Daniel G. Coit

To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database.The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria.Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm(2)), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic nodal metastases, regardless of extent of tumor burden, are classified as stage III. Micrometastases detected by immunohistochemistry are specifically included. (5) On the basis of a multivariate analysis of patients with distant metastases, the two dominant components in defining the M category continue to be the site of distant metastases (nonvisceral v lung v all other visceral metastatic sites) and an elevated serum lactate dehydrogenase level.Using an evidence-based approach, revisions to the AJCC melanoma staging system have been made that reflect our improved understanding of this disease. These revisions will be formally incorporated into the seventh edition (2009) of the AJCC Cancer Staging Manual and implemented by early 2010.

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.

PURPOSE: The American Joint Committee on Cancer (AJCC) recently proposed major revisions of the tumor-node-metastases (TNM) categories and stage groupings for cutaneous melanoma. Thirteen cancer centers and cancer cooperative groups contributed staging and survival data from a total of 30,450 melanoma patients from their databases in order to validate this staging proposal. PATIENTS AND METHODS: There were 17,600 melanoma patients with complete clinical, pathologic, and follow-up information. Factors predicting melanoma-specific survival rates were analyzed using the Cox proportional hazards regression model. Follow-up survival data for 5 years or longer were available for 73% of the patients. RESULTS: This analysis demonstrated that (1) in the T category, tumor thickness and ulceration were the most powerful predictors of survival, and the level of invasion had a significant impact only within the subgroup of thin (≤ 1 mm) melanomas; (2) in the N category, the following three independent factors were identified: the number of metastatic nodes, whether nodal metastases were clinically occult or clinically apparent, and the presence or absence of primary tumor ulceration; and (3) in the M category, nonvisceral metastases was associated with a better survival compared with visceral metastases. A marked diversity in the natural history of pathologic stage III melanoma was demonstrated by five-fold differences in 5-year survival rates for defined subgroups. This analysis also demonstrated that large and complex data sets could be used effectively to examine prognosis and survival outcome in melanoma patients. CONCLUSION: The results of this evidence-based methodology were incorporated into the AJCC melanoma staging as described in the companion publication.

More than 50,000 patients in the United States will present each year with liver metastases from colorectal cancers. The current study was performed to determine if liver resection for colorectal metastases is safe and effective and to evaluate predictors of outcome.Data for 456 consecutive resections performed between July 1985 and December 1991 in a tertiary referral center were analyzed.The perioperative mortality rate was 2.8%, with a mortality rate of 4.6% for resections that involved a lobectomy or more. The median hospital stay was 12 days and only 9% of patients were admitted to the intensive care unit. The 5-year survival rate is 38%, with a median survival duration of 46 months. By univariate analysis, nodal status of the primary lesion, short disease-free interval before detection of liver metastases, carcinoembryonic antigen (CEA) level greater than 200 ng/mL, multiple liver tumors, extrahepatic disease, large tumors, or positive resection margin was predictive of poorer outcome. Sex, age greater than 70 years, site of primary tumor, or perioperative transfusion was not predictive of outcome. By multivariate analysis, positive margin, size greater than 10 cm, disease-free interval less than 12 months, multiple tumors, and extrahepatic disease were independent predictors of poorer outcome. Short disease-free interval or multiple tumors were nevertheless associated with a 5-year survival rate greater than 24%.Liver resection for colorectal metastases is safe and effective therapy and currently represents the only potentially curative therapy for metastatic colorectal cancer. The only absolute contraindication to resection is extrahepatic disease. A randomized trial to examine efficacy of surgical resection cannot ethically be performed. Liver resection should be considered standard therapy for all fit patients with colorectal metastases isolated to the liver.

Merkel cell carcinoma (MCC) is an uncommon cutaneous malignancy. Most reports consist of single-institution experiences of fewer than 30 patients. The natural history of MCC is poorly defined.A review was performed of Memorial Sloan-Kettering Cancer Center's MCC database, identifying 251 patients who had been treated between 1970 and 2002. Patient, tumor, and treatment-related factors were analyzed for their association with recurrence and survival.The average follow-up for all patients was 40 months and 46 months for patients alive at last follow-up. The 5-year disease-specific survival rate was 64%. Disease stage was the only independent predictor of survival (stage I, 81%; stage II, 67%; stage III, 52%; stage IV, 11%; P = .001). Pathologic staging of the draining nodal basin was performed in 71 (40%) of 177 patients who presented with clinically negative nodes, and 16 of these patients (23%) were found to have node-positive disease. Pathologic nodal staging was associated with improved stage-specific survival probabilities (clinical node-negative, 75% v pathologic node-negative disease, 97%; P = .009) and decreased nodal recurrence (44% v 11%, P < .001). The median time to recurrence was 9 months, and 102 patients (43%) recurred. Local recurrence developed in 8% of patients after margin-negative excision.These data demonstrate that the natural history of MCC is variable and dependent on the stage of disease at presentation. Pathologic nodal staging identifies a group of patients with excellent long-term survival. After margin-negative excision and pathologic nodal staging, local and nodal recurrence rates are low.

Solitary fibrous tumors (SFTs) are rare fibrous neoplasms. Since their initial description as arising from the pleura, SFTs have been reported at a wide range of anatomic sites. To the authors's knowledge, there are no large series reporting both thoracic and extrathoracic SFTs nor are there any large series that analyze clinicopathologic correlates of tumor behavior.Institutional soft tissue tumor and pathology databases were reviewed to identify patients. Pathologic material was reviewed by an experienced soft tissue pathologist and scored for the presence of a histologically malignant component. Clinical information was obtained from medical records and phone calls to patients. Statistical analysis was performed using the Student t test, Pearson chi-square test, and log-rank test.Seventy-nine patients with SFTs treated at a single institution over an 18-year period were identified. These tumors arose in a wide range of anatomic sites. Thoracic and extrathoracic SFTs had similar clinical and pathologic features, although extrathoracic tumors were more likely to be symptomatic on diagnosis. Seventy-five patients underwent surgical excision of a SFT at our institution. Overall, SFTs had a low rate of local recurrence and metastasis after surgical treatment. Extrathoracic SFTs had an increased risk of local recurrence that was small but statistically significant. There was no difference in metastasis-free survival between thoracic and extrathoracic SFTs. Positive surgical margins and the presence of a histologically malignant component were factors predicting worse local recurrence-free survival. Positive surgical margins, tumor size greater than 10 cm, and the presence of a malignant component predicted worse metastasis-free survival.Solitary fibrous tumors are rare tumors that occur at all anatomic sites. Most SFT patients fare well after surgical treatment. Closer surveillance is warranted for those tumors that are larger than 10 cm or with the presence of a histologically malignant component.

To examine the natural history of lymph node metastasis from sarcomas and the utility of therapeutic lymphadenectomy, clinical histories of all adult patients identified by a prospective sarcoma database for the 10-year period July 1982 to July 1991 were examined. Of the 1772 sarcoma patients, 46 (2.6%) were identified with lymph node metastasis. Median follow-up of all patients from diagnosis of lymph node metastasis was 12.9 months (range, 0 to 100 months). Median survival for nonsurvivors was 12.7 months (range, 0 to 40.7). The tumor types with the highest incidence of lymph node metastasis are angiosarcoma (5/37 total cases; 13.5%), embryonal rhabdomyosarcoma (ERMS) (12/88 total cases; 13.6%), and epithelioid sarcoma (2/12 total cases; 16.7%). Lymph node metastasis from visceral primary (p = 0.004) and malignant fibrous histiocytomas (p = 0.006) were associated with particularly poor prognosis. Thirty-one patients underwent radical, therapeutic lymphadenectomy with curative intent, whereas 15 patients had less than curative procedures, in most cases biopsy only. Patients not treated with radical lymphadenectomy had a median survival of 4.3 months (range, 1 to 32) whereas radical lymphadenectomy was associated with a 16.3 month median survival and the only long-term survivors (46% 5-year survival by Kaplan-Meier). The authors conclude that lymph node metastases from sarcoma are rare in adults, but vigilance is warranted, especially in angiosarcoma, ERMS, and epithelioid subtypes. Radical lymphadenectomy is appropriate treatment for isolated metastasis to regional lymph nodes and may provide long-term survival.

To test the hypothesis that routine intraperitoneal drainage is not required after pancreatic resection.The use of surgically placed intraperitoneal drains has been considered routine after pancreatic resection. Recent studies have suggested that for other major upper abdominal resections, routine postoperative drainage is not required and may be associated with an increased complication rate.After informed consent, eligible patients with peripancreatic tumors were randomized during surgery either to have no drains placed or to have closed suction drainage placed in a standardized fashion after pancreatic resection. Clinical, pathologic, and surgical details were recorded.One hundred seventy-nine patients were enrolled in the study, 90 women and 89 men. Mean age was 65.4 years (range 23-87). The pancreas was the tumor site in 142 (79%) patients, with the ampulla (n = 24), duodenum (n = 10), and distal common bile duct (n = 3) accounting for the remainder. A pancreaticoduodenectomy was performed in 139 patients and a distal pancreatectomy in 40 cases. Eighty-eight patients were randomized to have drains placed. Demographic, surgical, and pathologic details were similar between both groups. The overall 30-day death rate was 2% (n = 4). A postoperative complication occurred during the initial admission in 107 patients (59%). There was no significant difference in the number or type of complications between groups. In the drained group, 11 patients (12.5%) developed a pancreatic fistula. Patients with a drain were more likely to develop a significant intraabdominal abscess, collection, or fistula.This randomized prospective clinical trial failed to show a reduction in the number of deaths or complications with the addition of surgical intraperitoneal closed suction drainage after pancreatic resection. The data suggest that the presence of drains failed to reduce either the need for interventional radiologic drainage or surgical exploration for intraabdominal sepsis. Based on these results, closed suction drainage should not be considered mandatory or standard after pancreatic resection.

Germline <i>CDH1</i> mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patient9s perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised <i>CDH1</i> testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, <i>CDH1</i> testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic <i>CDH1</i> mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a <i>CDH1</i> mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with <i>CDH1</i> variants of uncertain significance and those that fulfil hereditary DGC criteria without germline <i>CDH1</i> mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Sentinel node biopsy (SNB) has emerged as a potential alternative to routine axillary dissection in clinically node-negative breast cancer.From September 1995 to June 1996 at Memorial Sloan-Kettering Cancer Center, 60 patients with clinically node-negative cancer underwent SNB, which was immediately followed by standard axillary dissection. Both blue dye and radioisotope were used to identify the sentinel node. SNB was compared with standard axillary dissection for its ability to accurately reflect the final pathologic status of the axillary nodes.The sentinel node was successfully identified by lymphoscintigraphy in 75% (42 of 56), by blue dye in 75% (44 of 59), by isotope in 88% (52 of 59), and by the combination of blue dye and isotope in 93% (55 of 59) of all 59 evaluable patients. Of the 55 patients in this study where sentinel nodes were identified, 20 (36%) were histologically positive. The sentinel node was falsely negative in three patients, yielding an accuracy of 95%. SNB was more accurate for T1 (98%) than for T2-T3 tumors (82%).Lymphatic mapping is technically feasible, reliably identifies a sentinel node in most cases, and appears more accurate for T1 tumors than for larger lesions. Blue dye and radioisotope are complementary techniques, and the overall success of the procedure is maximized when the two are used together.

Hereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer.To determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry.Thirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.Classification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations.Thirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%).Recurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.

The American Joint Committee on Cancer Melanoma Staging Committee proposes major changes to the TNM classification and the stage grouping for cutaneous melanoma. Analyses of prognostic factors by major cooperative groups and cancer centers worldwide contributed data and clinical experience to the simplified and evidence-based recommendations.

