pfizer, Nektar and Epizyme. More articles by this author Surena F. Matin Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Christopher G. Wood Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Financial interest and/or other relationship with Pfizer, Ono Pharma, GlaxoSmithKline and Boehringer Ingelheim. More articles by this author Jose A. Karam Department of Urology, University of Texas M.D. Anderson Cancer Center, Houston, Texas More articles by this author Expand All Advertisement PDF downloadLoading ...

Pulmonary dysfunction is a common complication of head trauma and spinal cord injury. Abnormal breathing patterns reflect the influence of altered neural integration. Early arterial hypoxemia can result from ventilation-perfusion mismatching, microatelectasis, aspiration, fat embolism, or the development of the adult respiratory distress syndrome. Significant changes in lung volumes, ventilation, and gas exchange can occur in spinal cord injury as a result of the loss of diaphramatic or intercostal muscle function. Recruitment of accessory respiratory muscles plays an important role in stabilizing the rib cage and improving expiratory function. Strength training improves expiratory muscle function in quadriplegics and should be continued indefinitely. Most importantly, survival of patients with CNS injuries improves with meticulous and vigorous pulmonary hygiene. The pulmonary hygiene program should include regular changes in the patient's position, assisted coughing and deep breathing exercises, incentive spirometer, bronchodilators, fiberoptic bronchoscopy when indicated, and frequent monitoring of pulmonary mechanics. Long-term survival of the patient with head trauma or spinal cord injury is correlated to successful weaning from mechanical ventilation. Various forms of mechanical ventilator support can be adopted for the patient's ventilatory needs, and many patients will achieve some degree of freedom from mechanical ventilation. Newer ventilatory assist devices that do not require tracheostomy should be considered.

Outpatient clinical encounters are used to promote recovery after complex surgical procedures for cancer. These care episodes are resource intensive. Virtual clinical encounters (VCEs) can now be conducted using widely available videoconferencing technologies. However, whether these technologies may be used to monitor postoperative recovery is unknown.In this pilot study, we provided care using a comprehensive "TeleDischarge" protocol to 15 patients after pancreatectomy. In addition to routine follow-up, all patients participated in two scheduled and an unlimited number of unscheduled VCEs using mobile hardware and secure videoconferencing software. We evaluated feasibility, patient satisfaction, postoperative adverse events, and health care human resource utilization.The median age of enrolled patients was 63 y (range, 52-83 y) and 93% underwent pancreatoduodenectomy. Twenty-eight scheduled VCEs (93%) were completed successfully, and only one unscheduled VCE was requested. Twelve patients (80%) felt their postoperative care was enhanced by VCEs and 14 (93%) felt that VCEs should be a regular part of postoperative care. Minor interventions in four patients (27%) were performed on the basis of clinical data gathered during a VCE. On a per patient basis, the TeleDischarge pathway was estimated to take 36 min longer and to have a direct labor cost $39 greater than the standard pathway.Secure VCEs can be conducted using widely available hardware and software solutions. Although cancer patients support the introduction of mobile technology into postoperative care, further studies are needed to identify ways in which such technology can be used most effectively and efficiently to reduce barriers to recovery.

The KAI1 gene was identified as a metastasis suppressor gene for human prostate cancer. Recently, we showed that KAI1 mRNA levels were higher in an immortal, normal-like breast epithelial cell line and nonmetastatic breast cancer cell lines but lower substantially in highly metastatic breast cancer cell lines. In this study, we examined KAI1 protein expression in breast cancer cell lines by Western blot and immunohistochemical study. KAI1 protein levels paralleled KAI1 mRNA levels and were inversely correlated with the metastatic potential of breast cancer cells. Furthermore, we examined KAI1 protein expression immunohistochemically in specimens from 81 patients with breast cancer and then correlated the findings with the clinical and histopathological parameters of the patients. High levels of KAI1 protein expression were found in normal breast tissues and noninvasive breast cancer (ductal carcinoma in situ). In contrast, KAI1 expression was reduced in most of the infiltrating breast tumors. We found that, in general, more malignant tumors demonstrated significantly lower KAI1 expression (P = 0.004). Additionally, among 29 specimens demonstrating multiple stages of malignancy within a single specimen, 23 demonstrated significant differences in KAI1 expression between benign breast tissue, ductal carcinoma in situ, and invasive carcinoma. The higher the incidence for malignancy within a given specimen, the lower the KAI1 expression (P < 0.001). These data suggest that in advanced breast cancer, KAI1 expression is down-regulated. Therefore, KAI1 may be a potentially useful indicator of human breast cancer progression.

AIDS Patient Care and STDsVol. 23, No. 8 Letter to the EditorThe Prevalence of Rectal, Urethral, and Pharyngeal Neisseria gonorrheae and Chlamydia trachomatis among Asymptomatic Men Who Have Sex with Men in a Prospective Cohort in Washington, D.C.Joseph Baker, Michael Plankey, Yiga Josayma, Richard Elion, Philippe Chiliade, Akbar Shahkolahi, Max Menna, Kevin Miniter, Rebecca Slack, Yang Yang, Benjamin Masterman, and Joseph B. MargolickJoseph BakerWhitman Walker Clinic, Washington, D.C.Search for more papers by this author, Michael PlankeyGeorgetown University Medical Center, Washington, D.C.Search for more papers by this author, Yiga JosaymaWhitman Walker Clinic, Washington, D.C.Search for more papers by this author, Richard ElionWhitman Walker Clinic, Washington, D.C.Search for more papers by this author, Philippe ChiliadeFamily Health International, Arlington, Virginia.Search for more papers by this author, Akbar ShahkolahiAIDS Clinical Trials Group, Silver Spring, Maryland.Search for more papers by this author, Max MennaWhitman Walker Clinic, Washington, D.C.Search for more papers by this author, Kevin MiniterWhitman Walker Clinic, Washington, D.C.Search for more papers by this author, Rebecca SlackGeorgetown University Medical Center, Washington, D.C.Search for more papers by this author, Yang YangGeorgetown University Medical Center, Washington, D.C.Search for more papers by this author, Benjamin MastermanGeorgetown University Medical Center, Washington, D.C.Search for more papers by this author, and Joseph B. MargolickJohns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.Search for more papers by this authorPublished Online:18 Aug 2009https://doi.org/10.1089/apc.2008.0277AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byOptimizing Strategies for Chlamydia trachomatis and Neisseria gonorrhoeae Screening in Men Who Have Sex With Men: A Modeling Study14 June 2019 | Clinical Infectious Diseases, Vol. 70, No. 9Prevalence, incidence and predictors of anal Chlamydia trachomatis , anal Neisseria gonorrhoeae and syphilis among older gay and bisexual men in the longitudinal Study for the Prevention of Anal Cancer (SPANC)24 April 2019 | Sexually Transmitted Infections, Vol. 95, No. 7Pathways to recovery: recovery housing models for men who have sex with men (MSM)9 January 2019 | Addiction Research & Theory, Vol. 27, No. 5Improving recovery outcomes among MSM: The potential role of recovery housing3 October 2018 | Journal of Substance Use, Vol. 24, No. 2Anatomical site distribution and genotypes of Chlamydia trachomatis infecting asymptomatic men who have sex with men in northeast Thailand7 March 2018 | International Journal of STD & AIDS, Vol. 29, No. 9Prevalence of Rectal Chlamydial and Gonococcal Infections: A Systematic ReviewSexually Transmitted Diseases, Vol. 45, No. 5Saliva use in sex: Associations with use of smartphone dating applications in men who have sex with men23 August 2017 | International Journal of STD & AIDS, Vol. 29, No. 4Epidemiological, behavioural, and clinical factors associated with antimicrobial-resistant gonorrhoea: a review27 March 2018 | F1000Research, Vol. 7A multicentre double-blind randomised controlled trial evaluating the efficacy of daily use of antibacterial mouthwash against oropharyngeal gonorrhoea among men who have sex with men: the OMEGA (Oral Mouthwash use to Eradicate GonorrhoeA) study protocol28 June 2017 | BMC Infectious Diseases, Vol. 17, No. 1Asymptomatic anorectal Chlamydia trachomatis and Neisseria gonorrhoeae infections are associated with systemic CD8+ T-cell activationAIDS, Vol. 31, No. 15Incidence of Gonorrhea and Chlamydia Following Human Immunodeficiency Virus Preexposure Prophylaxis Among Men Who Have Sex With Men: A Modeling Study13 May 2017 | Clinical Infectious Diseases, Vol. 65, No. 5Chlamydia trachomatis Infection15 June 2017Chlamydiae15 April 2016Extragenital Infections Caused by Chlamydia trachomatis and Neisseria gonorrhoeae : A Review of the LiteratureInfectious Diseases in Obstetrics and Gynecology, Vol. 2016Screening for Asymptomatic Extragenital Gonorrhea and Chlamydia in Men Who Have Sex with Men: Significance, Recommendations, and Options for Overcoming Barriers to Testing Anthony R. Lutz3 March 2015 | LGBT Health, Vol. 2, No. 1Provider Barriers Prevent Recommended Sexually Transmitted Disease Screening of HIV-Infected Men Who Have Sex With MenSexually Transmitted Diseases, Vol. 41, No. 2Prevalence of pharyngeal infection by Neisseria gonorrhoeae among human immunodeficiency virus-positive men who have sex with men in downtown Madrid, 201119 July 2013 | International Journal of STD & AIDS, Vol. 24, No. 11HIV, Rectal Chlamydia, and Rectal Gonorrhea in Men Who Have Sex With Men Attending a Sexually Transmitted Disease Clinic in a Midwestern US CitySexually Transmitted Diseases, Vol. 40, No. 6Cobas ® 4800: a fully automated system for the detection of Chlamydia trachomatis and Neisseria gonorrhoeae9 January 2014 | Expert Review of Molecular Diagnostics, Vol. 13, No. 2Rates of Asymptomatic Nonurethral Gonorrhea and Chlamydia in a Population of University Men Who Have Sex With MenJournal of American College Health, Vol. 60, No. 6 Volume 23Issue 8Aug 2009 InformationCopyright 2009, Mary Ann Liebert, Inc.To cite this article:Joseph Baker, Michael Plankey, Yiga Josayma, Richard Elion, Philippe Chiliade, Akbar Shahkolahi, Max Menna, Kevin Miniter, Rebecca Slack, Yang Yang, Benjamin Masterman, and Joseph B. Margolick.The Prevalence of Rectal, Urethral, and Pharyngeal Neisseria gonorrheae and Chlamydia trachomatis among Asymptomatic Men Who Have Sex with Men in a Prospective Cohort in Washington, D.C..AIDS Patient Care and STDs.Aug 2009.585-588.http://doi.org/10.1089/apc.2008.0277Published in Volume: 23 Issue 8: August 18, 2009Online Ahead of Print:July 10, 2009PDF download

