Predictors and Survival Impact of False-Negative Sentinel Nodes in Melanoma.

BACKGROUND: The status of the sentinel lymph node in melanoma is an important prognostic factor. The clinical predictors and implications of false-negative (FN) biopsy remain debatable. METHODS: We compared patients with positive sentinel lymph node biopsy (SNB) [true positive (TP)] and negative SNB with and without regional recurrence [FN, true negative (TN)] from our prospective institutional database. RESULTS: Among 2986 patients (84 FN, 494 TP, and 2408 TN; median follow-up 93 months), the incidence of FN-SNB was 2.8%. While calculated FN rate was 14.5% [84 FN/(494 TP + 84 FN) × 100], when we accounted for local/in-transit recurrence (LITR) this rate was 8.5% [46 FN/(494 TP + 46 FN) × 100 %]. On multivariate analysis, male gender (OR 2.0, 95% CI 1.1-3.6, p = 0.018), head/neck primaries (OR 2.5, 95% CI 1.3-4.8, p < 0.006), and LITR (OR 3.5, 95% CI 2.1-5.8, p < 0.001) were associated with FN-SNB. Melanoma-specific survival (MSS) for the FN group was similar to the TP group at 5 years (68 vs. 73%, p = 0.539). However, MSS declined more for the FN group with a longer follow up and was significantly worse at 10 years (44 vs. 64%, p < 0.001). On multivariate analysis, FN-SNB was a significant predictor of worse MSS in melanomas <4 mm in Breslow thickness (HR 1.6; 95% CI 1.1-2.5, p = 0.021). CONCLUSIONS: Male gender, LITR, and head and neck tumors were associated with FN-SNB. FN-SNB was an independent predictor of worse MSS in melanomas <4 mm in thickness, but this survival difference did not become apparent until after 5 years of follow-up.

Incorporating surgical quality into the AJCC 7th edition improves staging accuracy in gastric cancer.

BACKGROUND: The staging of gastric cancer has become increasingly complex. With an emerging 15-node quality measure and a revised American Joint Committee on Cancer (AJCC) staging system, we evaluated the need for more intricate staging systems to predict survival outcomes in gastric cancer. METHODS: The Surveillance, Epidemiology and End Results Program (SEER) database was used to identify 124,972 patients with gastric cancer between 2000 and 2010. Primary endpoints were 5-year disease-specific survival (DSS) and overall survival (OS). Analysis was performed on patients with ≥15 nodes evaluated. Multivariable regression with/without the inclusion of lymph node (LN) assessment and LN ratio were compared using the Akaike information criterion. RESULTS: The number of patients included in the final analysis was 12,096. The proportion of patients with an adequate lymphadenectomy increased markedly from 27 % in 2000 to 52 % in 2010. Overall 5-year DSS and OS was 61.9 and 48.8 %, respectively, for patients with ≥15 nodes examined, versus 57.7 and 39.9 %, respectively, for those with <15 sampled nodes (p < 0.0001). In patients with ≥15 nodes evaluated, the addition of LN evaluation and LN ratio to the existing staging model improved its ability to predict 5-year DSS and OS (p < 0.0001). LN evaluation and LN ratio were comparable in their ability to supplement the existing AJCC 7th edition (AJCC7) staging system. CONCLUSION: The inclusion of a minimum 15-LN quality measure improves the prognostic ability of the AJCC7 staging system, without adding significant complexity.

Attitudes and Perceptions of Surgical Oncology Fellows on ACGME Accreditation and the Complex General Surgical Oncology Certification.

BACKGROUND: With the first qualifying examination administered September 15, 2014, complex general surgical oncology (CGSO) is now a board-certified specialty. We aimed to assess the attitudes and perceptions of current and future surgical oncology fellows regarding the recently instituted Accreditation Council for Graduate Medical Education (ACGME) accreditation. METHODS: A 29-question anonymous survey was distributed to fellows in surgical oncology fellowship programs and applicants interviewing at our fellowship program. RESULTS: There were 110 responses (79 fellows and 31 candidates). The response rate for the first- and second-year fellows was 66 %. Ninety-percent of the respondents were aware that completing an ACGME-accredited fellowship leads to board eligibility in CGSO. However, the majority (80 %) of the respondents stated that their decision to specialize in surgical oncology was not influenced by the ACGME accreditation. The fellows in training were concerned about the cost of the exam (90 %) and expressed anxiety in preparing for another board exam (83 %). However, the majority of the respondents believed that CGSO board certification will be helpful (79 %) in obtaining their future career goals. Interestingly, candidate fellows appeared more focused on a career in general complex surgical oncology (p = 0.004), highlighting the impact that fellowship training may have on organ-specific subspecialization. CONCLUSIONS: The majority of the surveyed surgical oncology fellows and candidates believe that obtaining board certification in CGSO is important and will help them pursue their career goals. However, the decision to specialize in surgical oncology does not appear to be motivated by ACGME accreditation or the new board certification.