Purpose To determine the survival rates and independent predictors of survival using a contemporary international cohort of patients with stage III melanoma. Patients and Methods Complete clinicopathologic and follow-up data were available for 2,313 patients with stage III disease in an updated and expanded American Joint Committee on Cancer (AJCC) melanoma staging database. Kaplan-Meier and Cox multivariate survival analyses were performed. Results Among all 2,313 patients with stage III disease, 81% had micrometastases, and 19% had clinically detectable macrometastases. The 5-year overall survival was 63%; it was 67% for patients with nodal micrometastases, and it was 43% for those with nodal macrometastases (P &lt; .001). Tremendous heterogeneity in survival was observed, particularly in the microscopically detected nodal metastasis subset (from 23% to 87% for 5-year survival). Multivariate analysis demonstrated that in patients with nodal micrometastases, number of tumor-containing lymph nodes, primary tumor thickness, patient age, ulceration, and anatomic site of the primary independently predicted survival (all P &lt; .01). When added to the model, primary tumor mitotic rate was the second-most powerful predictor of survival after the number of tumor-containing nodes. In contrast, for patients with nodal macrometastases, the number of tumor-containing nodes, primary ulceration, and patient age independently predicted survival (P &lt; .01). Conclusion In this multi-institutional analysis, we demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, especially among those with nodal micrometastases. These results should be incorporated into the design and interpretation of future clinical trials involving patients with stage III melanoma.

CA: A Cancer Journal for Clinicians publishes information about the prevention, early detection, and treatment of cancer, as well as nutrition, palliative care, survivorship, and additional topics of interest related to cancer care.

The current AJCC staging system for gastric cancer (AJCC7) incorporated several major revisions to the previous edition. The T and N categories and the stage groups were newly defined, and adenocarcinoma of the esophagogastric junction (EGJ) was reclassified and staged according to the esophageal system. Studies to validate these changes showed inconsistent results. The International Gastric Cancer Association (IGCA) launched a project to support evidence-based revisions to the next edition of the AJCC staging system. Clinical and pathological data on patients who underwent curative gastrectomy at 59 institutions in 15 countries between 2000 and 2004 were retrospectively collected. Patients lost to follow-up within 5 years of surgery were excluded. Patients treated with neoadjuvant therapy were excluded. The data were analyzed in total, and separately by region of treatment. Of 25,411 eligible cases, 84.8 % were submitted from 24 institutions of Japan and Korea, 6.4 % from other Asian countries, and 8.8 % from 29 Western institutions. The T and N categories of AJCC7 clearly stratified the patient survival. Patients with pN3a and pN3b showed distinct prognosis in all regions, and by introducing pN3a and pN3b into a cluster analysis, we established a new stage grouping with better stratification than AJCC7, especially among stage III subgroups. Survival of Siewert type 2 and 3 EGJ tumors was better stratified by this IGCA stage grouping than by either esophageal or gastric scheme of AJCC7. For the next revision of AJCC classification, we propose a new stage grouping based on a large, worldwide data collection.

• Seventy patients with Merkel cell carcinoma were treated at Memorial Sloan-Kettering Cancer Center between 1969 and 1989. The overall estimated 5-year survival rate was 64%. Factors predictive of improved survival included head and neck site and negative lymph nodes at presentation. Local recurrence was seen in 18 patients (26%) and did not correlate with patient-, tumor-, or treatment-related variables. Nine patients with local recurrence (50%) were free of disease following aggressive reoperation. Regional nodes were involved at some point during the course of the disease in forty-six patients (66%). Regional lymph node involvement was apparent within 2 years of diagnosis in 40 (87%) of 46 patients in whom it occurred. Systemic disease was nearly uniformly preceded by the appearance of nodal metastases and was uniformly fatal regardless of subsequent therapy. This suggests an orderly "cascade" pattern of spread for this tumor, in which elective regional lymph node dissection may be justified. Our recommendations for treatment include a wide excision of the primary tumor and either elective or early therapeutic regional node dissection. The role of adjuvant radiotherapy or chemotherapy remains unproven. (<i>Arch Surg</i>. 1991;126:1514-1519)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous melanoma have been significantly revised over the past few years in response to emerging data on immune checkpoint inhibitor therapies and BRAF-targeted therapy. This article summarizes the data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease.

To perform a meta-analysis of high-quality published trials, randomized and observational, comparing laparoscopic distal gastrectomy (LDG) and open distal gastrectomy (ODG) for gastric cancer.Controversy persists about the clinical utility of minimally invasive techniques for the treatment of gastric cancer. Prospective data is limited to a few small randomized trails.: Studies published from January 1992 to March 2010 that compare LDG and ODG were identified. No restrictions in pathologic stage were applied. All randomized controlled trials (RCTs) were included. Selection of high-quality, nonrandomized comparative studies (NRCTs) was based on a validated tool (Methodological Index for Nonrandomized Studies). Mortality, complications, harvested lymph nodes, operative time, blood loss, and hospital stay were compared using weighted mean differences (WMDs) and odds ratios (ORs).Twenty-five studies were included in the analyses, 6 RCTs and 19 NRCTs, compromising 3055 patients (1658 LDG, 1397 ODG). LDG was associated with longer operative times (WMD 48.3 minutes; P < 0.001) and lower overall complications (OR 0.59; P < 0.001), medical complications (OR 0.49; P = 0.002), minor surgical complications (OR 0.62; P = 0.001), estimated blood loss (WMD -118.9 mL; P < 0.001), and hospital stay (WMD -3.6 days; P < 0.001). Mortality and major complications were similar. Patients in the ODG group had a significantly higher number of lymph nodes harvested (WMD 3.9 nodes; P < 0.001), although the estimated proportion of patients with less than 15 retrieved nodes was similar (OR 1.26, P = 0.09).LDG can be performed safely with a shorter hospital stay and fewer complications than open surgery. The long-term significance of a difference of less than 5 nodes in the number of harvested lymph nodes remains unclear. Lymph node staging appears to be unaffected. These results need to be validated in Western patients with advanced gastric cancer.

To compare disease-specific survival (DSS) between the US and Korea following R0 resection for gastric carcinoma (GC).Many studies have described decreased 5-year survival after curative gastrectomy for GC in the West compared with the East. Although clinicopathological presentations of GC are known to vary widely between Eastern and Western countries, including histology, tumor location, and stage at presentation, it remains unclear whether these factors account for differences in survival.All patients undergoing curative intent resections (R0) for GC (1995-2005) were evaluated in 2 independent, single-institution prospectively maintained databases from the US (711 patients) and Korea (1646 patients). Patients receiving neoadjuvant chemotherapy were excluded from this analysis. Patient, surgical and pathologic variables were compared. DSS was determined via multivariate analysis using prognostic variables from an internationally validated GC nomogram that estimates the probability of 5- and 9-year survival.Age and body mass index were significantly higher in US patients. Location of tumors was more often proximal in the United States (39% vs. 9%, P < 0.0001) and distal in Korea (54% vs. 33%, P < 0.0001). Korean patients had more early stage tumors (42% vs. 28% stage Ia, P < 0.0001) with a higher number of lymph nodes identified (97% vs. 79%, >or=15 lymph nodes, P < 0.0001). The 5-year DSS was higher in Korea than in the United States. After multivariate analysis, applying factors used in the nomogram, DSS of Korean GC patients remained significantly better than that of US patients (HR = 1.3, 95% CI; 1.0-1.6, P = 0.008).This study demonstrates better survival for GC patients in Korea compared with the US as determined by multivariate analysis with a validated gastric cancer nomogram. Multiple possibilities can explain this difference.

The aim of this study was to assess the independent prognostic value of primary tumor mitotic rate compared with other clinical and pathologic features of stages I and II melanoma.From the American Joint Committee on Cancer (AJCC) melanoma staging database, information was extracted for 13,296 patients with stages I and II disease who had mitotic rate data available.Survival times declined as mitotic rate increased. Ten-year survival ranged from 93% for patients whose tumors had 0 mitosis/mm(2) to 48% for those with ≥ 20/mm(2) (P < .001). Mean number of mitoses/mm(2) increased as the primary melanomas became thicker (1.0 for melanomas ≤ 1 mm, 3.5 for 1.01 to 2.0 mm, 7.3 for 3.01 to 4.0 mm, and 9.6 for > 8 mm). Ulceration was also associated with a higher mitotic rate; 59% of ulcerated melanomas had ≥ 5 mitoses/mm(2) compared with 16% of nonulcerated melanomas (P < .001). In a multivariate analysis of 10,233 patients, the independent predictive factors for survival in order of statistical significance were as follows: tumor thickness (χ(2) = 104.9; P < .001), mitotic rate (χ(2) = 67.0; P < .001), patient age (χ(2) = 48.2; P < .001), ulceration (χ(2) = 46.4; P < .001), anatomic site (χ(2) = 34.6; P < .001), and patient sex (χ(2) = 33.9; P < .001). Clark level of invasion was not an independent predictor of survival (χ(2) = 3.2; P = .37).A high mitotic rate in a primary melanoma is associated with a lower survival probability. Among the independent predictors of melanoma-specific survival, mitotic rate was the strongest prognostic factor after tumor thickness.

In Brief Summary Background Data: Pseudomyxoma peritonei (PMP) is a clinical syndrome with a poorly defined natural history. Relative contributions of tumor biology, patient selection, and the extent of treatment on ultimate outcome are not well characterized. Methods: Patients treated at the Memorial Sloan-Kettering Cancer Center between 1980 and 2002 with a diagnosis of PMP were identified. Patient characteristics, pathologic features, and details of treatment were analyzed retrospectively. Results: The 97 patients included in this study underwent a mean 2.2 ± 0.1 operations (range, 1–6). Although complete cytoreduction was achieved in 55% (53/97), disease recurred in 91% (48/53) of patients. The median disease-free interval after complete cytoreduction was 24 months. The median overall survival was 9.8 years and was independently associated with low-grade pathologic subtype (P < 0.001) and the ability to achieve complete cytoreduction (P < 0.001). Ten-year survival was attained in 21% (20/97) of the patients, of which 90% (18/20) had low-grade pathologic features. At the time of death or completion of follow-up, only 12% (12/97) of the patients were disease free. Conclusions: Outcome in patients with PMP is strongly associated with tumor biology. Although improved survival is associated with low-grade pathology and tumors amenable to complete cytoreduction, recurrence of PMP is common. Treatment may be beneficial, particularly in controlling symptoms, but absolute cure, defined as a prolonged disease-free state, is uncommon. Pseudomyxoma peritonei describes a clinical syndrome which encompasses a spectrum of biologic behavior. Although improved survival is associated with low grade pathology and tumors amenable to complete cytoreduction, recurrence is common. Treatment may be beneficial, particularly in controlling symptoms, but absolute cure, defined as a prolonged disease-free state, is uncommon.

Overall results after operations for gastric cancer in Japan are far superior to results obtained in the US and Europe. We have reviewed the Japanese literature in an effort to determine what factors explain this difference. It appears that the survival differences are due mainly to a greater frequency of early gastric cancer in Japan; meticulous histopathologic evaluation of the surgical specimens, resulting in more accurate pathologic staging; and the presumed benefit of extended nodal dissection when it extends outside of the level of node-positive disease. Although patients with both apparent and confirmed direct adjacent organ invasion can be helped by resection of those organs, extended resections of uninvolved pancreas and spleen do not improve rate of survival beyond the benefit of improved nodal dissection. Overall, there would appear to be justification for reexamining extended nodal dissection for gastric cancer in the US. Opportunities for a meaningful national study are significant.