Recent studies have demonstrated a high prevalence of pharyngeal (P) and rectal (R) Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) infections among men who have sex with men (MSM). Guidelines by the Centers for Disease Control and Prevention recommend testing at least annually. But surveys of medical providers suggest that adherence to these guidelines is minimal as a result of limited time and staff. Because of these concerns, we evaluated the feasibility and accuracy of patient self-testing.Three-hundred seventy-four patients at a Washington, DC clinic who identified themselves as MSM and requested testing for sexually transmitted infections (STIs) participated in the study. Patients performed self-screening using the Gen-Probe APTIMA Combo 2 (AC2) kit after viewing written and pictorial instructions. Trained providers also screened patients. We randomized the order in which patients or providers performed testing.Among those receiving specific tests, 8% of patients tested positive for R-GC, 9.3% for P-GC, 12.7% for R-CT, and 1.3% for P-CT. We performed McNemar tests, stratified by infection type and anatomic site to evaluate concordance. Self-administered testing was significantly better at identifying P-GC (discordant: 3%) and R-GC (discordant: 2.9%) (P ≤.01), and had results similar to provider- administered testing for P-CT (discordant: 0.5%) and R-CT (discordant: 1.1%) detection.The equivalent or better detection rates for rectal and oral gonorrhea and chlamydia among patients suggest that patients are capable of performing their own screening for STIs, which may increase infection detection and treatment.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease occurring in 1 in 35,000 births and leads to an increased risk of a phenotypically diverse array of tumor types including, but not limited to, clear cell renal cell carcinoma (ccRCC) and hemangioblastomas (HBs). Previous studies of patients with VHL disease treated with the tyrosine kinase inhibitor (TKI) sunitinib did not show clinical response in HBs. Interestingly, VHL-related HBs displayed increased fibroblast growth factor receptor 3 (FGFR3) protein expression when compared to VHL-related ccRCCs. Therefore, in this pilot study, we assessed the safety and efficacy profile of TKI 258 (dovitinib), a multi-tyrosine kinase inhibitor of VEGF receptor and fibroblast growth factor (FGF), in patients with VHL disease who had measureable HBs. The trial was stopped after six patients enrolled after the toxicity stopping rule was triggered. With regards to safety, 6/6 subjects had at least one adverse event (AE). Best response in 6/6 subjects was stable disease (SD) in HBs. While the negative safety and efficacy results of this pilot study do not favor the use of dovitinib for the treatment of asymptomatic HBs in VHL disease patients, further investigation into alternative scheduling and other FGFR inhibitors for the treatment of HBs in VHL disease patients is warranted given the promising pre-clinical and molecular data.

ABSTRACT Background: Women with a family history of breast cancer (i.e., in a mother, sister or daughter) are at increased risk for this disease. Previous data also suggest that lesbians are at increased risk for breast cancer. While the screening behaviors of women with a family history have been described, little is known about factors that influence screening behaviors of lesbians with the same risk factor profile. Purpose: The purpose of this study was to characterize the perceptions of susceptibility to breast cancer and describe factors that influence adherence to breast cancer screening guidelines in a sample of lesbians with a first-degree relative with a diagnosis of breast cancer. Methods: Structured telephone interviews were conducted on a sample of 139 self-identified lesbians who had a first-degree relative with a diagnosis of breast cancer, were between the ages of 35 to 75 and had no previous history of cancer. Cross-sectional data obtained, included socio-demographics, breast cancer risk factors, breast cancer screening patterns, breast cancer perceptions, worries, and knowledge, and barriers and access to health care factors. Individual subject characteristics were examined for their association with adherence to mammography guidelines followed by a multivariate analysis to evaluate the most important combinations of factors. Outcome measures were age-specific adherence to ACS guidelines for both mammography and overall adherence (i.e., mammography, clinical breast examination and breast self-examination). Results: The 139 lesbians interviewed for this study were young (mean age = 43), almost exclusively white (94%), highly educated (78% = college graduate and beyond), and partnered (68%). In the bivariate analysis of individual factors, being employed and reporting breast cancer worries were significantly and positively associated with adherence to mammography guidelines. Higher income and insurance type were significantly associated with mammography adherence. No factors were significantly associated with overall adherence. Multivariate logistic regression analyses revealed that only income level and degree of breast cancer worries were significantly and positively associated with mammography adherence. However, since there was a high correlation between income level and employment status, a regression model with employment status and worry was also significantly related to mammography adherence. Conclusions: In lesbians who are at an increased risk for breast cancer because of family history, breast cancer worries may motivate, rather than deter, adherence for mammography use. High income levels also appear to enable adherence in this population. Implications: Additional studies are needed to validate these findings, identify the prevalence of lesbians in general samples of women at increased risk for breast cancer, and prospectively test lesbian sensitive educational intervention strategies designed to facilitate adherence to mammography screening guidelines in this population.

Hematopoietic stem cell transplantation has been increasingly used to replace a defective hematopoietic system and to treat various genetic defects as well as malignant diseases. However, the limitations of conventional bone marrow transplantation have stimulated an intense interest in exploring the use of alternative sources of hematopoietic stem cells, including peripheral blood mononuclear cells (PBMC) and cord blood (CB). A major investigative effort of our laboratory has been focused on evaluating fetal bone marrow (FBM) for transplantation. The current study compares and characterizes the functional and phenotypic characteristics of FBM, CB, adult bone marrow (ABM), and PBMC by clonogenicity assays, immunogenicity, and the quantification of progenitor cells. There was a striking difference in the proportion of CD34+ cells in FBM, ABM, PBMC, and CB (24.6%, 2.1%, 0.5%, and 2.0%, respectively). The clonogenic potential, as measured by colony forming unit in culture (CFU-C) assay, was significantly higher in FBM when compared with ABM, PBMC, and CB (202.5, 73.5, 40.8, and 65.5 colonies/10(5) cells, respectively). There was a significant decrease in proliferative responsiveness in mixed lymphocyte reaction (MLR) assay of FBM and CB compared with ABM and PBMC. These observations indicate that each source of hematopoietic stem cells has different intrinsic properties closely correlated with ontogenetic age that is a vital determinant for phenotypic characteristics, lineage commitments, immunogenicity, and proliferative potentials.

Abstract Coexpression of epidermal growth factor receptor (EGFR) and c-erbB-2 in 47–68% of ovarian cancer cells indicate their strong association with tumor formation. We examined the effects of simultaneous antisense- or immunosuppression of EGFR and c-erbB-2 expression on the invasive phenotype, aneuploidy, and genotype of cultured human ovarian carcinoma cells (NIH:OVCAR-8). We report here that suppression of both EGFR and c-erbB-2 results in regression of aneuploidy and genomic imbalances in NIH:OVCAR-8 cells, restores a more normal phenotype, and results in a more normal gene expression profile. Combined with cytogenetic analysis, our data demonstrate that the regression of aneuploidy is due to the selective apoptosis of double antisense transfected cells with highly abnormal karyotype.

Genes associated with proliferation are active in stem and progenitor cells, and their over-expression can promote cancer. Two such genes, c-Myc and TGFα, promote morphologically dissimilar mammary tumors in transgenic mice. We investigated whether their over-expression affects population size and cell cycle activity in stem and other cell populations in non-neoplastic mammary epithelia. Results indicated that both cell population and cell cycle regulation are cell type- and microenvironment-specific. To create a tool for identifying and categorizing the five cellular phenotypes by light microscopy, we adapted previously established ultrastructural criteria. Using nulliparous MMTV-c-myc or MT-tgfα mice, we determined and compared the relative sizes the putative stem, progenitor and differentiated cell populations. PCNA staining was used to compare the portion of each cell population in the cell cycle. Cell population sizes were analyzed relative to: (1) their location in ducts versus lobules (microenvironment), (2) genotype, and (3) cell type. Population sizes differed significantly by genotype, depending on microenvironment (p = 0.0008), by genotype, depending on cell type (p < 0.0001), and by microenvironment, depending on cell type (p = 0.03). The number of cycling cells was also affected by all three factors, confirming that the interplay of cell type, gene expression and three-dimensional organization are very important in tissue morphogenesis and function. We describe a structure in mammary epithelium consistent with that of a stem cell niche, and show that it is altered in MMTV-c-myc and likely altered in MT TGFα transgenic epithelia.

Pre-clinical data suggest that combining imatinib with traditional cytotoxic chemotherapy may improve imatinib efficacy. We conducted a Phase I study of imatinib in combination with paclitaxel in patients with advanced or metastatic solid tumors.Patients were accrued to the study in a standard 3 + 3 design. Patients were restaged every two cycles, and those with stable disease (SD), or better, continued study treatment without interruption. Maximally tolerated doses (MTDs) and pharmacokinetic profiles of combination imatinib and paclitaxel were assessed.Fifty-eight patients were enrolled, including 40 in the Phase I dose escalation portion. Alternating dose escalation of imatinib and paclitaxel on a 28-day cycle resulted in MTDs of 800 mg imatinib daily, on days 1-4, 8-11, 15-18, and 22-25, and 100 mg/m(2) paclitaxel weekly, on days 3, 10, and 17. Two expansion cohorts, comprising 10 breast cancer patients and 8 patients with soft-tissue sarcomas, were enrolled at the MTDs. The most common adverse events were flu-like symptoms (64 %) and nausea/vomiting (71 %). The most common Grade 3/4 toxicities were neutropenia (26 %), flu-like symptoms (12 %), and pain (12 %). There were no relevant differences in the pharmacokinetic profiles of either drug when given in combination compared with alone. Thirty-eight subjects were evaluable for response, 18 (47.4 %) of whom experienced clinical benefit. Five patients (13.2 %) had a partial response (PR) and 13 patients (34.2 %) had SD; the average time to progression in those with clinical benefit was 17 weeks (range: 7-28 weeks).This combination of imatinib and paclitaxel was reasonably safe and tolerable, and demonstrated evidence of anti-tumor activity. Further exploration in disease-specific Phase II trials is warranted.