Evolving Therapeutic Strategies in Mucosal Melanoma Have Not Improved Survival Over Five Decades.

Mucosal melanoma represents a distinct minority of disease sites and portends a worse outcome. The ideal treatment and role of adjuvant therapy remains unknown at this time. We hypothesized that a combination of neoadjuvant and adjuvant therapies would improve survival in these aggressive melanomas. Our large, prospectively maintained melanoma database was queried for all patients diagnosed with mucosal melanoma. Over the past five decades, 227 patients were treated for mucosal melanoma. There were 82 patients with anorectal, 75 with sinonasal, and 70 with urogenital melanoma. Five-year overall survival and melanoma-specific survival for the entire cohort were 32.8 and 37.5 per cent, respectively, with median overall survival of 38.7 months. One hundred forty-two patients (63.8%) underwent adjuvant therapy and 15 were treated neoadjuvantly (6.6%). There was no survival difference by therapy type or timing, disease site, or decade of diagnosis. There was improved survival in patients undergoing multiple surgeries (Hazard Ratio [HR] 0.55, P = 0.0005). Patients receiving neoadjuvant therapy had significantly worse survival outcomes (HR 2.49, P = 0.013). Over the past five decades, improvements have not been seen in outcomes for mucosal melanoma. Although multiple surgical interventions portend a better outcome in patients with mucosal melanoma, adjuvant treatment decisions must be individualized.

Impact of Completion Lymph Node Dissection on Patients with Positive Sentinel Lymph Node Biopsy in Melanoma.

BACKGROUND: Whether patients with positive SLNB should undergo complete lymph node dissection (CLND) is an important unanswered clinical question. STUDY DESIGN: Patients diagnosed with positive SLNB at a melanoma referral center from 1991 to 2013 were studied. Outcomes of patients who underwent CLND were compared with those who did not undergo immediate CLND (observation [OBS] group). RESULTS: There were 471 patients who had positive SLNB; 375 (79.6%) in the CLND group and 96 (20.4%) in the OBS group. The groups were similar except that the CLND group was younger and had more sentinel nodes removed. Five-year nodal recurrence-free survival was significantly better in the CLND group compared with the OBS group (93.1% vs 84.4%; p = 0.005). However, 5-year (66.4% vs 55.2%) and 10-year (59.5% vs 45.0%) distant metastasis-free survival rates were not significantly different (p = 0.061). The CLND group's melanoma-specific survival (MSS) rate was superior to that of the OBS group; 5-year MSS rates were 73.7% vs 65.5% and 10-year MSS rates were 66.8% vs 48.3% (p = 0.015). On multivariate analysis, CLND was associated with improved MSS (hazard ratio = 0.60; 95% CI, 0.40-0.89; p = 0.011) and lower nodal recurrence (hazard ratio = 0.46; 95% CI, 0.24-0.86; p = 0.016). Increased Breslow thickness, older age, ulceration, and trunk melanoma were all associated with worse outcomes. On subgroup analysis, the following factors were associated with better outcomes from CLND: male sex, nonulcerated primary, intermediate thickness, Clark level IV or lower extremity tumors. CONCLUSIONS: Treatment of positive SLNB with CLND was associated with improved MSS and nodal recurrence rates. Follow-up beyond 5 years was needed to see a significant difference in MSS rates.

Long-Term Survival with Long-Acting Somatostatin Analogues Plus Aggressive Cytoreductive Surgery in Patients with Metastatic Neuroendocrine Carcinoma.