Several small studies have reported that an adrenalectomy for isolated adrenal metastasis in non-small-cell lung cancer (NSCLC), along with a surgical resection for the primary lung cancer, can be curative. However, some suggest that the survival outcome among patients with a synchronous metastasis is poor. It remains unclear whether this treatment approach is warranted among those with synchronous metastasis.A search for publications on adrenalectomy for NSCLC was performed via the MEDLINE database. Studies reporting on survival outcomes and containing at least four analyzable patients who had surgery for primary lung cancer were included. Those not allowing separation of outcomes between synchronous and metachronous metastases were excluded. Synchronous metastasis was defined as a disease-free interval (DFI) of 6 months or less.There were 10 publications contributing 114 patients; 42% of patients had synchronous metastases and 58% had metachronous metastases. The median DFIs were 0 and 12 months, respectively. Patients in the synchronous group were younger than those in the metachronous group (median age 54 v 68 years). Complications from adrenalectomy were infrequent. Median overall survival was shorter for patients with synchronous metastasis than those with metachronous metastasis (12 months v 31 months, generalized Wilcoxon P value = .02). However, the 5-year survival estimates were equivalent at 26% and 25%, respectively.For an isolated adrenal metastasis from NSCLC, patients with a synchronous metastasis who underwent adrenalectomy had a shorter median overall survival than those with a metachronous metastasis. However, a durable long-term survival is achieved in approximately 25% in both groups.

From 1982 to 1987, 114 patients underwent operation at Memorial Sloan-Kettering Cancer Center for soft-tissue sarcoma of the retroperitoneum. A retrospective analysis of these patients defines the biologic behavior, surgical management of primary and recurrent disease, predictive factors for outcome, and impact of multimodality therapy. Complete resection was possible in 65% of primary retroperitoneal sarcomas and strongly predicts outcome (p less than 0.001). The rate of complete resection was not altered by histologic type, size, or grade of tumor. These patients had a median survival of 60 months compared to 24 months for those undergoing partial resection and 12 months for those with unresectable tumors. Forty-nine per cent of completely resected patients have had local recurrence. This is the site of first recurrence in 75% of patients. These patients undergo reoperation when feasible. Complete resection of recurrent disease was performed in 39 of 88 (44%) operations, with a 41-month median survival time after reoperation. Tumor grade was a significant predictor of outcome (p less than 0.001). High-grade tumors (n = 65) were associated with a 20-month median survival time compared to 80 months for low-grade tumors (n = 49). Gender, histologic type, size, previous biopsy, and partial resection versus unresectable tumors did not predict outcome by univariate analysis. Adjuvant radiation therapy and chemotherapy could not be shown to have significant impact on survival. Concerted attempt at complete resection of both primary and recurrent retroperitoneal soft-tissue sarcoma is indicated.

Abstract The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability–high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein–Barr virus–positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance. Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49–58. ©2017 AACR. See related commentary by Sundar and Tan, p. 14. See related article by Pectasides et al., p. 37. This article is highlighted in the In This Issue feature, p. 1

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Melanoma focuses on adjuvant therapy and treatment of in-transit disease, because substantial changes were made to the recommendations for the 2016 update. Depending on the stage of the disease, options for adjuvant therapy now include biochemotherapy and high-dose ipilimumab. Treatment options for in-transit disease now include intralesional injection with talimogene laherparepvec (T-VEC), a new immunotherapy. These additions prompted re-assessment of the data supporting older recommended treatment options for adjuvant therapy and in-transit disease, resulting in extensive revisions to the supporting discussion sections.

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.

Stage III melanoma is associated with a high risk of relapse and mortality. Nevertheless, follow-up guidelines have largely been empirical rather than evidence-based.Clinical records of stage III patients with no evidence of disease seen at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1992 and 2004, who ultimately relapsed, were reviewed retrospectively to evaluate date of first relapse, time to first relapse, method of first relapse detection, and survival. We also determined overall 5-year relapse-free survival (RFS) of all stage III patients seen at MSKCC during this period.The overall 5-year RFS for stage IIIA, IIIB, and IIIIC patients was 63%, 32%, and 11%, respectively. Among relapsing patients, 340 had adequate follow-up to be evaluable for all parameters. Site of first relapse was local/in-transit (28%), regional nodal (21%), or systemic (51%). First relapses were detected by the patient or family, physician, or by screening radiologic tests in 47%, 21%, and 32% of patients, respectively. Multivariate analysis revealed that better overall survival was associated with younger age and first relapse being local/in-transit or nodal, asymptomatic, or resectable. For each substage, we estimated site-specific risk of first relapse.Patients detected almost half of first relapses. Our data suggest that routine physical examinations beyond 3 years for stage IIIA, 2 years for stage IIIB, and 1 year for stage IIIC patients and radiologic imaging beyond 3 years for stages IIIA and IIIB and 2 years for stage IIIC patients would be expected to detect few first systemic relapses.

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared.We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases.Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006-2010 and 2011-2013 had better overall survival than patients diagnosed in 2000-2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes.Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma.Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy.

Objective The purpose of this study was to determine if an endosurgical approach that mimics open exploration would improve the accuracy of simple diagnostic laparoscopy. Summary Background Data Most patients with peripancreatic malignancy are found at exploration to be unable to undergo resection. Laparoscopy has been suggested as a sensitive method for detecting metastatic disease in this group of patients. However, the ability to assess resectability with simple diagnostic laparoscopy remains relatively low (<40%). Methods Between December 1992 and August 1994, 115 patients with radiologically resectable peripancreatic tumors underwent extended laparoscopy before undergoing a planned curative resection. This technique required assessment of the peritoneal cavity, liver, lesser sac, porta hepatis, duodenum, transverse mesocolon, and celiac and portal vessels. Results Sixty male and 55 female patients were included in the current study. The pancreatic head was involved in 74 patients (64%), followed by the body in 21 (18%), tail in 8 (7%), ampulla in 8 (7%), duodenum in 3 (3%), and distal bile duct in 1 (1%). An abdominal computed tomography (CT) scan was performed for all patients before laparoscopy, ultrasonography for 74 patients (64%), endoscopic retrograde choleangiopancreatography for 59 patients (51%), and mesenteric angiography for 9 patients (8%). Pneumoperitoneum was established successfully in all but 2 cases (98%). A complete examination of 108 patients was performed. Sixty-seven patients were considered to have resectable disease, and 61 resections were performed. Laparoscopy failed to identify hepatic metastases in 5 patients and portal venous encasement in 1 patient. Unresectable disease was identified in 41 patients. Hepatic metastases were observed in 20 patients, mesenteric vascular encasement in 14, extrapancreatic/peritoneal involvement in 16, and celiac or portal lymphatic metastases in 8. There were no intraoperative or postoperative complications related to the laparoscopic procedure. The positive predictive index, negative predictive index, and accuracy of laparoscopy were 100%, 91%, and 94%, respectively. Conclusions This study demonstrates that extended laparoscopy is accurate and safe and makes exploration unnecessary in many patients with potentially resectable peripancreatic malignancy. In this series, 76% of patients explored were resected, compared with the authors' experience between 1983 and 1993 of 35%. The authors believe that laparoscopy is an important component in the staging of this group of patients and should be performed before exploration.

BACKGROUND Clinically isolated adrenal metastasis is rare. The role of surgical resection is unknown. The aim of this study was to define clinical and pathologic parameters that might predict long term survival after resection of adrenal metastasis. METHODS The authors conducted a retrospective review of 37 patients who had undergone adrenalectomy for metastatic disease at the Memorial Sloan-Kettering Cancer Center (MSKCC) between July 1986 and October 1996. Patients who underwent resection of tumors that locally invaded the adrenal gland were excluded from the study, as were all patients with primary adrenal tumors. RESULTS There were 24 men and 13 women, with a median age of 58 years (range, 42-77 years). Lung carcinoma was the most common primary tumor (n = 17), followed by renal cell carcinoma (n = 9), and colorectal carcinoma (n = 5). The median length of stay at MSKCC was 8 days (range, 3-21 days). There was a 19% incidence of complications (12% major). There was one perioperative death. Five-year survival for the entire group was 24% (median, 21 months). Disease free interval (DFI) of > 6 months and complete resection were the only predictors of improved survival. CONCLUSIONS Adrenalectomy for clinically solitary, resectable lesions can be performed safely, and prolonged survival can be achieved in such selected patients. Adrenalectomy should be considered for patients with completely resectable disease and a DFI of > 6 months. Cancer 1998,82:389-94. © American Cancer Society.

To characterize the natural history of Merkel cell carcinoma (MCC) and to analyze the influence of patient, tumor, and treatment-related variables on survival and recurrence.Approximately 425 cases of MCC have been described in the literature. This study represents the largest experience reported.A review was performed of patients who had been treated at Memorial Sloan-Kettering Cancer Center for MCC between 1969 and 1996. Follow-up data were available for 102 of the 109 (94%) patients identified.The overall 5-year disease-specific survival rate was 74%. The median follow-up was 35 months. For all patients, the only independent predictor of survival was the tumor stage at presentation. For patients with stage I disease, the tumor size at presentation was also an independent predictor of survival. Recurrence of disease occurred in 55 patients (55%), and the most common site of first recurrence was within the draining lymph nodes (n = 35). Elective lymph node dissection was the only parameter independently predictive of improved relapse-free survival. The overall disease-specific survival rate after recurrence was 62%. Predictors of improved disease-specific survival after recurrence included nodal as compared to local or distant recurrence, the ability to render the patient free of disease after recurrence, and a disease-free interval of >8 months.The prognosis for patients with MCC is favorable, and even after recurrence the majority of patients experience long-term survival. Incorporation of size into the staging system more accurately predicts survival in patients with stage I disease. Although elective lymph node dissection decreased the rate of recurrence, it was not associated with improved overall survival.

To analyze the authors' experience with sentinel lymph node biopsy (SLNB) and the subsequent incidence and pattern of recurrence in patients with positive and negative nodes.Lymphatic mapping with SLNB has become widely accepted in the management of patients with melanoma who are at risk for occult regional lymph node metastases. Because this procedure is relatively new, the pattern of recurrence after SLNB is not yet clear.All patients with primary cutaneous melanoma who underwent SLNB from 1991 through 1998 were identified from a prospective single-institution melanoma database.Three hundred fifty-seven consecutive patients with localized primary cutaneous melanoma who underwent SLNB were identified. The sentinel node was identified in 332 patients (93%) and was positive in 56 (17%). Fourteen percent of patients had developed a recurrence at a median follow-up of 24 months. The median time to recurrence was 13 months. The 3-year relapse-free survival rates for patients with positive and negative nodes were 56% and 75%, respectively. SLN status was the most important predictor of disease recurrence. The site of first recurrence in patients with negative and positive nodes was more commonly locoregional than distant. Reexamination of the SLN in 11 patients with negative nodes with initial nodal and in-transit recurrence showed evidence of metastases in 7 (64%).Patients with positive sentinel nodes have a significantly increased risk for recurrence. The early pattern of first recurrence for patients with negative and positive results is characterized by a preponderance of locoregional sites, similar to that reported in previous series of elective lymph node dissection. These data underscore the need for careful pathologic analysis of the SLN as well as a careful, directed locoregional physical examination in the follow-up of these patients.

Although sentinel lymph node (SLN) biopsy for melanoma has been adopted throughout the United States and abroad as a standard method of determining the pathologic status of the regional lymph nodes, some controversy still exists regarding the validity and utility of this procedure. SLN biopsy is a minimally invasive procedure, performed on an outpatient basis at the time of wide local excision of the melanoma, with little morbidity. Numerous studies have documented the accuracy of this procedure for identifying nodal metastases. There are four major reasons to perform SLN biopsy. First, SLN biopsy improves the accuracy of staging and provides valuable prognostic information for patients and physicians to guide subsequent treatment decisions. Second, SLN biopsy facilitates early therapeutic lymph node dissection for those patients with nodal metastases. Third, SLN biopsy identifies patients who are candidates for adjuvant therapy with interferon alfa-2b. Fourth, SLN biopsy identifies homogeneous patient populations for entry onto clinical trials of novel adjuvant therapy agents. Overall, the benefit of accurate nodal staging obtained by SLN biopsy far outweighs the risks and has important implications for patient management.