We hypothesized that pretreatment serum levels of insulin and other serum markers would predict Progression-free survival (PFS), defined as time to castration-resistant progression or death, in metastatic androgen-dependent prostate cancer (mADPC).Serum samples from treatment-naïve men participating in a randomized phase 3 trial of ADT +/- chemotherapy were retrospectively analyzed using multiplex assays for insulin and multiple other soluble factors. Cox proportional hazards regression models were used to identify associations between individual factor levels and PFS.Sixty six patients were evaluable (median age = 72 years; median prostate surface antigen [PSA] = 31.5 ng/mL; Caucasian = 86 %; Gleason score ≥8 = 77 %). In the univariable analysis, higher insulin (HR = 0.81 [0.67, 0.98] p = 0.03) and C-peptide (HR = 0.62 [0.39, 1.00]; p = 0.05) levels were associated with a longer PFS, while higher Hepatocyte Growth Factor (HGF; HR = 1.63 [1.06, 2.51] p = 0.03) and Osteopontin (OPN; HR = 1.56 [1.13, 2.15]; p = 0.01) levels were associated with a shorter PFS. In multivariable analysis, insulin below 2.1 (ln scale; HR = 2.55 [1.24, 5.23]; p = 0.011) and HGF above 8.9 (ln scale; HR = 2.67 [1.08, 3.70]; p = 0.027) levels were associated with longer PFS, while adjusted by OPN, C-peptide, trial therapy and metastatic volume. Four distinct risk groups were identified by counting the number of risk factors (RF) including low insulin, high HGF, high OPN levels, and low C-peptide levels (0, 1, 2, and 3). Median PFS was 9.8, 2.0, 1.6, and 0.7 years for each, respectively (p < 0.001).Pretreatment serum insulin, HGF, OPN, and C-peptide levels can predict PFS in men with mADPC treated with ADT. Risk groups based on these factors are superior predictors of PFS than each marker alone.

ABSTRACT For long-term central lines (CL), the lumen is the major source of central line-associated bloodstream infections (CLABSI). The current standard of care for maintaining catheter patency includes flushing the CL with saline or heparin. Neither agent has any antimicrobial activity. Furthermore, heparin may enhance staphylococcal biofilm formation. We evaluated the safety and efficacy of a novel nonantibiotic catheter lock solution for the prevention of CLABSI. Between November 2015 and February 2016, we enrolled 60 patients with hematologic malignancies who had peripherally inserted central catheters (PICC) to receive the study lock solution. The study lock consisted of 15 or 30 μg/ml of nitroglycerin in combination with 4% sodium citrate and 22% ethanol. Each lumen was locked for at least 2 h once daily prior to being flushed. After enrollment of 10 patients at the lower nitroglycerin dose without evidence of toxicity, the dose was escalated to the higher dose (30 μg/ml). There were no serious related adverse events or episodes of hypotension with lock administration. Two patients experienced mild transient adverse events (one headache and one rash) possibly related to the lock and that resolved without residual effect. The CLABSI rate was 0 on lock days versus 1.6/1,000 catheter days (CD) off lock prophylaxis, compared with a rate of 1.9/1,000 CD at the institution in the same patient population. In conclusion, the nitroglycerin-based lock prophylaxis is safe and well tolerated. It may prevent CLABSI when given daily to cancer patients. Large, prospective, randomized clinical trials are needed to validate these findings. (This study has been registered at ClinicalTrials.gov under identifier NCT02577718.)

The purpose of our study was to evaluate surgical enteric access in pediatric cancer patients to determine factors associated with postoperative complications. We performed a single-institution retrospective review of all patients below 21 years old with a primary cancer diagnosis who underwent surgical procedures for enteral access between 2004 and 2014. Multivariate logistic regression was performed to determine independent predictors of postoperative complications. During the study period, 122 patients had surgically placed feeding tubes, of whom 58% developed ≥1 complication(s) and 16% experienced a major complication. No single factor was significantly associated with developing any complication or major complication. Several trends were noted including increased complications associated with jejunostomy tubes, percutaneous endoscopic gastrostomy tubes, and abdominal radiation. Surgically placed enteric access in pediatric and adolescent cancer patients is associated with an extremely high complication rate emphasizing the importance of careful evaluation of these patients before embarking on surgical feeding access. Future work should evaluate mechanisms to decrease complications and/or explore alternative methods to provide supplemental nutrition in children and adolescents with cancer.

After therapy of localized gastric adenocarcinoma (GAC) patients, the costs of surveillance, relapse patterns, and possibility of salvage are unknown.We identified 246 patients, who after having a negative peritoneal staging, received therapy (any therapy which included surgery) and were surveyed (every 3-6 months in the first 3 years, then yearly; ∼10 CTs and ∼7 endoscopies per patient). We used the 2016 Medicare dollars reimbursed as the "costs" for surveillance.Common features were: Caucasians (57%), men (60%), poorly differentiated histology (76%), preoperative chemotherapy (74%), preoperative chemoradiation (59%), and had surgery (100%). At a median follow-up of 3.7 years (range, 0.1 to 18.3), the median overall survival (OS) was 9.2 years (95% CI, 6.0 to 11.2). Tumor grade (p = 0.02), p/yp stage (p < 0.001), % residual GAC (p = 0.05), the R status (p = 0.01), total gastrectomy (p = 0.001), and relapse type (p = 0.02) were associated with OS. Relapse occurred in 79 (32%) patients (only 8% were local-regional) and 90% occurred within 36 months of surgery. P/yp stage (p < 0.001) and total gastrectomy (p = 0.01) were independent prognosticators for OS in the multivariate analysis. Only 1 relapsed patient had successful salvage therapy. The estimated reimbursement for imaging studies and endoscopies was $1,761,221.91 (marked underestimation of actual costs).The median OS of localized GAC patients was excellent with infrequent local-regional relapses. Rigorous surveillance had a low yield and high "costs". Our data suggest that less frequent surveillance intervals and limiting expensive investigations to symptomatic patients may be warranted.

We present a modification to Simon's optimal design for phase II trials in which the objective is to minimize the median sample size rather than the expected sample size when the true response rate is poor p = p0. We argue that the modified design may be preferred in smaller institutions when the focus is on a single or small number of phase II trials rather than a large program of phase II trials. Control Clin Trials 1999;20:555–566

The frequencies of 30 HLA-DRB1∗13 alleles and 15 DRB3 alleles were determined for the 5 major U.S. ethnic populations: Caucasians, African Americans, Asian/Pacific Islanders, Hispanics, and Native Americans. A random sampling (163) of DRB1∗13-positive individuals from each self-described ethnic group was selected out of a pool of 82,979 unrelated individuals, providing at least an 80% probability of detecting a rare allele that occurred at 1%. These 815 samples were subjected to allele-level SSOP typing and/or DNA sequencing which identified 11 different DRB1∗13 alleles. DRB1∗1301 and DRB1∗1302 were the most common alleles seen in the five major ethnic groups while DRB1∗1304 was not detected among Caucasians and DRB1∗1305 was not detected among African Americans. DRB1∗13 allele diversity was surprisingly more limited among African Americans compared to both Caucasians and Asian/Pacific Islanders. To determine the extent of DRB1∗13-DRB3 associations, 504 of these samples expressing only one DRB3-associated DRB1 allele were subjected to PCR-SSOP typing and 14 DRB1∗13-DRB3 haplotypes were detected. The distribution revealed that African Americans were significantly different from Caucasians, Asian/Pacific Islanders, and Hispanics. Allele frequency studies such as this further support previous findings that the distribution of HLA types can differ significantly among different ethnic populations.

The frequencies of alleles in the HLA-DRB1*01 family were determined in each of five US populations from a database of 82,979 individuals. Individuals typed as DR1 (or DRB1*01) comprised between 7.6%-21.3% of the individuals in each population group. Fifty-nine DR1 individuals were randomly selected from each group and subjected to high-resolution DNA typing by polymerase chain reaction using sequence-specific oligonucleotide probes. DRB1*0101 was the most common allele in the Caucasian, Asian/Pacific Islander, and Native American groups while the DRB1*0102 allele was found in the majority of African Americans and Hispanics. DRB1*0103 was present at a similar frequency in all populations. DRB1*0104, DRB1*0105, and DRB1*0106 alleles were not observed.

Abstract Cytokine single nucleotide polymorphisms and consequent production levels have been associated with acute graft‐ vs ‐host disease (aGVHD) development. The aim of this pilot study was to determine whether polymorphisms in tumor necrosis factor ( TNF ), lymphotoxin alpha ( LTA ) and transforming growth factor beta 1 ( TGFB1 ) showed any association with aGVHD severity. Novel alleles and polymorphisms were identified for each cytokine locus. Genotype distributions were examined in 38 recipient–donor pairs (all chronic myelogenous leukemia in the first chronic phase) with either low‐grade (grades 0–I) or high‐grade (grades III–IV) aGVHD. Although no significant differences were found, some trends were noted in genotype distributions among aGVHD‐grade groups. Power calculations determined that substantially more pairs would be required to show significant associations in distributions among aGVHD‐grade groups.

Educating medical students in surgical subspecialty fields can be challenging, and the optimal timing and curriculum remain unknown. Despite advocacy for earlier exposure, competing core clerkship rotations often leave little time for subspecialty fields. We report our experience with a novel, short, and focused curriculum in surgical oncology for the third-year medical students.A 2-wk (2009-2010) and a 4-wk (2010-2011) curriculum in surgical oncology were developed for the third-year students at a tertiary-referral cancer center, including formal didactics, rotation in clinical service of students' choosing (breast, gastrointestinal, endocrine, or melanoma), and case-based learning and presentation. Paired pre- and postrotation questionnaires were prospectively completed, including 20 items assessing knowledge and four items assessing experience. Grading was anonymous, and change in score was assessed by Wilcoxon signed-rank test.Paired questionnaires from 47 students (2-wk rotation, n = 26; 4-wk rotation, n = 21) showed a median improvement of three points (21.4%) from pre- to posttests (P < 0.001). The improvement did not differ by the length of rotation or by the specific clinical service. Nearly all (93%) reported a positive and inspiring experience. The most valuable avenue of learning was reported as the time spent with resident or fellow or attending (92%), followed by self-directed reading (62%) and didactic lectures (28%).A short and focused curriculum in surgical oncology, including structured didactics and clinical rotation, had positive impact for the third-year students. Given the increasing work-hour limits, it is important to note that the time spent in the clinical setting continues to be ranked as the most educationally valuable by medical students.

Patients with metastatic gastroesophageal adenocarcinoma (MGEAC) have a poor but heterogeneous clinical course. Some patients have an unusually favorable outcome. We sought to identify clinical variables associated with more favorable outcomes.Of 246 patients with MGEAC, we identified 64 who received systemic therapy and eventually received local consolidation therapy. Univariate and multivariate Cox regression models were used, and a nomogram was developed.Of these 64 patients, 61% had received consolidation chemoradiation (CRT) with doses of 50-55 Gy and 78% did not undergo surgery. The median follow-up time of survivors was 3.9 years, and the median overall survival (OS) from CRT start was 1.5 years (95% CI, 1.2-2.2). Surgery (as local consolidation) was an independent prognosticator for longer OS in the multivariate analysis (p = 0.02). The 5-year OS rate was 25% (SE = 6%). The contributors to the nomogram were longer duration of systemic therapy before CRT and the type of local therapy.Our data suggest that a subset of patients with MGEAC have an excellent prognosis (OS >5 years). However, these patients need to be identified during their clinical course so that local consolidation (CRT, surgery, or both) may be offered.

A randomised phase 2 trial of trimodality with or without induction chemotherapy (IC) in oesophageal cancer (EC) patients showed no advantage in overall survival (OS) or pathologic complete response rate. To identify subsets that might benefit from IC, a secondary analysis was done.The trial had accrued 126 patients (NCT 00525915). Recursive partitioning and proportional hazards regression with interactions were performed.The median follow-up of surviving patients was 6.7 years and the median OS duration was 3.8 years (95% confidence interval (CI), 2.6-5.8 years). OS was associated with tumour length (P=0.03), cT (P=0.02), cN (P=0.04), clinical stage (P=0.01), and tumour grade (P<0.001). The effect of IC differed according to tumour grade. Among patients with well or moderately differentiated (WMD) ECs (n=59), the 5-year survival rate was 74% with IC and 50% without IC, P=0.001. IC had no effect on OS of patients with poorly differentiated (PD) ECs (31% and 28%, respectively; interaction, P=0.04; IC, P=0.03). In the multivariate reduced model, WMD with IC was an independent prognosticator for better OS (HR=0.41, 95% CI, 0.25-0.67; P=<0.001). The following four EC phenotypes emerged for OS: (1) very high risk (PD, cN2/N3), (2) high risk (PD, cN0/N1, stage cIII), (3) moderate risk (PD, cN0/N1, stage cI/II or WMD without IC), and (4) low risk (WMD with IC). The 5-year survival rates were 11%, 27%, 48%, and 74%, respectively (P<0.001).Our data show that IC significantly prolonged OS of WMD EC patients who undergo trimodality; prospective evaluation is needed.

The authors retrospectively determined the clinical outcome of patients with inflammatory breast carcinoma (IBC) treated with high dose chemotherapy (HDC) and autologous bone marrow (ABM) or peripheral blood stem cell (PBSC) support.Twenty-four consecutive patients with IBC received HDC, including escalating doses of carboplatin (range, 1.2-1.8 g/m2) and cyclophosphamide (range, 4.8-6.0 g/m2) over 3 days followed by ABM (n=5) or PBSC infusion (n=19). Restaging evaluation was performed 100 days after transplant, every 6 months for 2 years, and then yearly thereafter. After transplantation, fifteen patients received immunotherapy with interleukin-2 (IL-2) or IL-2 and interferon-alpha.The 2-year estimated disease free survival (DFS) and overall survival (OS) for these patients were 71% (90% confidence interval [CI], 55-87%) and 73% (90% CI, 53-93%), respectively. The median follow-up of surviving patients was 19 months (range, 8-68 months). Six patients developed disease recurrence at a median of 10 months (range, 4-16 months) after transplantation. Four of these 6 patients died from metastatic disease at a median of 18 months (range, 14-21 months). Using the generalized Wilcoxon test and the Cox proportional hazards regression model, patients with tumors that demonstrated estrogen receptors had an improved DFS (P=0.03).Combining HDC and ABM or PBSC for patients with IBC may yield an improved OS and DFS.

The frequency of each B*40 allele was determined by DNA sequencing in four major United States populations: Caucasians, African Americans, Asians/Pacific Islanders, and Hispanics. Thirty-two individuals from each ethnic group, who were previously described serologically as B40, B60, or B61, were randomly selected out of a pool of 82,979 unrelated individuals for allele characterization. Out of nine different B*40 alleles identified in this study, B*4001 and B*4002 were the two most frequent B*40 alleles in all the population groups. B*4001 was the primary B*40 allele seen in Caucasians (83%) and African Americans (76%), while B*4002 was found in the majority of Hispanics (62%). The distributions of both alleles were comparable in the Asian/Pacific Islander population. These two alleles were the only B*40 alleles detected in Caucasians while four to five additional B*40 alleles were seen in the other population groups. The other B*40 alleles detected in this study included: B*4003 and B*4010 in Asian/Pacific Islanders; B*4012 and B*4016 in African Americans; and B*4004, B*4006, and B*4027 in Hispanics. Analysis revealed significant differences between Hispanics and all other groups as well as between African Americans and Asian/Pacific Islanders. This report also describes five novel B*40 alleles: B*4019, B*4020, B*4024, B*4027, and B*4028.

One hundred sixty-one DRB1∗03 positive individuals from each of five U.S. population groups (Caucasoids, African Americans, Asians/Pacific Islanders, Hispanics, and Native Americans) were randomly selected from a database of 82,979 individuals. DRB1∗03 alleles were identified by polymerase chain reaction-sequence-specific oligonucleotide probe typing. A total of six DRB1∗03 alleles out of 21 known alleles were detected. DRB1∗03011 was the predominant DRB1∗03 allele in all populations. Caucasoids were found to be the least diversified; only DRB1∗03011 was observed. African Americans carried DRB1∗03021 at a high frequency. This allele was observed in three other populations. DRB1∗0304 was found in Asians/Pacific Islanders and DRB1∗0305, DRB1∗0307 and a new allele, DRB1∗0316, was found in Hispanics. A subset of individuals was also typed for DRB3 alleles. DRB3∗0101, DRB3∗0202, and DRB3∗0301 were detected and seven DRB1-DRB3 haplotypes were defined. Testing of other individuals not included in the DRB1∗03 frequency study identified a variation of a common extended haplotype, A1, B8, DR3, which carries DRB1∗0304 and two previously unreported DRB1∗03 alleles, DRB1∗0311 and ∗0320, are also described.

In an attempt to reduce the high relapse rate associated with ABMT, five children with high-risk first CR and 19 in second or subsequent CR lacking matched family allogeneic donors underwent ABMT with chemopurged bone marrow utilizing verapamil (VPL), vincristine, and VP-16. Patients were conditioned with TBI, VPL bolus and infusion with VP-16 and cyclophosphamide. The first cohort of patients (n = 4) received only cyclosporin A (CsA). The second cohort (n = 7) received CsA and alpha interferon (total = 11 with post-transplant immunotherapy alone.) The third cohort (n = 13) received CsA and six alternating cycles of alphaIFN and chemotherapy and six additional cycles of chemotherapy (vincristine, VP-16, Ara-C, prednisone) followed by G-CSF (post-transplant immune chemotherapy (PTIC)). The 2-year DFS is 42+/-10% (90% confidence interval (CI) is 26.5-58.5%) and 2-year overall survival is 54+/-10% (90% CI is 37.5-70.5%). Furthermore, patients receiving PTIC (n = 13) vs immunotherapy alone (CsA+/-aIFN) (n = 11) had a substantially better 2 year DFS and OS: 69+/-13% vs 13+/-12% and 85+/-10% vs 25+/-15% (P = 0.008 and P = 0.06, respectively). These results suggest that the use of ABMT with chemopurging, combined with PTIC is well tolerated and may be an alternative new approach in the treatment of a subset of children with high-risk first CR or > or = second CR ALL who lack closely matched family-related allogeneic donors.

3502 Background: Inhibitors of poly(ADP-ribose) polymerase (PARP), such as ABT-888 are potent sensitizing agents for, and have been safely combined with DNA-damaging chemotherapeutic agents such as temozolomide (TMZ). The sensitizing effects of PARP inhibitors are magnified when cancer cells harbor underlying defects in DNA repair mechanisms. Methods: We performed a single arm, open label phase II study. Patients with metastatic, unresectable colorectal cancer (CRC) whose disease had progressed on all standard therapies were eligible. Patients received TMZ (150mg/m2 orally daily) days 1-5, and ABT-888 (40mg orally twice-a-day) days 1-7 of each 28-day cycle. Restaging studies were performed every 8 weeks. The primary endpoint was the disease control rate (DCR), defined as complete response, partial response (PR), or stable disease (after two cycles). This trial followed a Simon’s two-stage optimal design using p0=0.10 and p1=0.25 and type I and II errors of 0.10. Secondary clinical endpoints included response rate (RR) and time to progression (TTP). Archived tumor specimens were used for immunohistochemistry (IHC) to assess mismatch repair enzyme (MMR) and PTEN protein expression. Results: Between 09-2010 and 01-2011, 47 patients received treatment. The median age was 54, and most patients had an ECOG PS of 1. The average number of prior therapies was 4. The combination of ABT-888 plus TMZ was very well tolerated. There were only five grade 3 adverse events, all related to myelosuppression, which resolved with a one week treatment delay. The primary endpoint was successfully met, with a DCR of 23%. There were two confirmed PRs, for a RR of 5%. The median TTP was 11 weeks overall, but was 23 weeks in the patients who had disease control. 45 archived tumor samples were obtained, and the results of IHC for the MMR and PTEN proteins will be reported. Conclusions: In this heavily pretreated CRC patient population, the combination of ABT-888 and TMZ was very well tolerated and exhibited clinical activity. Further molecular analyses of patients’ tumor samples, and enrollment of a 20 patient MMR-deficient expansion cohort may help identify which patient subgroups are most likely to respond to therapy.