In Brief Objective: To determine whether the length of esophageal resection or the operative approach influences outcome for patients with adenocarcinoma of the gastroesophageal junction (GEJ). Summary Background Data: While R0 resection remains the mainstay of curative treatment of patients with GEJ cancer, the optimal length of esophageal resection remains controversial. Methods: Patients with Siewert I, II, or III adenocarcinoma who underwent complete gross resection without neoadjuvant therapy were identified from a prospectively maintained database. Proximal margin lengths were recorded ex vivo as the distance from the gross tumor edge to the esophageal transection line. Operative approaches were grouped into gastrectomy (limited esophagectomy) or esophagectomy (extended esophagectomy). Results: From 1985 through 2003, 505 patients underwent R0/R1 gastrectomy (n = 153) or esophagectomy (n = 352) without neoadjuvant treatment. There were no differences in R1 resection rate, number of nodes examined or operative mortality between gastrectomy and esophagectomy. Univariate analysis found >3.8 cm to be the ex vivo proximal margin length (approximately 5 cm in situ) most predictive of improved survival. Multivariable analysis in patients who underwent R0 resection with ≥15 lymph nodes examined (n = 275) found the number of positive lymph nodes, T stage, tumor grade, and ex vivo proximal margin length >3.8 cm to be independent prognostic factors. Subset analysis found that the benefit associated with >3.8 cm margin was limited to patients with T2 or greater tumors and ≤6 positive lymph nodes. Conclusions: In patients not receiving neoadjuvant therapy, the goal for patients with adenocarcinoma of the GEJ should be R0 resection including at least 15 lymph nodes, preferably with 5 cm of grossly normal in situ proximal esophagus for those with ≤6 positive lymph nodes. The operative approach may be individualized to achieve these goals. For patients with adenocarcinoma of the GEJ who underwent R0 resection without neoadjuvant therapy, proximal margins >5 cm of in situ esophagus were associated with improved outcome. The operative approach was not a prognostic factor, and surgery may be individualized to achieve proximal margin clearance.

The incidence of multiple primary melanomas ranges from 1.3% to 8.0% in large retrospective reviews; however, the impact of certain risk factors is not understood.To determine the incidence of multiple primary melanomas (MPM) from a prospective, single-institution, multidisciplinary database, and to describe the clinical and pathological characteristics and risk factors specific to these patients.Review of a prospectively maintained database at Memorial Sloan-Kettering Cancer Center in New York, NY.A total of 4484 patients diagnosed with a first primary melanoma between January 1, 1996, and December 31, 2002.Incidence of and risk factors for MPM.Three hundred eighty-five patients (8.6%) had 2 or more primary melanomas, with an average of 2.3 melanomas per MPM patient. Seventy-eight percent had 2 primary melanomas. For 74% of patients, the initial melanoma was the thickest tumor. Fifty-nine percent presented with their second primary tumor within 1 year. Twenty-one percent of MPM patients had a positive family history of melanoma compared with only 12% of patients with a single primary melanoma (SPM) (P<.001). Thirty-eight percent of MPM patients had dysplastic nevi compared with 18% of SPM patients (P<.001). The estimated cumulative 5-year risk of a second primary tumor for the entire cohort was 11.4%, with almost half of that risk occurring within the first year. For patients with a positive family history or dysplastic nevi, the estimated 5-year risk of MPM was significantly higher at 19.1% and 23.7%, respectively. The most striking increase in incidence for the MPM population was seen for development of a third primary melanoma from the time of second primary melanoma, which was 15.6% at 1 year and 30.9% at 5 years.The incidence of MPM is increased in patients with a positive family history and/or dysplastic nevi. These patients should undergo intensive dermatologic screening and should consider genetic testing.

Despite the importance of early detection in preventing mortality from melanoma, little is known regarding how patients with the disease come to diagnosis.The authors prospectively evaluated 471 newly diagnosed melanoma patients between 1995 and 1998. Patients completed a questionnaire that included 1) identification of the person who detected the lesion, 2) the anatomic location of the lesion, and 3) family history of melanoma. Logistic regression analysis was performed to examine the relation between detection patterns and lesion thickness, adjusting for age, gender, anatomic site of the primary lesion, and family history of melanoma.The majority of patients detected their own melanoma (n = 270; 57%). Females were more likely to self-detect than males (69% vs. 47%; P < 0.0001). Physicians detected the melanoma in 16% of patients (n = 74), followed by "spouse" in 11% of patients (n = 51). Within this group, detection by wives was 7.5 times more common than detection by husbands (P < 0.0001). Logistic regression analysis revealed that physicians were 3.6 times more likely to detect thin lesions (</=0.75 mm) compared with nonphysician detectors (95% confidence interval [95% CI], 2.1, 6.5; P = 0.0001). In addition, patients who reported a family history of melanoma had a 2.7-fold increased likelihood of presenting with a thin lesion (95% CI, 1.6, 4.7; P = 0.0003).Physician detection and a report of a family history of melanoma are associated with the presentation of patients with early melanoma, suggesting that awareness of the disease among physicians and the public is critical for preventing mortality from melanoma. Increasing melanoma awareness in males may be a particularly effective means of secondary prevention.

Currently, little is known regarding the potential prognostic value of histologic features in primary cutaneous neuroendocrine (Merkel cell) carcinomas (MCC).In a retrospective review of the tumor histology and clinical outcome data (median follow-up, 51 months; range, 3-224 months) of 156 patients with a diagnosis of MCC, the following histologic features were evaluated: tumor thickness, tumor size (greatest dimension of the tumor), microanatomic compartment involved by tumor (dermis and/or subcutis and/or deeper), tumor growth pattern (nodular circumscribed vs infiltrative), lymphovascular invasion (LVI), tumor-infiltrating lymphocytes, tumor necrosis, ulceration, and solar elastosis.The overall 5-year survival rate was 67.5%. On univariate analysis, parameters that were associated significantly with survival were tumor thickness (P= .001), tumor size (P= .0002), deepest anatomic compartment involved by tumor (P= .0003), tumor growth pattern (P= .003), LVI (P< .00001), tumor-infiltrating lymphocytes (P= .05), and solar elastosis (P= .04). On multivariate analysis, the presence of a nodular growth pattern, low tumor depth, and absence of LVI were associated with longer survival.In addition to the known prognostic value of tumor stage, 3 histologic features were identified to have prognostic significance: tumor thickness (depth of tumor invasion), the presence of LVI, and tumor growth pattern.

Desmoplastic melanoma (DM) is a variant of melanoma, which may be confused with nonmelanocytic benign or malignant spindle cell proliferations. The histologic hallmark of DM is the presence of fusiform melanocytes dispersed in a prominent collagenous stroma. Phenotypic heterogeneity of DM is underrecognized. Desmoplasia may be prominent throughout the entire tumor ("pure" DM) or represent a portion of an otherwise nondesmoplastic melanoma ("combined" DM). We reviewed melanomas with desmoplasia from 92 patients seen at a single institution between 1980 and 2002. Fifty-five of the tumors were pure DM. Thirty-seven were classified as combined. Mean follow-up of patients was 46 months for those alive at the last follow-up. Univariate analysis of clinical and pathologic parameters revealed four significant variables for disease-free survival: Clark level (IV vs. V; P = 0.005), DM subtype (pure vs. combined; P = 0.01), tumor mitotic rate (<1, 1-4, >4 mitoses/mm; P = 0.01), and tumor thickness (<1 mm, 1-4 mm, >4 mm; P = 0.02). Only histologic subtype (P = 0.02) and Clark level (P = 0.05) were independently significant by Cox regression analysis. Our results indicate that distinguishing pure from combined forms of DM is clinically relevant for prognosis (pure forms being associated with longer disease-specific survival). Failure to make this distinction may account for conflicting reports in the literature on the biologic behavior and prognosis of DM.

Activation of the mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase/AKT pathway seems to be critical for melanoma proliferation. Components of these pathways are client proteins of heat-shock protein 90 (hsp90), suggesting that inhibition of hsp90 could have significant antimelanoma effects. We conducted a phase II trial using the hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in melanoma patients. The primary end points were clinical responses and whether treatment inhibited MAPK pathway activity.Melanoma patients with measurable disease were stratified on the basis of whether or not their tumor harbored a V600E BRAF mutation. The hsp90 inhibitor 17-AAG was administered i.v. once weekly x 6 weeks at 450 mg/m2. Tumor biopsies were obtained pretreatment and 18 to 50 hours after the first dose of 17-AAG, and were snap-frozen.Fifteen evaluable patients were treated; nine had BRAF mutations and six were wild-type. No objective responses were observed. Western blot analysis of tumor biopsies showed an increase in hsp70 and a decrease in cyclin D1 expression in the posttreatment biopsies but no significant effect on RAF kinases or phospho-extracellular signal-regulated kinase expression. Plasma analyzed by mutant-specific PCR for V600E BRAF showed 86% sensitivity and 67% specificity in predicting tumor DNA sequencing results.At this dose and schedule of 17-AAG, the effects of 17-AAG on RAF kinase expression were short-lived, and no objective antimelanoma responses were seen. Future trials in melanoma should focus on a more potent hsp90 inhibitor or a formulation that can be administered chronically for a more prolonged suppression of the MAPK pathway.

Lymphatic mapping and sentinel lymph node (SLN) biopsy are widely used as a staging technique for patients with cutaneous malignant melanoma who are at risk for metastases. SLN status has been shown to be a strong predictor of prognosis, and a variety of techniques have been used to identify minimal metastatic disease in SLNs. However, there is no validated consensus method for the optimal histologic analysis of SLNs harvested from melanoma patients. This study was conducted: 1) to assess the yield of metastatic melanoma detected in SLNs deemed negative by initial routine pathologic analysis (RPA) by subjecting them (after review of the original slides) to enhanced pathologic analysis (EPA) that included complete step-sectioning and immunohistochemistry (IHC); 2) to characterize the distribution of metastatic melanoma deposits within the SLNs; 3) to determine a preferred method of pathologic analysis applicable to daily practice; and 4) to attempt to assess the clinical significance of disease detected by EPA. A total of 105 SLNs were harvested from 49 patients who underwent successful SLN biopsy procedures during the period of study. Ten SLNs from 10 patients were positive on initial RPA and were not analyzed further. Ninety-five SLNs from the remaining 39 patients were reviewed and processed with additional hematoxylin and eosin, S-100 protein, and HMB-45 stains at 50-μm intervals for 20 levels or until the SLN tissue was exhausted. A single pathologist reviewed all sections without knowledge of the results of the other stains. Overall, metastatic melanoma was discovered in SLNs from 20 of the 39 patients: SLNs from 6 patients were found to have melanoma on review of the original hematoxylin and eosin slides, and SLNs from 14 patients were positive only after EPA. Twenty-one individual positive SLNs from these 14 patients were detected by EPA; of these, 10 positive SLNs were identified solely by IHC, representing 12% of the patient cohort and 10% of all SLNs studied by EPA. Detection rates were significantly associated with the staining method and the number of levels performed (P < 0.01). S-100 protein staining resulted in the highest yield of SLN positivity (86%), followed by HMB-45 (81%) and hematoxylin and eosin (52%). No single method detected all of the micrometastases. A detailed topographic mapping of metastatic deposits in SLNs was carried out. When using all three staining techniques, all 20 levels were required to identify 100% of the micrometastases; 95% of positive SLNs were identified with 17 levels, 90% with 15 levels, 75% with 10 levels, and 42% with 3 levels. Projected rates of detection for various different sectioning strategies were determined, with alteration of either the number of levels examined, the interval between the levels, or both. Detection of SLN positivity can be increased to 71% by performing three levels at 250-μm intervals, each level being composed of a set of three sections stained with hematoxylin and eosin, S-100 protein, and HMB-45, respectively. Therefore, this is the methodology we propose for the study of SLNs in melanoma patients. After a median follow-up of 87 months (range, 9-134 months), patients with EPA-detected disease and those with negative SLNs by EPA demonstrated improved recurrence-free and disease-specific survival compared with patients with RPA-detected disease in SLNs. Sampling error introduced by variations in pathologic processing should be addressed by standardization of pathologic methods, and the clinical significance of minimal SLN disease should be addressed in prospective studies of homogeneously staged patients.