The frequencies of 29 HLA-DRB1*04 alleles were determined for five major U.S. populations found within a hematopoietic stem cell volunteer donor registry. One hundred sixty-one DRB1*04 positive individuals from each of the self-described groups, Caucasians, African-Americans, Asian/Pacific Islanders, Hispanics, and Native Americans, were randomly chosen from a database of 82,979 unrelated persons. Subjected to polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) typing, these 805 individuals carried a total of ten different DRB1*04 alleles, ranging from DRB1*0401 to DRB1*0411 with DRB1*0409 conspicuously absent from all five groups. The distribution of DRB1*04 alleles varied among the groups, with DRB1*0401 being predominant in Caucasians, African-Americans, and Native Americans. DRB1*0404 and DRB1*0407 were the two most commonly observed alleles in Hispanics, whereas DRB1*0405 and DRB1*04031 were most common in Asian/Pacific Islanders. The remaining 18 DRB1*04 alleles known at the time of the study were not observed. Although not observed in the frequency study, seven previously unreported DRB1*04 alleles are also described.

Pediatric patients with solid tumors treated with prolonged dose-intensive chemoradiotherapy are poor mobilizers of peripheral blood stem cells (PBSC). We have conducted a pilot study to mobilize PBSC in eight pediatric patients with relapsed solid tumors using ifosfamide, carboplatin, and etoposide (ICE) followed-up by IL-11 plus granulocyte colony-stimulating factor (G-CSF).Patients received ifosfamide 1.8 g/m2 per day for 5 days, carboplatin 400 mg/m2 per day for 2 days, and etoposide 100 mg/m2 per day for 5 days. After completion of ICE chemotherapy, patients received daily subcutaneous injections of G-CSF (5 microg/kg per day) and IL-11 (50-100 microg/kg per day) until peripheral stem cell apheresis.The median age was 11 years. Diagnosis included three relapsed Hodgkin disease, three relapsed central nervous system tumors, one relapsed Wilms tumor, and one relapsed rhabdomyosarcoma. The median number of apheresis procedures required to obtain 5 x 10(6) CD34+ cells/kg was one. The mean +/- standard error of mean (SEM) total CD34+ cells collected was 14.0+/-2.7 x 10(6)/kg. The mean +/- SEM total CD34+/CD41+ cells collected was 4.6+/-1.9 x 10(6)/kg. Seven of the eight patients have subsequently undergone myeloablative chemotherapy with autologous PBSC transplantation and have reconstituted hematopoiesis with a median time to neutrophil recovery of 10 days and platelet recovery of 15.5 days.We conclude that the regimen of ICE/IL-11 plus G-CSF is successful in mobilizing large numbers of CD34+ PBSC cells with a limited number (one) of apheresis collections in patients that have previously been heavily pretreated with chemotherapy/radiotherapy.

The frequency of each A*28 allele was determined by PCR-SSOP typing in 5 major U.S. ethnic populations: Caucasians, African Americans, Asians/Pacific Islanders, Hispanics, and Native Americans. The percent of serologically defined A28-positive individuals in the 5 populations ranged from 2.7-17.9%. Fifty-nine individuals who were previously serologically typed as A28, A68 or A69 were randomly chosen for allele-level typing from each ethnic group from a database of 82,979 consecutively typed unrelated individuals. The most common A*28 allele for Caucasians, Asians/Pacific Islanders, Hispanics, and Native Americans was A*68012, while A*6802 was found in the majority of African Americans. Only four and three A*28 alleles were seen in Caucasians and African Americans, respectively, while five to six A*28 alleles were seen in the other population groups. The A*6804 and A*6806 alleles were not observed in any of the five ethnic groups.

One hundred sixty-one individuals from each of five US population groups, Caucasians (CAU), African Americans (AFA), Asians/Pacific Islanders (API), Hispanics (HIS), and Native Americans (NAT), were randomly selected from a volunteer bone marrow registry database consisting of 14,452 HLA-DRB1*11 positive individuals. This sampling provided at least an 80% probability of detecting a rare allele that occurred at 1% in the DRB1*11 positive population. Samples were typed for DRB1*11 alleles by polymerase chain reaction-sequence specific oligonucleotide probe typing (PCR-SSOP). A total of 10 DRB1*11 alleles out of 27 possible alleles were detected. The distribution and diversity of DRB1*11 alleles varied among populations although DRB1*1101 was the predominant DRB1*11 allele in all populations. Caucasians were the least diversified; only four common alleles (DRB1*1101-*1104) were observed. As well as the four common alleles, other groups also carried one or two other less frequent alleles including DRB1*1105 (API), *1106 (API), *1110 (AFA), *1114 (HIS), *1115 (NAT), and *1117 (AFA). A subset (418) of these individuals were also typed for DRB3 alleles. Most (97.6%) showed a strong association of DRB1*11 with DRB3*0202.

Abstract: At least 59 DRB1*14 positive individuals from each of four U.S. population groups, Caucasoids, African Americans, Asians/Pacific Islanders, and Hispanics, were randomly selected from a database of 82,979 individuals. DRB1*14 alleles were identified by DNA sequence analysis using intron‐specific primers to obtain complete exon 2 sequences. Only 23% of the known DRB1*14 alleles were detected. DRB1*14011 was the predominant DRB1*14 allele in three populations while Hispanics carried DRB1*1402 and DRB1*1406 more frequently. Asians/Pacific Islanders were the most diversified carrying seven alleles. DRB3*0101, DRB3*02021 and DRB3*0210 were detected in a subset of individuals typed for this locus and 15 DRB1‐DRB3 haplotypes were defined. This study completes the exon 2 sequences of previously identified alleles, DRB1*1405‐*1408, including the identification of two silent codon 90 variants of DRB1*1407. In addition, two new DRB1*14 alleles, DRB1*1441 and DRB1*1442, are described.

4520 Background: Since ipi and nivo use distinct mechanisms for T cell activation and bev promotes antigen presentation, we hypothesize that nivo+bev or nivo+ipi would safely lead to measurable immunologic changes and improved clinical activity in MRCC. Methods: In this open-label, randomized trial (NCT02210117), adults with MRCC w/o prior immune checkpoint therapy and anti-VEGF therapy were enrolled and randomized 2:3:2 to receive nivo, nivo+bev or nivo+ipi, followed by surgery (CN or MS), or Bx, and subsequent nivo maintenance therapy up to 2 years. Response was assessed at ≥12 weeks. Pre- and post-treatment blood and tumors were obtained for correlative studies. Results: One hundred patients have been accrued and 90 are evaluable for responses (table below, W = withdrawal; BOR = Best overall response; BRES = Best Response excluding surgical effect). Clinical trial information: NCT02210117. BOR was 50% complete response (CR) + partial response (PR) nivo, 48% CR+PR nivo+bev, 39% CR+PR nivo+ipi. For patients getting surgery, BOR was: 77% nivo, 93% nivo+bev, and 70% nivo+ipi. Grade 3 or 4 toxicities were 30% for nivo, 45% for nivo+bev (including 18% bev-specific hypertension), and 57% for nivo+ipi. We identified a number of immune signatures in relation to clinical responses. Conclusions: Patients able to stay on therapy and receive surgery had BOR ranging from 70%-93%. Combination therapy nivo ± [bev or ipi] plus cytoreductive surgery deserves to be tested in a larger phase 3 trial for MRCC. We will also report correlative biomarker data. Nivo (N = 26) Nivo+Bev (N = 38) Nivo+Ipi (N = 26) CR PR SD PD W CR PR SD PD W CR PR SD PD W All Patients BOR 1 (4%) 12 (46%) 5 (19%) 7 (27%) 1 (4%) 1 (3%) 17 (45%) 7 (18%) 11 (29%) 2 (5%) 1 (4%) 9 (35%) 2 (8%) 13 (50%) 1 (4%) BRES 0 10 (38%) 8 (31%) 7 (27%) 1 (4%) 0 14 (37%) 11 (29%) 11 (29%) 2 (5%) 0 7 (27%) 4 (15%) 14 (54%) 1 (4%) Patients with Surgery BOR 1 (8%) 9 (69%) 2 (15%) 1 (8%) 0 1 (8%) 11 (85%) 1 (8%) 0 0 1 (10%) 6 (60%) 2 (20%) 1 (10%) 0 BRES 0 7 (54%) 5 (38%) 1 (8%) 0 0 8 (62%) 5 (38%) 0 0 0 4 (40%) 4 (40%) 2 (20%) 0 Patients without Surgery BOR 0 3 (23%) 3 (23%) 6 (46%) 1 (8%) 0 6 (24%) 6 (24%) 11 (44%) 2 (8%) 0 3 (19%) 0 12 (75%) 1 (6%)

Nearly 50% of gastric cancer patients are diagnosed with advanced gastric cancer (AGC). Therapy is palliative but results in ill effects. The median overall survival (OS) of AGC patients is often <12 months. It is unclear if the early initiation of therapy in all AGC patients is beneficial.A retrospective analysis of AGC patients in our database was carried out. The patients were divided into two groups: asymptomatic or symptomatic. We sought to assess whether the delay of systemic therapy was harmful in asymptomatic patients.A total of 135 patients were analyzed. Most patients were symptomatic (68%), males (67%), and had low ECOG scores (0-1; 85%). In univariate analyses, ECOG performance status 0 (p = 0.005), delayed initiation of therapy (p = 0.03), and lack of symptoms (p = 0.03) were associated with a longer OS. The multivariate model for OS identified only ECOG performance status as an independent prognosticator of longer OS (p = 0.02). Asymptomatic patients who had delayed (≥ 4 weeks) systemic therapy had an OS rate of 77% at 1 year compared to 58% for patients treated within 4 weeks (p = 0.47).Symptomatic AGC patients had a poor outcome compared to asymptomatic AGC patients. Treatment delay in asymptomatic patients had no detrimental effect on OS, suggesting that the timing of therapy can be based on patient selection.

At least 60 DRB1*02 positive individuals from each of four US population groups found within a hematopoietic stem cell volunteer donor registry - Caucasoids, African Americans, Asians/Pacific Islanders, and Hispanics - were randomly selected from a database of 82,979 individuals. DRB1*02 alleles were identified by DNA sequencing. A total of five of 23 known DRB1*02 alleles were detected. DRB1*15011 was the predominant DRB1*02 allele in Caucasoids and Hispanics. The most common DRB1*02 allele observed in African Americans was DRB1*1503, and DRB1*15021 in Asians/Pacific Islanders. Caucasoids were found to be the least diversified; only DRB1*15011 and DRB1*16011 were observed. A subset of individuals was also typed for DRB5 alleles by DNA sequencing. DRB5*01011, DRB5*0102, DRB5*0103, DRB5*0108N and DRB5*0202 were detected and nine DRB1-DRB5 haplotypes defined.

e16524 Background: In patients with muscle-invasive bladder cancer (MIBC), especially those with high risk features including lymphovascular invasion, hydronephrosis, T3b disease, or variant histology, cisplatin-based neoadjuvant chemotherapy followed by cystectomy improves overall survival as compared to cystectomy alone. However, it is estimated that over 50% of patients with MIBC are ineligible for cisplatin-containing therapy. Therefore, we propose to use durva plus treme as neoadjuvant therapy for this population of patients. Methods: We carried out a single-arm, pre-surgical clinical trial with durva + treme in patients with localized, high-risk MIBC who are ineligible for cisplatin-containing chemotherapy due to decreased renal function, neuropathy, hearing loss, or heart failure (NCT02812420). Each patient will receive durva (1500 mg) plus treme (75 mg) on weeks 1 and 5. Patients will then undergo surgery at week 9-11. Pre- and post-treatment blood and tumor samples will be collected for immunological and genomic analyses for clinical correlation. Results: Twelve patients have been enrolled on this trial. Six patients have completed cystectomy as of January 30, 2018. Of these 6 patients, 3 (50%) had pathologically complete response (pCR); one (17%) did not respond; two (33%) had upstaging of disease. Of the two upstaged patients, one was found to have tumor progression in a pre-existing pelvic lymph node and was taken off trial, treated with chemotherapy, then had cystectomy with pCR. Only 1 of 12 patients developed grade 3 immune related toxicity. Immunologic and molecular analyses are ongoing on all collected samples. Conclusions: To date, out data indicate that durva plus treme may be an effective and well tolerated neoadjuvant therapy for patients with MIBC ineligible for cisplatin-based therapy. Based upon these data, we have expand this pilot trial from 15 to 35 patients. We will also report correlative biomarker data. Clinical trial information: NCT02812420.

Electromagnetic trackers have found inroads into medical applications as a tool for navigation in recent years. Their susceptibility to interference from both electromagnetic and ferromagnetic sources have prompted several accuracy assessment studies in past years. To the best of our knowledge, this is the first accuracy study conducted to characterize measurement accuracy of an NDI AURORA electromagnetic tracker within a CyberKnife radiosurgery suite. CyberKnife is a frameless, stereotactic radiosurgery device used to ablate tumors within the brain, spine and in recent years, the chest and abdomen. This paper uses a data collection protocol to collect uniformly distributed data points within a subset of the AURORA measurement volume in a CyberKnife suite. The key aim of the study is to determine the extent to which large metal components of the CyberKnife stereotactic radiosurgery device and robot mount contribute to overall system performance for the AURORA electromagnetic device. A secondary goal of the work is to determine the variation in accuracy and device behavior with the presence of ionizing radiation when the LINAC is turned on.

Abstract Background: Studies are focusing on agents which may overcome endocrine therapy resistance in patients with hormone receptor positive (ER/PR+) MBC. Activation of the Ras-Raf-MAPK pathway has been proposed as a mechanism of resistance to AIs. Thus, we are evaluating the use of sorafenib (SOR), a multi (Raf)-kinase inhibitor targeting both tumor cells and the tumor vasculature in patients with AI-resistant MBC.Methods: We are conducting a phase I/II study of SOR in combination with anastrozole 1 mg po daily (ANT) in MBC patients utilizing an optimal 2-stage design. Eligible patients include post-menopausal women with ER/PR+ MBC with disease recurrence or progression on an AI. Participants may not have received &amp;gt; 2 prior chemotherapies for MBC. Primary objectives are to determine the recommended dose and clinical benefit rate (CBR) (CR, PR and SD ≥ 24 weeks) of SOR with ANT. Secondary objectives are to determine toxicity, enumerate circulating endothelial cells (CECs) as an angiogenesis biomarker, and analyze the effect of treatment on CYP3A4-metabolized steroids.Results: 0/3 patients in cohort 1 (200mg BID) and 0/3 in cohort 2 (400mg BID) had dose-limiting toxicities in cycle 1. Thus, our recommended Phase II dose of SOR was 400 mg BID. Interim analysis of the first 12 patients showed &amp;gt;30% CBR, allowing for continued accrual to planned 35 patients. All patients had ECOG PS of 0-2. The median age was 55 years. Among 35 enrolled patients, 5 had stable disease for &amp;gt; 24 weeks, 2 had durable PR &amp;gt; 6 months, and 19 had progressive disease before 6 months. 8 patients were not response-evaluable. 1 patient on active therapy is too early to evaluate response. Clinical benefit rate is 20%. Adverse events (AEs) were generally Grade 1/2. The most common AEs (all; Grade 3/4) were fatigue (66%; 14%), diarrhea (54%; 6%), nausea/vomiting (60%; 9%), and skin rash of any kind (66%; 43%) including hand-foot syndrome (57%; 34%). G3/4 hypertension occurred in 11%. Preliminary analysis suggests that decrease in CECs from baseline to 1 week after treatment predicts for a response. Correlative science analyses are ongoing.Conclusions: The combination of SOR and ANT in patients with ER/PR+ AI-resistant MBC demonstrated an encouraging 20% CBR and is worthy of further study. A decrease in CECs appears to predict response. Toxicity with 400 mg po bid SOR occurred frequently but was manageable with dose reductions. Given the negligible activity of single-agent SOR in MBC, we believe that the benefit may be attributable to the restoration of sensitivity to AIs through inhibition of the Ras-Raf-MAPK pathway. Supported Patient for Progress Award 3 P30CA051008-15S3 and Sorafenib provided by CTEP-NCI. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3090.

Maintenance chemotherapy is not routinely used in gastrointestinal (GI) cancers. Capecitabine is an oral formulation that is enzymatically converted to 5-fluorouracil preferentially in tumor tissue. We hypothesize that capecitabine could be used as a long-term maintenance therapy to improve outcomes in patients with high-risk GI cancers following standard chemotherapy regimens.We conducted a retrospective study to assess the toxicity of maintenance capecitabine in 28 patients with a variety of advanced GI malignancies. Capecitabine 1,000 mg twice daily without interruption was used for the first 11 patients. The dose was reduced to 1,000 mg twice daily 5 days per week in 8 patients who developed hand-foot syndrome. The remaining patients began treatment on the same abbreviated schedule. All documented clinical adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (v3.0, 2003).Main toxicities were grade 1/2 fatigue and hand-foot syndrome. Only one grade 3 toxicity was observed and no grade 4 toxicities were seen. We also observed a significant increase in red blood cell mean corpuscular volume in participants, which may have potential use as a biomarker to monitor therapeutic response.Fixed therapeutic doses of oral capecitabine 1,000 mg twice daily, 5 days on, 2 days off, can be administered chronically with a high level of safety and should be explored in larger prospective studies to demonstrate efficacy in GI malignancies, especially pancreatic and metastatic colorectal cancers.

TPS170 Background: Inhibitors of Poly(ADP-ribose) polymerase (PARP) are potent sensitizing agents for DNA-damaging chemotherapeutic agents such as the platinum analogs. The sensitizing effects of PARP inhibitors are magnified when cancer cells harbor defects in DNA repair enzymes including BRCA-2, FANCD2, PTEN, and the mismatch repair proteins, and DNA repair defects occur often in patients with pancreatic cancer. ABT-888 is a novel small molecule PARP inhibitor that demonstrates PARP inhibition, in vivo, and has synergistic anti-cancer activity when combined with oxaliplatin, in pre-clinical models. Methods: We have initiated an open label Phase I/II study. Patients with metastatic, unresectable pancreatic cancer who have an adequate performance status and normal hepatic and renal function will be eligible. Patients will receive mFOLFOX-6 (oxaliplatin (85mg/m2), leucovorin (400mg/m2) and 5-FU (400mg/m2) on day 1, followed by a continuous infusion of 5-FU (2400mg/m2) over 46 hours on days 1-3). Patients will also receive ABT-888 orally twice-a-day on Days 1-7 of each 14-day cycle. Patients will be restaged every 4 cycles (every 8 weeks). The Phase I portion will be a traditional 3+3 dose escalation of ABT-888, from 40mg to 100mg twice daily. The Phase II portion is designed as two parallel studies: Arm A for previously untreated patients; Arm B for patients who have received one or more prior therapies for metastatic disease. The primary endpoint is objective response rate (ORR), and each Arm will follow a Simon’s two-stage optimal design. For each Arm, 9 patients will be accrued in the first Stage, and up to 24 patients in the second Stage. The sample sizes of 9 and 24 patients and the decision rules, in Stages 1 and 2 respectively, are designed to differentiate a 5% ORR from a 25% ORR at a 1-sided 10% significance level and 90% power. Secondary clinical endpoints include disease control rate (CR+PR+SD at 6 months), progression free survival, and overall survival. In addition, each patient will undergo a fresh tumor biopsy to assess the expression of a panel of DNA repair proteins, including those listed above. The trial opened in January, 2011 and has accrued the first cohort.