Melanomas can be difficult to diagnose histologically if they deviate in their growth pattern or cytology only minimally from a nevus. On occasion, even experts on melanocytic lesions may not reach a consensus on whether a lesion is a benign but unusual nevus or a malignant melanoma mimicking a nevus. This diagnostic dilemma is particularly well known for the distinction of Spitz nevus from melanoma. Diagnostic uncertainty and disagreement among consultant pathologists lead to confusion about the prognosis and clinical management of patients. In this study we present the clinical and pathologic findings of 10 patients with diagnostically controversial melanocytic tumors, who underwent sentinel lymph node biopsy. In all of these cases, the diagnostic controversy among experts was between Spitz nevus and melanoma. Seven patients were female, and three were male, ranging in age from 7 to 46 years (mean 21 years). Histologic examination of the sentinel lymph nodes revealed tumor deposits in the lymph node parenchyma in 5 of 10 patients. Among patients with positive sentinel lymph nodes, two had satellite nodules and one showed additional tumor deposits in three nonsentinel regional lymph nodes. All patients are alive and free of disease with a follow-up of 10-54 months (mean 34 months). Our study illustrates the role of a sentinel lymph node biopsy in the evaluation of patients with diagnostically controversial melanocytic tumors. Although the presence of metastatic tumor deposits in the sentinel lymph node supports the diagnosis of malignant melanoma, further studies are needed to determine the prognostic significance of the sentinel lymph node findings in such patients.

Although pathologic nodal status is a major determinant of outcome in melanoma, there is substantial prognostic heterogeneity among node-positive patients. This study was undertaken to further clarify significant variables predicting survival in patients with melanoma metastatic to axillary or groin nodes. From 1019 patients with melanoma undergoing axillary or groin dissection between 1974 and 1984, the authors identified 449 patients with histologically positive nodes. Both univariate and multivariate analyses were performed using the Kaplan-Meier product limit method and the Cox model of proportional hazard regression. The major determinant of survival was pathologic stage (PS) according to the 1983 AJCC staging system. Three hundred fifty patients (78%) were classified PS-III (one nodal group involved), with a survival of 39% at 5 years and 32% at 10 years. Factors independently predictive of a favorable outcome in these patients were nontruncal primary site (p = 0.0002), microscopic nodal involvement (p = 0.001), number of positive nodes less than three (p = 0.003), and absence of extranodal disease (p = 0.01). Ninety-nine patients (22%) were classified PS-IV, 51 with two nodal stations involved (N2), 25 with intransit disease and one nodal station involved (N2), 7 with extraregional soft tissue metastases (M1), and 16 with visceral metastases (M2). Survival for PS-IV patients was 9% at 5 and 10 years, respectively. Within PS-IV, factors independently predictive of a more favorable outcome were the absence of extranodal disease (p = 0.0001), female sex (p = 0.03), and a long interval from diagnosis to lymph node dissection (p = 0.04). These factors were incorporated into a model predicting relative risk of death from disease for both PS-III and PS-IV patients, separating patients into groups at high, intermediate, and low risk of recurrence after lymphadenectomy.

1) Characterize changes in the surgical treatment of anorectal melanoma over time. 2) Determine if the extent of surgical resection is associated with outcome. 3) Identify prognostic factors correlating with survival.Although early data suggested improved survival in patients undergoing abdominoperineal resection (APR) for primary anorectal melanoma, such an aggressive approach may be unwarranted as distant relapse rates are high. We have seen a trend toward less aggressive surgical treatment of the local disease over the past 20 years.A retrospective review was performed of all patients with anorectal melanoma treated at our institution between 1984 and 2003. Extent of primary resection and pathologic factors were studied.Forty-six patients underwent a curative resection with a median follow-up of 29 months, and 5-year disease-specific survival (DSS) rate of 35%. While patient and tumor characteristics remained similar, there was a dramatic shift in surgical treatment toward less radical procedures. Prior to 1997, the majority of patients (15 of 21, 71%) underwent APR. After 1997, the majority of patients (21 of 25, 84%) underwent local excision (LE) (P < 0.0001). Local recurrence was noted in 11 of 46 (24%) patients: 4 of 19 (21%) who underwent APR and 7 of 27 (26%) who underwent LE (P = not significant). Five-year DSS was similar: 34% following APR and 35% following LE. Tumor perineural invasion (PNI) was the only factor identified as an independent predictor of worse outcome (P = 0.01).The extent of surgical treatment is not associated with outcome in primary anorectal melanoma. Therefore, LE of the primary tumor is recommended when technically feasible. The presence of PNI is an important prognostic factor and should be considered in future clinical trials.

Merkel cell carcinoma (MCC) is a cutaneous neuroendocrine neoplasm with propensity for lymphatic spread. The rarity of MCC has limited analysis of factors associated with a positive sentinel lymph node biopsy (SLNB) and survival. Review of a prospective MCC database was performed. Factors associated with SLNB positivity were analyzed. Univariate and multivariate analyses of factors associated with recurrence and survival were performed using the cumulative incidence (CI) function, treating death from other causes as a competing risk. From 1996 to 2010, a total of 153 patients with localized MCC underwent SLNB, of whom 45 (29%) were positive. Factors associated with SLNB positivity were primary tumor size (25% ≤2 cm vs. 45% >2 cm; P = 0.02) and presence of lymphovascular invasion (LVI) (55% LVI positive vs. 4% LVI negative; P < 0.01). SLNB-positive patients were more likely to receive radiation or chemotherapy (60% vs. 7%, P < 0.01). With median follow-up of 41 months, there were 16 nodal/distant recurrences (10%), 11 deaths from MCC (7%), and 27 death from other causes (18%). The 2-year CIs of recurrence or death from MCC were 12% and 6%, respectively. There was no difference in recurrence or death from MCC between SLNB-positive and -negative patients. The 2-year CIs of recurrence or death from MCC for LVI-positive patients were 30% and 15%, respectively. No LVI-negative patient experienced recurrence of disease or died of MCC. SLNB identifies occult nodal metastases in 29% of patients with localized MCC. Predictors of SLNB positivity are tumor size and presence of lymphovascular invasion (LVI). Patients with SLNB-positive disease are more likely to receive further treatment; however, sentinel lymph node (SLN) status is not associated with recurrence or survival. In contrast, LVI is strongly associated with both recurrence and survival.

Completion lymph node dissection (CLND) is considered the standard of care in melanoma patients found to have sentinel lymph node (SLN) metastasis. However, the therapeutic utility of CLND is not known. The natural history of patients with positive SLNs who do not undergo CLND is undefined. This multi-institutional study was undertaken to characterize patterns of failure and survival rates in these patients and to compare results with those of positive-SLN patients who underwent CLND.Surgeons from 16 centers contributed data on 134 positive-SLN patients who did not undergo CLND. SLN biopsy was performed by using each institution's established protocols. Patients were followed up for recurrence and survival.In this study population, the median age was 59 years, and 62% were male. The median tumor thickness was 2.6 mm, 77% of tumors had invasion to Clark level IV/V, and 33% of lesions were ulcerated. The primary melanoma was located on the extremities, trunk, and head/neck in 45%, 43%, and 12%, respectively. The median follow-up was 20 months. The median time to recurrence was 11 months. Nodal recurrence was a component of the first site of recurrence in 20 patients (15%). Nodal recurrence-free survival was statistically insignificantly worse than that seen in a contemporary cohort of patients who underwent CLND. Disease-specific survival for positive-SLN patients who did not undergo CLND was 80% at 36 months, which was not significantly different from that of patients who underwent CLND.This study underscores the importance of ongoing prospective randomized trials in determining the therapeutic value of CLND after positive SLN biopsy in melanoma patients.

In Brief Objective: To identify factors associated with survival in Merkel cell carcinoma (MCC). Background: Merkel cell carcinoma is a rare cutaneous neoplasm. Staging and treatment are based on studies, which incompletely characterize the disease. Methods: Review of a prospective database was performed. Overall survival (OS) was estimated by the Kaplan-Meier method. Disease-specific death (DSD) was analyzed by the competing risks method. Factors associated with OS and DSD were determined by the log-rank test and Gray's test, respectively. Results: A total of 500 patients with MCC treated at our institution from 1969 to 2010 were identified. Eighty-eight patients presented older than 6 months after diagnosis and were excluded from further analysis. Of the remaining 412 patients, the median age at diagnosis was 71 years. Median follow-up was 3 years. Fifty percent of patients died during follow-up: 25% died of disease, 24% died of other causes. Five-year OS and DSD were 56% and 30%, respectively. Pathologic stage and lymphovascular invasion were independent predictors of DSD. Patients with metastatic disease (stage 4) or clinically positive lymph nodes (stage 3b) had increased DSD compared with patients with microscopically positive (stage 3a) or negative lymph nodes (stage 1 and 2). There was no difference in DSD between stage 3a or 2 compared with stage 1. Importantly, only 1 of 132 patients without lymphovascular invasion died of MCC. Conclusions: OS is a poor measure of the influence of MCC on life expectancy. The presence of lymphovascular invasion and clinically, but not microscopically, positive lymph nodes were associated with increased DSD. These factors should be incorporated into MCC staging and treatment recommendations. Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine neoplasm. Staging and treatment are based on studies that incompletely characterize the disease. Here we present the largest single-center series of patients with MCC and identify factors associated with survival.

Laparoscopic resection of gastric GISTs appears technically feasible and associated with favorable outcomes. Tumor size however frequently plays a role in surgical approach with larger tumors tending toward laparotomy, raising concern that favorable outcomes reported for the laparoscopic approach may reflect this selection bias. From a prospectively collected sarcoma database, 155 primary gastric GIST resections were identified (1998–2009); 40 patients underwent successful laparoscopic resection for non-GE junction GIST and were randomly matched (1:1) by tumor size (±2.0 cm) to patients with open resection. Clinical and pathologic variables and surgical outcomes were associated with surgery type using conditional logistic regression analyses. The two surgical approaches were comparable for clinical and pathologic variables. Median operating room (OR) time was similar, although median length of stay postsurgery was lower in the laparoscopic versus open group (4 vs. 7 days, P = 0.002), as was estimated blood loss (EBL) (25 vs. 100 ml, P = 0.006). There was no operative mortality, and 30-day morbidity was similar. Oncologic outcomes were also similar with no positive microscopic margins, and 1 recurrence in each group with a median follow-up of 34 months. There were 13 conversions overall, 5 secondary to tumor location at the GE junction or lesser curve. When matched for tumor size, laparoscopic resection of primary gastric GISTs ≤8 cm results in shorter hospital stays with similar OR time while maintaining sound oncologic outcomes compared with open resection.

Previous comparisons of gastric cancer between the West and the East have focused predominantly on Japan and Korea, where early gastric cancer is prevalent, and have not included the Chinese experience, which accounts for approximately half the world's gastric cancer.Patient characteristics, surgical procedures, pathologic information, and survival were compared among gastric cancer patients who underwent curative intent gastrectomy at two large volume cancer centers in China and the US between 1995 and 2005.Median age and body mass index were significantly higher in US patients. The proportion of proximal gastric cancer was comparable. Gastric cancer patients in China had larger tumors and a later stage at presentation. The median number of positive lymph nodes was higher (5 vs 4, P < 0.02) despite a lower lymph node retrieval (16 vs 22, P < 0.001) in Chinese patients. The probability of death due to gastric cancer in Chinese patients was 1.7 fold of that in the US (P < 0.0001) after adjusting for important prognostic factors.Even after adjusting for important prognostic factors Chinese gastric cancer patients have a worse outcome than US gastric cancer patients. The differences between Chinese and US gastric cancer are a potential resource for understanding the disease.