Abstract Background: Immune checkpoint blockade including anti-CTLA-4 (ipilimumab, BMS) and anti-PD1 (nivolumab, BMS) as monotherapies have been known to have clinical activity against metastatic renal cell carcinoma (MRCC), but with relatively low clinical response rate (10-25%). Anti-VEGF antibody bevacizumab is a standard therapy for MRCC also with a low response rate (&amp;lt;20%). Since anti-PD1 and anti-CTLA-4 use distinct mechanisms for T cell activation and bevacizumab can promote the function of antigen presenting cells, we hypothesize that combination therapy with nivolumab + bevacizumab or nivolumab + ipilimumab will lead to measurable immunological changes and improved clinical activity. Methods: In this open-label, pilot, pre-surgical/pre-biopsy trial (NCT02210117), adults with MRCC without prior immune checkpoint therapy and anti-VGEF therapy were enrolled, stratified by planned surgical procedure, and randomized 1:2:1 to receive nivolumab monotherapy, nivolumab + bevacizumab or nivolumab + ipilimumab, followed by cytoreductive nephrectomy, metastasectomy, or post-treatment biopsy, and subsequent maintenance therapy with nivolumab for up to 2 years until disease progression and intolerable toxicity. Pre- and post-treatment blood and tumor samples were obtained for dynamic monitoring of immune and molecular correlates to clinical activity. Results: Sixty patients were treated (median duration 17.1 weeks, range 2.74 to 85.1 weeks as of 12/6/16). Fourty-four were evaluable for clinical responses post-procedures. Five of 12 (42%) nivolumab monotherapy treated patients had partial response (PR), 4 (33%) had stable disease (SD), and 3 (25%) had progression of disease (PD) and 0 withdrew early (W). In the nivolumab + bevacizumab arm, 1 of 19 (5%) had complete response and 9 (47%) patients had PR, for a response rate of 53%, 3 (16%) had SD, 3 (16%) with PD and 3 (16%) W. In the nivolumab + ipilimumab arm, 5 of 13 (38%) patients had PR, 1 (8%) had SD and 5 (38%) had PD and 2 (15%) W. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Grade 3 or higher toxicities were 19% in the nivolumab arm, 41% in the nivolumab + bevacizumab arm (including 17% bevacizumab-specific hypertension that was well controlled by anti-hypertensive medications), and 27% in the nivolumab + ipilimumab arm. Correlative laboratory studies including flow cytometry, IHC, and gene profiling analysis identified a number of immune gene signatures including an IFN-γ gene signature that we will report in more details. Conclusions: Combination therapy with nivolumab + bevacizumab and nivolumab + ipilimumab showed promising clinical activities in patients with MRCC. Immune and molecular correlative studies may allow us to identify novel biomarkers that can be used for correlation with clinical outcomes in patients with MRCC. Citation Format: Jianjun Gao, Jose A. Karam, Christopher G. Wood, Surena Matin, Kamran Ahrar, Eric Jonasch, Nizar Tannir, Matthew Campell, Chaan S. Ng, Rebecca S. Slack, Priya Rao, James P. Allison, Jorge M. Blando, Luis M. Vence, Sreyashi Basu, Hao Zhao, Tenghui Chen, Hong Chen, Padmanee Sharma. Clinical activity, immune and molecular correlates of nivolumab vs. nivolumab plus bevacizumab vs nivolumab plus ipilimumab in metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT083. doi:10.1158/1538-7445.AM2017-CT083

Ex vivo activation of peripheral blood stem cells (PBSC) using interleukin-2 (IL-2) results in cytotoxic effector cells that may possess beneficial in vivo effects. We proposed to evaluate ex vivo stimulation of PBSC using various cytokines alone or in combination to optimize their function. Cytokine-activated PBSC were analyzed for tumor-directed cytotoxicity and their ability to remove tumor cells from long-term clonogenic assays. Mononuclear cells were obtained from the apheresis products of normal donors and cultured with IL-2 (1000 U/ml), interferon-alpha (IFN-alpha) (1000 U/ml), or IL-12 (50 U/ml) either alone or in combinations at 37 degrees C and 5% CO(2) for 24 h. Colony-forming unit-tumor (CFUT) assays were initiated using cytokine-activated PBSC with varying concentrations of MCF-7 or SKBR-3 human breast cancer cells. Standard 4-h (51)Cr-release assays were performed with cytokine-activated PBSC using MCF-7 or SKBR-3 cells as targets. Activation of PBSC with IL-2, IFN-alpha, or IL-12 resulted in enhanced cytotoxicity against the two breast cancer cell lines when compared to controls. PBSC activated with IL-2 and IFN-alpha or IL-2 and IL-12 were more cytotoxic than PBSC activated with single cytokines (p = 0.0004 for MCF-7 cells and p < 0.001 for SKBR-3 cells). Using clonogenic assays, IL-2-activated PBSC reduced the number of CFU-T to a greater extent than did IL-12 or IFN-alpha-activated PBSC (p = 0.0006). However, PBSC activated with a combination of IL-2 and IFN-alpha or IL-2 and IL-12 demonstrated 95% and 90% reductions, respectively, compared to 79% reduction using IL-2-activated PBSC (p < 0.0001). The greatest reduction in cytotoxicity occurred in the cell populations depleted of CD56(+) cells (p = 0.016) and CD8(+) CD56(+) cells (p = 0.002), suggesting that the effector cell population includes a combination of cytotoxic CD8(+) T cells and CD56(+) natural killer cells. These results demonstrate that the ex vivo activation of PBSC with cytokines, either alone or in combination, enhances cytotoxicity against, and removal of two human breast cancer cells. The combinations of IL-2 with IFN-alpha or IL-12 are most beneficial in cytotoxicity and purging assays. These results could play an important role in designing adoptive cellular immunotherapy clinical trials in the autologous hematopoietic stem cell transplant setting.

e16038 Background: Duration of response to androgen-deprivation therapy (ADT) is highly variable in patients with mADPC and prognostic markers are needed. Insulin resistance and hyperinsulinemia may contribute to prostate cancer progression. We hypothesized that pretreatment serum insulin levels would predict time to castration-resistant progression (PFS) and overall survival (OS). Methods: Sera from men treated on a randomized phase 3 trial of first line ADT vs. ADT plus chemotherapy were retrospectively analyzed using a multiplex ELISA for cytokines and angiogenic factors (CAFs). Univariate and multivariate Cox proportional hazards regression models were used to identify associations between CAFs and PFS/OS. Results: 66 pts were evaluable, 86% Caucasian, median age 72 yrs, median PSA 31.5ng/mL, 77% Gleason score of ≥8, and 53% high volume metastatic disease (HVM). Thirty-five pts received ADT; 31 pts received ADT+chemo. In univariate analysis, higher pretreatment insulin and C-peptide were positively correlated with PFS, whereas higher hepatocyte-growth factor (HGF), osteopontin (OPN) and HVM were negatively correlated with PFS. In multivariate analysis, only higher insulin was associated with longer PFS (HR=0.72, 95%CI 1.32 -0.87; p&lt;0.001), whereas higher HGF and OPN were associated with reduced PFS (HR=1.82, 95%CI 0.59-2.83, p&lt;0.01 and HR=1.81, 95%CI 1.18-2.47, p&lt;0.001, respectively). Higher Insulin and Program Death 1 (PD1) were associated with longer OS on multivariate analysis (HR=0.78 p&lt;0.02 and HR=0.55 p&lt;0.02, respectively), whereas HVM and higher OPN were associated with reduced OS (HR=2.28 p&lt;0.01 and HR=1.60 p&lt;0.02). Using low insulin, high HGF and high OPN as 3 independent risk factors (RF), 3 distinct risk groups could predict PFS: good (zero RF), intermediate (1 or 2 RF) and poor risk (3 RF), with median PFS of 6.90, 1.97, and 0.86 years, respectively (p&lt;0.001). Conclusions: Higher pretreatment insulin was associated with prolonged PFS and OS in men with mADPC treated with ADT. Our data suggest that insulin levels are a biomarker for sensitivity to ADT and highlight the complex interactions between metabolism and PCa progression.

Implicationsof assessing the proximal and far para-tracheal or sub-carinal nodes (para-tracheal [PTN] or sub-carinal [SCN]) associated with lower primary esophageal carcinomas (ECs) are unclear.To evaluate the value of endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) for PTN and SCN, we analyzed results by positron emission tomography (PET) avidity, 4 EUS node malignancy features, and EUS-FNA results in all patients with Siewert's I or II EC.Of 133 patients (PTN, n=102; SCN, n=31) with EUS-FNA, 47 (35%) patients had malignant node, leading to treatment modifications.EUS-FNA diagnosed significantly more patients with malignant nodes (p=0.02) even when PET and EUS features were combined.Among 94 PET-negative and EUS-negative patients, 9 (10%) had malignant EUS-FNA.At a minimum follow-up of 1 year, only 3 (5%) of 62 patients with benign EUS-FNA had evidence of malignancy in the nodal area of prior EUS-FNA.Patients with malignant EUS-FNA independently had a much shorter overall survival (OS) than those with benign EUS-FNA (p<0.001).Our data suggest that a benign EUS-FNA is highly accurate and need not be pursued further.However, malignant EUS-FNA of PTN/SCN was independently prognostic, conferred a shorter OS, and altered the management of 35% of patients.

To characterize the depiction of protective eyewear use in scripted children's television programs.Viewership ratings data were acquired to generate a list of the most-watched scripted broadcast and cable programs for the 2- to 12-year-old age group. The three highest average viewership programs from broadcast and cable programming that met the inclusion criteria were analyzed by two independent reviewers.Review of 30 episodes revealed a total of 244 exposure-scenes in which an individual was engaged in an activity requiring eye protection. There were 5.5 (mean = 8.1) exposure-scenes per episode, with 26 of 30 (87%) episodes containing at least one exposure-scene. There were 19 depictions of protective eyewear use (8% of total exposure-scenes). Fifteen of the 19 cases of protective eyewear use occurred on broadcast programming. Six eye injuries were depicted in the media content.The depiction of protective eyewear use during eye-risk activities is rare in scripted children's television programs and eye injuries are rarely depicted.