We postulated that the worse prognosis of melanoma with advancing age reflected more aggressive tumor biology and that in younger patients the prognosis would be more favorable. The expanded AJCC melanoma staging database contained 11,088 patients with complete data for analysis, including mitotic rate. With increasing age by decade, primary melanomas were thicker, exhibited higher mitotic rates, and were more likely to be ulcerated. In a multivariate analysis of patients with localized melanoma, thickness and ulceration were highly significant predictors of outcome at all decades of life (except for patients younger than 20 years). Mitotic rate was significantly predictive in all age groups except patients <20 and >80 years. For patients with stage III melanoma, there were four independent variables associated with patient survival: number of nodal metastases, patient age, ulceration, and mitotic rate. Patients younger than 20 years of age had primary tumors with slightly more aggressive features, a higher incidence of sentinel lymph node metastasis, but, paradoxically, more favorable survival than all other age groups. In contrast, patients >70 years old had primary melanomas with the most aggressive prognostic features, were more likely to be head and neck primaries, and were associated with a higher mortality rate than the other age groups. Surprisingly, however, these patients had a lower rate of sentinel lymph node metastasis per T stage. Among patients between the two age extremes, clinicopathologic features and survival tended to be more homogeneous. Melanomas in patients at the extremes of age have a distinct natural history.

MET, the receptor for hepatocyte growth factor, has been proposed as a therapeutic target in gastric cancer. This study assessed the incidence of MET expression and gene amplification in tumors of Western patients with gastric cancer.Tumor specimens from patients enrolled on a preoperative chemotherapy study (NCI 5700) were examined for the presence of MET gene amplification by FISH, MET mRNA expression by quantitative PCR, MET overexpression by immunohistochemistry (IHC), and for evidence of MET pathway activation by phospho-MET (p-MET) IHC.Although high levels of MET protein and mRNA were commonly encountered (in 63% and 50% of resected tumor specimens, respectively), none of these tumors had MET gene amplification by FISH, and only 6.6% had evidence of MET tyrosine kinase activity by p-MET IHC.In this cohort of patients with localized gastric cancer, the presence of high MET protein and RNA expression does not correlate with MET gene amplification or pathway activation, as evidenced by the absence of amplification by FISH and negative p-MET IHC analysis.This article shows a lack of MET amplification and pathway activation in a cohort of 38 patients with localized gastric cancer, suggesting that MET-driven gastric cancers are relatively rare in Western patients.

The NCCN Guidelines for Melanoma provide multidisciplinary recommendations on the clinical management of patients with melanoma. This NCCN Guidelines Insights report highlights notable recent updates. Foremost of these is the exciting addition of the novel agents ipilimumab and vemurafenib for treatment of advanced melanoma. The NCCN panel also included imatinib as a treatment for KIT-mutated tumors and pegylated interferon alfa-2b as an option for adjuvant therapy. Also important are revisions to the initial stratification of early-stage lesions based on the risk of sentinel lymph node metastases, and revised recommendations on the use of sentinel lymph node biopsy for low-risk groups. Finally, the NCCN panel reached clinical consensus on clarifying the role of imaging in the workup of patients with melanoma.

We have previously reported that older patients with clinical stage I and II primary cutaneous. Melanoma had lower survival rates compared to younger patients. We postulated that the incidence of nodal metastasis would therefore be higher among older melanoma patients. The expanded American Joint Committee on Cancer melanoma staging database contains a cohort of 7,756 melanoma patients who presented without clinical evidence of regional lymph node or distant metastasis and who underwent a sentinel node biopsy procedure as a component of their staging assessment. Although older patients had primary melanoma features associated with more aggressive biology, we paradoxically observed a significant decrease in the incidence of sentinel node metastasis as patient age increased. Overall, the highest incidence of sentinel node metastasis was 25.8 % in patients under 20 years of age, compared to 15.5 % in patients 80 years and older (p < 0.001). In contrast, 5-year mortality rates for clinical stage II patients ranged from a low of 20 % for those 20–40 years of age up to 38 % for those over 70 years of age. Patient age was an independent predictor of sentinel node metastasis in a multifactorial analysis (p < 0.001). Patients with clinical stage I and II melanoma under 20 years of age had a higher incidence of sentinel lymph node metastasis but, paradoxically, a more favorable survival outcome compared to all other age groups. In contrast, patients >70 years had the most aggressive primary melanoma features and a higher mortality rate compared to all other age groups but a lower incidence of sentinel lymph node metastasis.

Gastrectomy remains a major operation with potential for significant deterioration in patients' health-related quality of life (QOL). This study assessed differences in QOL among patients after distal (DG), proximal (PG), or total (TG) gastrectomy.We prospectively enrolled patients undergoing gastrectomy at our institution between 2002 and 2007. Participants completed the European Organization for Research and Treatment of Cancer cancer (QLQ-C30) and gastric (QLQ-STO22) questionnaires preoperatively and at 5 postoperative intervals up to 18 months. We compared changes from baseline in patients based on extent of resection (proximal, distal, or total) using generalized linear models, adjusting for age, stage of disease, and (neo)adjuvant therapy. We converted QOL raw scores to reflect the proportion of patients with clinically significant deterioration based on the minimal important difference.We included 134 patients: 82 DG, 16 PG, and 36 TG. In the immediate postoperative period, 55% of patients suffered significant impairment in their global QOL. This improved in most patients by 6 months, although 20% to 35% continued to have substantially worse QOL than before surgery. Patients who underwent PG suffered from significantly more clinical reflux [70% vs 35% (DG), 40% (TG)], nausea/vomiting (60% vs 25%, 30%), and global QOL impairment (60% vs 30%, 30%) than patients who underwent DG or TG, whose QOL scores were similar. These differences persisted up to 18 months postoperatively.Surgeons should discuss expectations of QOL impairment with their patients before gastrectomy and reassure them that most symptoms resolve by 6 months after operation. Patients who undergo PG suffer from worse QOL impairment than patients who undergo DG or TG.

The role for neoadjuvant systemic therapy in resectable pancreas adenocarcinoma remains undefined.We evaluated the efficacy of gemcitabine and oxaliplatin administered as preoperative therapy in patients with resectable pancreas adenocarcinoma.Eligible patients were screened using computed tomography-pancreas angiography, laparoscopy, endoscopic ultrasonography, and fine-needle aspiration cytology to identify 38 patients who received 4 cycles of neoadjuvant gemcitabine 1000 mg/m intravenously over 100 minutes and oxaliplatin 80 mg/m intravenously over 2 hours, every 2 weeks. Patients whose tumors remained resectable at restaging proceeded to operation and subsequently received 5 cycles of adjuvant gemcitabine (1000 mg/m intravenously over 30 minutes days 1, 8, and 15 every 4 weeks). The primary endpoint was 18-month overall survival and secondary endpoints included radiological, tumor marker and pathological response to neoadjuvant therapy, time to recurrence, patterns of failure, and feasibility of obtaining preoperative core biopsies.Thirty-five of 38 patients (92%) completed neoadjuvant therapy. Twenty-seven patients underwent tumor resection (resectability rate 71%), of which 26 initiated adjuvant therapy for a total of 23 patients (60.5%) who completed all planned therapy. The 18-month survival was 63% (24 patients alive). The median overall survival for all 38 patients was 27.2 months (95% confidence interval: 17-NA) and the median disease-specific survival was 30.6 months (95% confidence interval: 19-NA).This study met its endpoint and provided a signal suggesting that exploration of neoadjuvant systemic therapy is worthy of further investigation in resectable pancreas adenocarcinoma. Improved patient selection and more active systemic regimens are key. Clinical trials identification: NCT00536874.

Preoperative methods to estimate disease-specific survival (DSS) for resectable gastroesophageal (GE) junction and gastric adenocarcinoma are limited. We evaluated the relationship between DSS and pretreatment neutrophil to lymphocyte ratio (NLR).The patient's inflammatory state is thought to be associated with oncologic outcomes, and NLR has been used as a simple and convenient marker for the systemic inflammatory response. Previous studies have suggested that NLR is associated with cancer-specific outcomes.A retrospective review of a prospectively maintained institutional database was undertaken to identify patients who underwent potentially curative resection for GE junction and gastric adenocarcinoma from 1998 to 2013. Clinicopathologic findings, pretreatment leukocyte values, and follow-up status were recorded. The Kaplan-Meier method was used to estimate DSS, and Cox proportional hazards models were used to evaluate the association between variables and DSS.We identified 1498 patients who fulfilled our eligibility criteria. Univariate analysis showed that male sex, Caucasian race, increased T and N stage, GE junction location, moderate/poor differentiation, nonintestinal Lauren histology, and vascular and perineural invasion were associated with worse DSS. Elevated NLR was also associated with worse DSS [hazard ratio (HR) = 1.11; 95% CI: 1.08-1.14; P < 0.01]. On multivariate analysis, pretreatment NLR as a continuous variable was a highly significant independent predictor of DSS. For every unit increase in NLR, the risk of cancer-associated death increases by approximately 10% (HR = 1.10; 95% CI: 1.05-1.13; P < 0.0001).In patients with resectable GE junction and gastric adenocarcinoma, pretreatment NLR independently predicts DSS. This and other clinical variables can be used in conjunction with cross-sectional imaging and endoscopic ultrasound as part of the preoperative risk stratification process.

Data on laparoscopic gastrectomy in patients with gastric cancer in the Western hemisphere are lacking. This study aimed to compare outcomes following laparoscopic versus open gastrectomy for gastric adenocarcinoma at a Western center. Eighty-seven consecutive patients who underwent laparoscopic gastrectomy from November 2005 to April 2013 were compared with 87 patients undergoing open resection during the same time period. Patients were matched for age, stage, body mass index, and procedure (distal subtotal vs. total gastrectomy). Endpoints were short- and long-term perioperative outcomes. Overall, 65 patients (37 %) had locally advanced disease, and 40 (23 %) had proximal tumors. The laparoscopic approach was associated with longer operative time (median 240 vs.165 min; p < 0.01), less blood loss (100 vs.150 mL; p < 0.01), higher rate of microscopic margin positivity (9 vs.1 %; p = 0.04), decreased duration of narcotic and epidural use (2 vs. 4 days, p = 0.04, and 3 vs. 4 days, p = 0.02, respectively), decreased minor complications in the early (27 vs. 16 %) and late (17 vs. 7 %) postoperative periods (p < 0.01), decreased length of stay (5 vs. 7 days; p = 0.01), and increased likelihood of receiving adjuvant therapy (82 vs. 51 %; p < 0.01). There was no difference in the number of lymph nodes retrieved (median 20 in both groups), major morbidity, or 30-day mortality. Laparoscopic gastrectomy for gastric adenocarcinoma is safe and effective for select patients in the West.

Abstract BACKGROUND: The aim of this study was to examine prospectively the utility of adding preoperative [ 18 F]fluorodeoxyglucose positron emission tomography (FDG‐PET)/computed tomography (CT) to routine CT, endoscopic ultrasound (EUS), and laparoscopic staging of localized gastric cancer. METHODS: Patients with locally advanced gastric/gastroesophageal cancer were screened for 2 institutional review board–approved Memorial Sloan‐Kettering Cancer Center neoadjuvant chemotherapy protocols. Locally advanced disease was defined as T3 or T4, or lymph node–positive, based on EUS and high‐resolution CT scan. All patients underwent both standard FDG‐PET/CT and laparoscopy with cytological examination of washings. The sensitivity and specificity of FDG‐PET/CT for the identification of metastatic disease not seen on CT was determined. An economic model using Medicare/Medicaid reimbursement charges was developed to assess the cost‐effectiveness of these interventions. RESULTS: A total of 113 patients were enrolled from 2003 to 2010. All patients were assessed as having locally advanced disease by CT/EUS. FDG uptake in the primary tumor was associated with male sex, proximal tumors, and nondiffuse Lauren's subtype. 31 (27%) patients had occult metastatic disease detected by PET/CT (n = 11, 10%) and/or laparoscopy (n = 21, 19%), with a single overlap. Economic modeling suggests that the addition of FDG‐PET/CT to the standard staging evaluation of patients with locally advanced gastric cancer resulted in an estimated cost savings of ∼US $13,000 per patient. CONCLUSIONS: FDG‐PET/CT identifies occult metastatic lesions in approximately 10% of patients with locally advanced gastric cancer. Because of reduced morbidity from fewer futile surgeries and lower patient care costs, PET/CT should be considered as a component of the standard staging algorithm for localized gastric cancer. Cancer 2012. © 2012 American Cancer Society.