<h3>Background</h3> Recent studies have demonstrated a high prevalence of pharyngeal (P) and rectal (R) <i>Neisseria gonorrheae</i> (GC) and <i>Chlamydia trachomatis</i> (CT) infections among men who have sex with men (MSM), which is concerning given the potential for harmful sequelae and their relationship to increased HIV transmission. CDC guidelines advocate testing MSM at least annually for these infections, but surveys of medical providers suggest that adherence to these guidelines is minimal. Because providers cite limited time and staff as common reasons for not following the guidelines, we evaluated the feasibility and accuracy of performing self-administered testing for GC and CT. <h3>Methods</h3> 286 clients who attended Whitman-Walker Clinic in Washington, DC for HIV/STI testing participated in the study. Enrolled clients had a mean age of 36±11, represented a variety of racial/ethnic backgrounds with 52.8% identifying as Caucasian, and had an average of two male partners in the last 30 days. Clients performed screening using the GenProbe APTIMA 2 Combo (AC2) kit after viewing written and pictorial instructions. A trained provider also performed the testing with the order of client vs provider randomised to adjust for any training effect. This provider remained in the room while the client performed screening to observe, but did not provide assistance. <h3>Results</h3> The overall prevalence of GC and CT in this sample was 8.9% for P-GC, 8.5% for R-GC, 1.77% for P- CT, and 13.3% for R-CT. McNemar tests were performed stratified by type of infection and anatomic site to evaluate concordance of the client vs provider results. Clients were found to be significantly better at identifying P-GC (91.3% vs 94.4%; 8.8% vs 5.6%; p=0.01) and R-GC (91.5% vs 94.3%; 8.5% vs 5.7%; p=0.03) and to have results equivalent to providers for P-CT (98.3% vs 98.9%; 1.8% vs 1.1%; p=0.50) and R-CT (88.7% vs 88.2%; 13.3% vs 11.9%, p=0.25) detection. <h3>Conclusions</h3> The positive predictive value of the AC2 test makes it unlikely that clients obtained false positives, and observation of subjects while they performed screening ruled out cross-contamination of samples. Therefore, the higher detection rate among the clients is most likely attributable to a more rigorous swabbing technique that sampled an increased surface area. These results suggest that individuals are capable of performing their own STI screening and that allowing them to do so may increase infection detection rates and treatment.

e14542 Background: Anti-EGFR therapy erlotinib was FDA approved for the treatment of patients with advanced pancreas cancer. Human epidermal growth factor receptor 2 (HER-2) is another member of the ErbB family of growth factor receptor tyrosine kinases, is found overexpressed in 20% of pancreatic cancers . Target EGFR and HER-2 with separate specific monoclonal antibodies showed synergistic inhibition of pancreas cancer tumor progression compared with single mAb injection (P = 0.006) or no treatment (P = 0.0004) and even induced some complete remissions in xenograft mice. Lapatinib is a tyrosine kinase inhibitor which binds to both EGFR and HER-2. We propose a single arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic pancreatic cancer. Methods: We have initiated an open label phase II study. Patients with metastatic, unresectable pancreatic cancer who have failed first line Gemcitabine-based therapy, who have an adequate performance status (ECOG 0-2) and normal hepatic and renal function will be eligible. Patients will receive lapatinib 1,250 mg PO daily one hour before or after meals, and capecitabine 1,000 mg/m2 PO twice daily on days 1-14 of 21 day cycle.The primary endpoint is median overall survival (OS). A total of 51 patients will be enrolled over a total of 2 years, with 6 additional months of follow-up time for the final patient. Calculation using Stplan shows that this would provide 90% power to detect 6 months as significantly greater than four months at a one-sided 10% significance level. If eight of the first fourteen patients die within four months of enrolling on the trial, then the trial will stop to protect patients from receiving ineffective therapy. In addition to the clinical study endpoints, circulating microRNA is analyzed during the treatment course in each patient to correlates patient’s outcome. Results: The trial opened in September, 2009 and has accrued seventeen patients, beyond the early stopping rule. Conclusions: The combination is well tolerated and shows promising clinical activity.

The ASGE has recommended adenoma detection rate (ADR) as a quality metric to Medicare. Manual extraction of data to calculate ADR in routine clinical practice is difficult. To overcome this difficulty, we developed a NLP program to measure colonoscopy quality metrics.

Supplementary Table 1 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line

&lt;div&gt;Abstract&lt;p&gt;Coexpression of epidermal growth factor receptor (EGFR) and c-erbB-2 in 47–68% of ovarian cancer cells indicate their strong association with tumor formation. We examined the effects of simultaneous antisense- or immunosuppression of EGFR and c-erbB-2 expression on the invasive phenotype, aneuploidy, and genotype of cultured human ovarian carcinoma cells (NIH:OVCAR-8). We report here that suppression of both EGFR and c-erbB-2 results in regression of aneuploidy and genomic imbalances in NIH:OVCAR-8 cells, restores a more normal phenotype, and results in a more normal gene expression profile. Combined with cytogenetic analysis, our data demonstrate that the regression of aneuploidy is due to the selective apoptosis of double antisense transfected cells with highly abnormal karyotype.&lt;/p&gt;&lt;/div&gt;

&lt;div&gt;Abstract&lt;p&gt;Coexpression of epidermal growth factor receptor (EGFR) and c-erbB-2 in 47–68% of ovarian cancer cells indicate their strong association with tumor formation. We examined the effects of simultaneous antisense- or immunosuppression of EGFR and c-erbB-2 expression on the invasive phenotype, aneuploidy, and genotype of cultured human ovarian carcinoma cells (NIH:OVCAR-8). We report here that suppression of both EGFR and c-erbB-2 results in regression of aneuploidy and genomic imbalances in NIH:OVCAR-8 cells, restores a more normal phenotype, and results in a more normal gene expression profile. Combined with cytogenetic analysis, our data demonstrate that the regression of aneuploidy is due to the selective apoptosis of double antisense transfected cells with highly abnormal karyotype.&lt;/p&gt;&lt;/div&gt;

Supplementary Table 2 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line

Supplementary Table 1 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line

Supplementary Table 2 from Simultaneous Suppression of Epidermal Growth Factor Receptor and c-erbB-2 Reverses Aneuploidy and Malignant Phenotype of a Human Ovarian Carcinoma Cell Line

The antigen encoded by B*5002 differs in sequence from that encoded by B*5001 only at amino acid residue 167 (consensus tryptophan vs. serine) which results in B45 serologic reactivity. To search for B*5002, the frequencies of alleles encoding the serologically defined B45 antigen were determined by sequence-based typing in 5 major U.S. populations: Caucasians, African Americans, Asians/Pacific Islanders, Hispanics, and Native Americans. The percent of serologically defined B45-positive individuals in the 5 populations ranged from 0.7-9.0%. Thirty-two B45-positive individuals were randomly chosen, when available, for sequence-based typing from each ethnic group from a database of 82,979 consecutively typed unrelated individuals. The B*5002 allele was most prevalent in Hispanic (22%) and Caucasian (9%) individuals, while conspicuously absent in African Americans. In addition, a new allele associated with the B45 antigenic specificity, B*4502, has been identified from an African American individual of Middle Eastern descent. In light of the continuing need to reconcile differences between relationships determined by the sequence homologies among alleles and relationships based on the serologic determinants carried by allelic products when determining the level of HLA match for hematopoietic stem cell transplantation, it is suggested that B*5002 be recognized individually from other B*50 alleles when reporting HLA-B typings for clinical purposes.

Preclinical studies have demonstrated the rapid and efficient mobilization of hematopoietic peripheral blood stem cells (PBSC) in a mouse model using the combination of paclitaxel with recombinant human granulocyte colony-stimulating factor (rhG-CSF). On the basis of these results, a clinical trial was initiated using rhG-CSF with paclitaxel for PBSC mobilization in high-risk breast cancer patients. The mobilized PBSC were evaluated for CD34+ cell number, mononuclear cell content, and clonogenic potential. One-hundred and seventeen breast cancer patients received paclitaxel (300 mg/m2) administered as a 24-h continuous intravenous infusion. Forty-eight hours after completing paclitaxel, rhG-CSF (5 μg/kg) was initiated and continued until completion of PBSC collection. Leukapheresis was initiated once the white blood cell count reached 1.0 × 109/L. Each collection was evaluated for the numbers of mononuclear cells (MNC) and CD34+ cells. Clonogenic potential was enumerated using colony-forming units-granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). Patients receiving paclitaxel with rhG-CSF mobilized a large number of mononuclear cells/apheresis (mean, 3.7 × 108; range, 3.3-4.1) and CD34+ cells/apheresis (mean, 7.2 × 106; range, 6.1-8.4). The average number of leukophereses needed was 1.8 (mean, range 1.6-2.0). Colony growth was normal with 178.9 × 105 and 214.8 × 105 colonies counted in CFU-GM and BFU-E assays, respectively. Patients engrafted platelets and neutrophils on day 10 following transplantation. In conclusion, PBSC mobilization with paclitaxel and rhG-CSF results in a large number of mononuclear cells and CD34+ cells with normal clonogenic potential. The cells engraft normally following high-dose chemotherapy and autologous stem cell transplantation in high-risk breast cancer patients. These results demonstrate that paclitaxel with rhG-CSF is an efficient mobilizing agent in high-risk breast cancer patients.

The frequencies of DRB1*08 alleles within four major United States populations found within a hematopoietic stem cell volunteer donor database were determined by DNA sequencing of over 60 DRB1*08 positive individuals from each group. Seven of 30 known DRB1*08 alleles were identified within this study population (080101, 080201, 080302, 080401, 0806, 0807, and 0811). Each ethnic group was characterized by a different highly prevalent allele: DRB1*080101 in Caucasians; DRB1*080401 in African-Americans; DRB1*080302 in Asians; and DRB1*080201 in Hispanics. The alleles DRB1*080101, DRB1*080201, and DRB1*080401 were present in all four populations. This report also describes five novel DRB1*08 alleles uncovered during routine human leukocyte antigen typing.

The frequencies of DRB1*12 alleles were determined in four US population groups by DNA sequencing. Only DRB1*120101 (or DRB1*1206 or *1210) and DRB1*120201 alleles were identified, the latter primarily in the Asian American population. Additional testing of a subset of samples to detect the presence of DRB1*1206 found all of the alleles to be DRB1*120101 (or DRB1*1210). Retesting of six samples previously typed as DRB1*1206 found only DRB1*120101 (or DRB1*1210).