We sought to develop a reliable and reproducible statistical model to predict the survival outcome of patients with localized melanoma. A total of 25,734 patients with localized melanoma from the 2008 American Joint Committee on Cancer (AJCC) Melanoma Database were used for the model development and validation. The predictive model was developed from the model development data set (n = 14,760) contributed by nine major institutions and study groups and was validated on an independent model validation data set (n = 10,974) consisting of patients from a separate melanoma center. Multivariate analyses based on the Cox model were performed for the model development, and the concordance correlation coefficients were calculated to assess the adequacy of the predictive model. Patient characteristics in both data sets were virtually identical, and tumor thickness was the single most important prognostic factor. Other key prognostic factors identified by stratified analyses included ulceration, lesion site, and patient age. Direct comparisons of the predicted 5- and 10-year survival rates calculated from the predictive model and the observed Kaplan-Meier 5- and 10-year survival rates estimated from the validation data set yielded high concordance correlation coefficients of 0.90 and 0.93, respectively. A Web-based electronic prediction tool was also developed ( http://www.melanomaprognosis.org/ ). This is the first predictive model for localized melanoma that was developed based on a very large data set and was successfully validated on an independent data set. The high concordance correlation coefficients demonstrated the accuracy of the predicted model. This predictive model provides a clinically useful tool for making treatment decisions, for assessing patient risk, and for planning and analyzing clinical trials.

Background An elevated neutrophil‐to‐lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD‐1 inhibition. Methods Patients undergoing initial treatment with PD‐1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan‐Meier and landmark analyses. Results Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow‐up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3‐2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2‐2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P &lt; .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months). Conclusions Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD‐1 inhibitor monotherapy. Combined, these biomarkers can widely risk‐stratify patients for treatment failure and survival.

Abstract Both the combination of nivolumab + ipilimumab and single‐agent anti‐ PD ‐1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti‐ PD ‐1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single‐center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial ( n = 122) or commercial use ( n = 87). Baseline routine laboratory values were correlated with overall survival ( OS ) and overall response rate ( ORR ). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded ( CR / PR ). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH , and a low neutrophil‐to‐lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti‐ PD ‐1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti‐ PD ‐1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti‐ PD ‐1 alone.

<h2>Abstract</h2><h3>Background</h3> Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant. Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients. <h3>Methods</h3> Using a prospectively maintained database, patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified. NLR was calculated before treatment and at 3-week intervals after treatment initiation until 9weeks. Baseline NLR was tested for association with overall survival (OS), progression free survival (PFS), and clinical response to treatment. On-treatment NLRs were tested for association with the same outcomes using landmark survival analyses and time-dependent Cox regression models. The association of relative change of NLR from baseline with outcomes was also examined. A multivariate model tested the association of NLR and OS/PFS with additional clinical factors. <h3>Results</h3> There were 197 IPI patients and 65 BRAFi patients. In multivariable analysis adjusting for M stage, and disease type (in OS)/gender (in PFS), an NLR value of 5 or above at every timepoint was associated with worse OS (HR 2.03–3.37, p<0.001), PFS (HR 1.81–2.51, p<0.001), and response to therapy (OR 3.92–9.18, p<0.007), in the IPI cohort. In addition, a >30% increase in NLR above baseline at any timepoint was associated with a worse OS and PFS (HR 1.81 and 1.66, p<0.004). In BRAFi patients, NLR was not consistently associated with outcomes. <h3>Conclusions</h3> A high NLR, whether measured prior to or during treatment with IPI, is associated with worse OS, PFS, and clinical response in patients with advanced melanoma. An increasing NLR from baseline during treatment was correlated with worse OS and PFS in IPI-treated patients. In comparison, as NLR was not associated with outcomes in BRAFi patients, NLR may have a uniquely predictive value in patients treated with immunotherapy.

The NCCN Guidelines for Melanoma have been significantly revised over the past few years in response to emerging data on a number of novel agents and treatment regimens. These NCCN Guidelines Insights summarize the data and rationale supporting extensive changes to the recommendations for systemic therapy in patients with metastatic or unresectable melanoma.

Objective: To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. Background: Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. Methods: We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). Results: OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size &gt;10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00–7.40, P &lt; 0.0001) and OS (HR 3.37, 95% CI 1.60–7.13, P = 0.001)]. Conclusions: Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size &gt;10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.

<h3>Importance</h3> Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care. <h3>Objective</h3> To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. <h3>Evidence Review</h3> The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed. <h3>Findings</h3> The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility. <h3>Conclusions and Relevance</h3> More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

We sought to define criteria associated with low lymph node metastasis risk in patients with submucosal (pT1b) gastric cancer from 3 Western and 3 Eastern countries.Accurate prediction of lymph node metastasis risk is essential when determining the need for gastrectomy with lymph node dissection following endoscopic resection. Under present guidelines, endoscopic resection is considered definitive treatment if submucosal invasion is only superficial, but this is not routinely assessed.Lymph node metastasis rates were determined for patient groups defined according to tumor pathological characteristics. Clinicopathological predictors of lymph node metastasis were determined by multivariable logistic regression and used to develop a nomogram in a randomly selected subset that was validated in the remainder. Overall survival was compared between Eastern and Western countries.Lymph node metastasis was found in 701 of 3166 (22.1%) Eastern and 153 of 560 (27.3%) Western patients. Independent predictors of lymph node metastasis were female sex, tumor size, distal stomach location, lymphovascular invasion, and moderate or poor differentiation. Patients fulfilling the National Comprehensive Cancer Network guideline criteria, excluding the requirement that invasion not extend beyond the superficial submucosa, had a lymph node metastasis rate of 8.9% (53/594). Excluding moderately differentiated tumors lowered the rate to 3.4% (10/296). The nomogram's area under the curve was 0.690. Regardless of lymph node status, overall survival was better in Eastern patients.The lymph node metastasis rate was lowest in patients with well differentiated tumors that were ≤3 cm and lacked lymphovascular invasion. These criteria may be useful in decisions regarding endoscopic resection as definitive treatment for pT1b gastric cancer.

Patients with melanoma are selected for sentinel lymph node biopsy (SLNB) based on their risk of a positive SLN. To improve selection, the Memorial Sloan Kettering Cancer Center (MSKCC) and Melanoma Institute Australia (MIA) developed predictive models, but the utility of these models remains to be tested.To determine the clinical utility of the MIA and MSKCC models.This was a population-based comparative effectiveness research study including 10 089 consecutive patients with cutaneous melanoma undergoing SLNB from the Swedish Melanoma Registry from January 2007 to December 2021. Data were analyzed from May to August 2023.The predicted probability of SLN positivity was calculated using the MSKCC model and a limited MIA model (using mitotic rate as absent/present instead of count/mm2 and excluding the optional variable lymphovascular invasion) for each patient. The operating characteristics of the models were assessed and compared. The clinical utility of each model was assessed using decision curve analysis and compared with a strategy of performing SLNB on all patients.Among 10 089 included patients, the median (IQR) age was 64.0 (52.0-73.0) years, and 5340 (52.9%) were male. The median Breslow thickness was 1.8 mm, and 1802 patients (17.9%) had a positive SLN. Both models were well calibrated across the full range of predicted probabilities and had similar external area under the receiver operating characteristic curves (AUC; MSKCC: 70.8%; 95% CI, 69.5-72.1 and limited MIA: 69.7%; 95% CI, 68.4-71.1). At a risk threshold of 5%, decision curve analysis indicated no added net benefit for either model compared to performing SLNB for all patients. At risk thresholds of 10% or higher, both models added net benefit compared to SLNB for all patients. The greatest benefit was observed in patients with T2 melanomas using a threshold of 10%; in that setting, the use of the nomograms led to a net reduction of 8 avoidable SLNBs per 100 patients for the MSKCC nomogram and 7 per 100 patients for the limited MIA nomogram compared to a strategy of SLNB for all.This study confirmed the statistical performance of both the MSKCC and limited MIA models in a large, nationally representative data set. However, decision curve analysis demonstrated that using the models only improved selection for SLNB compared to biopsy in all patients when a risk threshold of at least 7% was used, with the greatest benefit seen for T2 melanomas at a threshold of 10%. Care should be taken when using these nomograms to guide selection for SLNB at the lowest thresholds.

Hepatic metastases from soft-tissue sarcoma are evaluated to define treatment and its limitations.From 981 adult patients with diagnoses of soft-tissue sarcoma, 65 patients with hepatic metastases were studied.An intra-abdominal primary site was present in 61 of 65 patients, with 85% high-grade leiomyosarcoma. Hepatic resection was performed in 14 patients (22%). All patients have had recurrences after hepatic resection-11 of 14 in the liver--with a median survival of 30 months. Chemotherapy resulted in partial response in three patients and no complete responses. Survival is not influenced by grade, type, primary site, disease-free interval, chemotherapy, or hepatic resection.The uncommon response to conventional chemotherapy does not support its use in the treatment of hepatic metastases from soft-tissue sarcoma. Extent of disease limits the application and success of hepatic resection for soft-tissue sarcoma, and anything less than complete resection is not indicated.

Abstract Background Merkel cell carcinoma is a rare cutaneous neoplasm which commonly spreads to the regional lymph nodes. The feasibility of identifying the sentinel node in patients with clinically node-negative Merkel cell carcinoma was evaluated. Methods Sentinel lymphatic mapping was performed in 18 patients with stage 1 Merkel cell carcinoma using the combination of isosulphan blue dye and 99mTc-radiolabelled sulphur colloid. Patients with tumour metastasis in the sentinel node underwent complete dissection of the remainder of the lymph node basin. Results Eighteen patients underwent removal of 35 sentinel nodes. Two patients demonstrated metastatic disease in the sentinel lymph nodes; complete dissection of the involved nodal basin revealed no additional positive nodes suggesting that the sentinel lymph node had been identified. The node-negative patients received no further surgical therapy, with no evidence of recurrent disease in the sentinel nodal basin at a median of 7 months' follow-up. Conclusion Sentinel node biopsy is feasible in patients with Merkel cell carcinoma. It can be used to stage patients and provides important prognostic information. In those with subclinical nodal disease, it may direct early regional lymphadenectomy but the effect of such surgery on survival remains unclear.

Two new cases of papillary and cystic neoplasm of the pancreas are reported. One patient was a 20-year-old woman with massive unresectable liver metastases, and the other was a 15-year-old boy. To study the natural history and malignant potential of this tumor, the English literature was reviewed to obtain an additional 56 cases. Clinical characteristics include pain and a mass in most patients, although many are found incidentally. Jaundice, hemoperitoneum, nausea, and vomiting are unusual findings. Most patients are treated by wide resection with good results. These tumors appear to be indolent. However, 16% of patients had major organ or blood vessel invasion, and 7% had liver metastases at some time during the course of their disease, illustrating the malignant nature of this tumor. Long-term follow-up is necessary to evaluate the efficacy of treatment, especially in the case of locally advanced and metastatic disease.

This study was performed to evaluate the effect of a silver-impregnated cuff on the incidence of catheter-related bacteremia/fungemia or tunnel tract infection in cancer patients with chronic dual-lumen tunneled venous access catheters.Infection is a frequent and potentially life-threatening complication of tunneled chronic cuffed silastic central venous access catheters in cancer patients. Recent experience with antimicrobial silver-impregnated cuffs placed on nontunneled percutaneously inserted central venous catheters suggests that such a cuff may render the catheter less prone to infection.The authors prospectively randomized 200 cancer patients to receive either a dual-lumen 10 French tunneled cuffed silastic central venous access catheter or the same catheter with a second more proximal subcutaneous silver-impregnated cuff. All patients then were followed prospectively for infectious morbidity until the device was removed or the patient died.The hazard rate for infection/day (95% confidence limits) was 0.0022 (0.0015 to 0.0030) for standard catheters compared with 0.0027 (0.0019 to 0.0037) for catheters with silver-impregnated cuffs (p = not significant). Regression analysis of infection-free interval of both catheter types shows no difference over the lifetime of catheter as well as the over the first 48 days after insertion.The study indicated no effect of a silver-impregnated cuff in decreasing the incidence of catheter-related bacteremias/fungemias, tunnel infections, or the spectrum of causative microorganisms involved in cancer patients with tunneled chronic venous access catheters.

Abstract The American Joint Committee on Cancer (AJCC) implemented major revisions of the melanoma TNM and stage grouping criteria in the recently published 6th edition of the Staging Manual. The new staging system better reflects independent prognostic factors that are used in clinical trials and in reporting the outcomes of various melanoma treatment modalities. Major revisions include: 1) melanoma thickness and ulceration but not level of invasion to be used in the T classification, 2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of microscopic vs. macroscopic nodal metastases to be used in the N classification, 3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase (LDH) to be used in the M classification, 4) an upstaging of all patients with Stage I, II, and III disease when a primary melanoma is ulcerated, 5) a merging of satellite metastases around a primary melanoma and in transit metastases into a single staging entity that is grouped into Stage III disease, and 6) a new convention for defining clinical and pathological staging so as to take into account the new staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. Semin. Surg. Oncol. 21:43–52, 2003. © 2003 Wiley‐Liss, Inc.

BACKGROUND Long term intravenous access is a common requirement for cancer patients. This analysis was designed to determine device-related morbidity and factors predictive of poor long term outcome for patients with subcutaneous single lumen intravenous access ports. METHODS Six hundred eighty patients who underwent subcutaneous intravenous port placement between June 1987 and May 1989 at Memorial Sloan-Kettering Cancer Center were followed prospectively until port removal, death, or a maximum of 1960 days. Indications for and circumstances of placement, patient diagnoses, patient demographics, and subsequent courses of treatment were recorded, as well as technical and microbiologic device-related complications. Total, device specific, and complication free device durations were calculated. RESULTS The median patient age was 52.4 years (range, 1.6-83.9 years). The female-to-male ratio was 1.5 to 1. Cancer diagnoses included solid organ tumors (84%), leukemia (4%), lymphoma (11%), and others (1%). Indications included access for systemic chemotherapy (98%), total parenteral nutrition (0.5%), and others (1.5%). One insertion complication and six insertion failures occurred, without mortality. The estimated mean overall actuarial device specific duration was 1191 days (range, 2-1960 days). Actuarial mean complication free, device specific duration was 952 days. Complications included sepsis (n = 31; 4.4%), site infection (n = 31; 4.4%), and accessibility failures such as thrombosis and leakage (n = 40, 5.7%). Reasons for end of port duration were patient death (72.4%), end of treatment (13.5%), functional failure or intractable infection (11.2%), and others (2.9%). Independent factors correlating with decreased port specific, complication free duration included placement site, age, tumor type, and catheter tip position. CONCLUSIONS Subcutaneous intravenous access ports in cancer patients are safe and well tolerated. Long term device duration is primarily influenced by patient survival. In this study, 90% of patients alive at 1 year and 70% of patients alive at 4 years had a functional port. Cancer 1997; 79:1635-40. © 1997 American Cancer Society.

To define a group of patients with pancreatic cysts who do not require resection.The increased use of cross-sectional imaging has resulted in an increased identification of small, asymptomatic pancreatic cysts. Data have not been available to determine which lesions should be resected.All patients evaluated at our institution between January 1995 and January 2005 for the ICD-9 diagnosis of pancreatic cyst were reviewed. Analysis was performed to identify associations between patient and cyst characteristics, and selection of operative or nonoperative management.Pancreatic cysts were evaluated in 539 patients. Initial management was operative in 170 patients (32%), and nonoperative (radiographic follow-up) in 369 patients (68%). Factors associated with initial operative management included presence of a solid component (45% vs. 6%, P < 0.001), larger size of the lesion (mean 4.8 cm vs. 2.4 cm, P = 0.001), and presence of symptoms (44% vs. 16%, P = 0.001). Malignancy was present in 18% (32 of 170) of patients initially resected. Mucinous tumors (n = 18) were the most common malignant histologic subtype. None of the invasive cancers arising from mucinous cysts was <3 cm. Median radiographic follow-up in patients initially managed nonoperatively was 24 months (range, 1-172 months). In 29 patients (8%), changes developed within the cyst that resulted in resection; malignancy was present in 11 of 39 (38%), representing 3% (11 of 369) of all patients being followed radiographically.Selected patients with cystic lesions <3 cm in diameter and without a solid component may be followed radiographically with a malignancy risk (3% this study) that approximates the risk of mortality from resection. Malignancy within mucinous tumors is associated with size, and small mucinous tumors are very unlikely to be malignant.

In Brief Objective: This article reviews the pathogenesis, diagnosis, and treatment of patients with primary gastric lymphoma, with special attention to the changing role of surgery. Summary Background Data: Primary gastric lymphomas are non-Hodgkin lymphomas that originate in the stomach and are divided into low-grade (or indolent) and high-grade (or aggressive) types. Low-grade lesions nearly always arise from mucosa-associated lymphoid tissue (MALT) secondary to chronic Helicobacter pylori (H. pylori) infection and disseminate slowly. High-grade lesions may arise from a low grade-MALT component or arise de novo and can spread to lymph nodes, adjacent organs and tissues, or distant sites. Methods: A review of the relevant English-language articles was performed on the basis of a MEDLINE search from January 1984 to August 2003. Results: About 40% of gastric lymphomas are low-grade, and nearly all these low-grade lesions are classified as MALT lymphomas. For low-grade MALT lymphomas confined to the gastric wall and without certain negative prognostic factors, H. pylori eradication is highly successful in causing lymphoma regression. More advanced low-grade lymphomas or those that do not regress with antibiotic therapy can be treated with combinations of H. pylori eradication, radiation therapy, and chemotherapy. Nearly 60% of gastric lymphomas are high-grade lesions with or without a low-grade MALT component. These lymphomas can be treated with chemotherapy and radiation therapy according to the extent of disease. Surgery for gastric lymphoma is now often reserved for patients with localized, residual disease after nonsurgical therapy or for rare patients with complications. Conclusion: The treatment of gastric lymphoma continues to evolve, and surgical resection is now uncommonly a part of the initial management strategy. Gastric lymphomas consist of low- and high-grade non-Hodgkin lymphomas. Most low-grade lesions arise from mucosa-associated lymphoid tissue (MALT) associated with Helicobacter pylori (H. Pylori) infection and can often be treated solely with H. pylori eradication. High-grade gastric lymphomas are effectively treated with chemotherapy and radiation therapy. Surgical resection is rarely indicated in the initial management of patients with primary gastric lymphoma.

To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma.A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed.From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01).Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted.

Immunohistochemical detection of DNA mismatch repair proteins and polymerase chain reaction detection of microsatellite instability have enhanced the recognition of mismatch repair–deficient neoplasms in patients with Lynch syndrome and, consequently, led to the identification of tumors that have not been included in the currently known Lynch syndrome tumor spectrum. Here, we report 4 such unusual tumors. Three of the 4, a peritoneal mesothelioma, a pancreatic acinar cell carcinoma, and a pancreatic well-differentiated neuroendocrine tumor, represented tumor types that, to the best of our knowledge, have not been previously reported in Lynch syndrome. The fourth tumor was an adrenocortical carcinoma, which has rarely been reported previously in Lynch syndrome. Three of our 4 patients carried a pathogenic germ-line mutation in a mismatch repair gene. The unusual tumor in each of the 3 patients showed loss of the mismatch repair protein corresponding to the mutation. The fourth patient did not have mutation information but had a history of colonic and endometrial carcinomas; both lacked MSH2 and MSH6 proteins. Interestingly, none of the 4 unusual tumors revealed microsatellite instability on polymerase chain reaction testing, whereas an appendiceal carcinoma from 1 of the study patients who was tested simultaneously did. The recognition of such tumors expands the repertoire of usable test samples for the workup of high-risk families. As yet, however, there are no data to support the inclusion of these tumors into general screening guidelines for detecting Lynch syndrome, nor are there data to warrant surveillance for these tumors in patients with Lynch syndrome.

Children and teenagers with a positive sentinel lymph node (SLN) after a prior diagnosis of an atypical spitzoid melanocytic tumor (ASMT) are usually cared for clinically in the same way as patients with melanoma. Little is known about long-term follow-up of these individuals to determine whether this practice is appropriate. To learn more about the biology of these tumors we retrospectively reviewed the clinical and pathologic findings of children and teenagers (<18 y of age at the time of diagnosis) with an ASMT, positive SLN and follow-up of at least 3 years. Their findings were compared with histologically unambiguous melanomas of children or teenagers, who had a positive SLN or died of metastatic melanoma. Eleven individuals, 6 girls and 5 boys, with primary ASMT and positive SLN were identified. The primary tumors ranged in thickness from 2.1 to 12 mm (median, 4.6 mm; mean, 5 mm). The tumor mitotic rate ranged from 1 to 10 mitoses/mm2 (median, 3/mm2, median, 3/mm2). The positive SLNs included 6 nodes with intranodal melanocytic aggregates measuring <1 mm in greatest dimension, and 5 nodes, in which the size of the melanocyte deposits was ≥1 mm. All the patients with ASMT and positive SLN remained free of disease with a median follow-up of 47 months (mean, 61 mo, range: 36 to 132 mo). In contrast, 2 of 5 patients <18 years of age with a histologically unambiguous melanoma and a positive SLN died of metastatic melanoma. The overall disease-specific mortality rate for all patients <18 years of age diagnosed with melanoma was 12%. Our findings confirm that children and teenagers with ASMTs and positive SLNs have a less aggressive clinical course than those with histologically unambiguous melanoma.

Abstract BACKGROUND: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine neoplasm whose natural history is poorly understood. Here, the authors describe their experience with a large cohort of patients who were treated at a single institution to describe patterns of recurrence after curative therapy. METHODS: Review of a prospective database was performed. Patient‐related, tumor‐related, and treatment‐related variables were recorded, and the site and timing of initial recurrence were recorded. Factors associated with receipt of adjuvant therapy and recurrence were determined. RESULTS: In total, 364 patients with stage I through III MCC who underwent complete resection were identified. Adjuvant local radiation therapy (RT), lymph node RT, and chemotherapy were received selectively by 23%, 23%, and 15% of patients, respectively. Factors associated with the receipt of adjuvant therapy included younger age, primary tumor features (larger size, lymphovascular invasion [LVI], positive margin excision), and increasing pathologic stage. With median follow‐up of 3.6 years, 108 patients (30%) developed a recurrence, including 11 local recurrences (3%), 12 in‐transit recurrences (3%), 43 lymph node recurrences (12%), and 42 distant recurrences (12%). Clinically involved lymph nodes, primary tumor LVI, and a history of leukemia/lymphoma were predictive of recurrence. The majority of recurrences (80%) occurred in patients who had clinically involved lymph nodes or patients who did not undergo pathologic lymph node evaluation. CONCLUSIONS: A low recurrence rate in patients with clinically lymph node‐negative MCC was achieved with adequate surgery (including sentinel lymph node biopsy) and the selective use of adjuvant RT for high‐risk tumors. In contrast, patients with clinically lymph node‐positive MCC had significantly higher rates of recurrence, especially distant recurrence. The authors concluded that contemporary natural history studies are critical in designing treatment pathways and clinical trials for MCC. Cancer 2011. © 2011 American Cancer Society.