BACKGROUND: Long-acting somatostatin analogues (S-LAR) improve recurrence-free survival in patients with metastatic neuroendocrine tumor (NET) from gastrointestinal (GI) primary, but their impact on overall survival when combined with aggressive cytoreductive surgery is unclear. STUDY DESIGN: We reviewed our institutional cancer database to identify patients who underwent cytoreductive surgery for metastatic NET from GI primary between December 1997 and June 2013. Additionally, a cohort selected from 3,384 metastatic neuroendocrine cases in the SEER-Medicare database (January 2003 to December 2009) was used to verify and expand on our results. RESULTS: Most of the 49 patients from our institution had primary lesions in the small intestine (22 of 49 [44.9%]) or pancreas (14 of 49 [28.6%]); 37 patients (75.5%) had metastatic disease at initial diagnosis. These patients underwent 1 (32 of 49 [65.3%]), 2 (11 of 49 [22.4%]), or at least 3 (6 of 49 [12.3%]) surgical procedures; 33 patients (67.3%) underwent resection plus ablation, 19 (38.7%) underwent major hepatectomy, and 34 (69.4%) received S-LAR (29.4% administered preoperatively). Median follow-up was 112 months. Rates of 1-, 5-, 10-, and 15-year disease-specific survival (DSS) were 94%, 78%, 64%, and 31%, respectively, in the 34 patients undergoing aggressive cytoreductive surgery plus S-LAR. Of the SEER-Medicare population, 1,741 patients met inclusion criteria. The DSS for the 104 patients treated with combination therapy was 68.3% at 5 years and 60.6% at 10 years, as compared with 54.7% and 51.8%, respectively, for the 202 patients receiving surgery alone, and 50.0% and 36.0%, respectively, for the 342 patients receiving S-LAR alone (p < 0.0001). The group receiving neither treatment (n = 1,093) had 5-year and 10-year DSS of 34.3% and 26.3%, respectively. CONCLUSIONS: Long-acting somatostatin analogues combined with aggressive cytoreductive surgery improves the long-term survival of select patients with metastatic NET from GI primary.

Overall Survival Is Impacted by Birthplace and Not Extent of Surgery in Asian Americans with Resectable Gastric Cancer.

Survival from gastric cancer in the USA still lags behind Asia. Genetic, environmental, and tumor biology differences, along with extent of surgery have been implicated. Our aim was to evaluate survival outcomes in Asian-American gastric cancer patients undergoing surgical resection by comparing place of birth and clinicopathologic characteristics (including evaluation of 15 lymph nodes).The Surveillance, Epidemiology, and End Results database was queried to identify patients treated surgically for gastric cancer with curative intent in the USA (2000-2010). US-born versus foreign-born Asian-American patients were analyzed for survival. Secondary comparison was made to non-Asian patients. Stage IV and non-surgical patients were excluded. Of 10,089 patients identified, 1467 patients were Asian: 271 were born in the USA, and 1196 were born outside the USA. Median survival was 32 months for non-Asians and 29 months for US-born Asians versus 61 months for Asian immigrants (p < 0.001). On multivariable analysis of overall survival in Asian patients, only US birthplace, older age, and higher stage yielded a significantly poorer outcome. Asian-American patients have a worse prognosis if born in the USA. Anatomic and surgical differences do not explain this disparity; environmental factors may be responsible.

Immunoprofiling for prognostic assessment of colon cancer: a novel complement to ultrastaging.

BACKGROUND: Although AJCC/TNM staging remains the gold standard for prognostic assessment of colon cancer, stage-specific outcomes vary. We therefore prospectively evaluated the prognostic role of immunoprofiling. METHODS: Our cohort included 35 patients from an ongoing prospective trial of ultrastaging for colon cancer. Specimens were analyzed for T cell markers (CD3, CD4, CD8, and FoxP3). The number of tumor-infiltrating lymphocytes was analyzed at the tumor's margin and center and correlated with AJCC/TNM stage, clinicopathologic variables, and disease-free survival. RESULTS: There was a significant inverse association between number of CD3(+) cells in the tumor center and tumor stage (P = 0.05). The tumor center/margin ratio of CD3(+) cells also showed an inverse but non-significant relationship with nodal involvement (P = 0.07). Body mass index was inversely associated with numbers of CD3(+)(P = 0.04) and CD8(+)(P = 0.02) cells. Longer disease-free survival was correlated with higher CD8+ counts (P = 0.07), lower CD4(+)/CD8(+) ratios (P = 0.008), and higher CD8(+)/FoxP3(+) ratios (P = 0.02). CONCLUSIONS: This is the first prospective validation of immunoprofiling in patients whose colon cancer is staged with strict surgical and pathology quality measures. The apparent correlation between immunophenotypic response and clinical outcome warrants evaluation in a larger prospective trial.

A 20-year experience of hepatic resection for melanoma: is there an expanding role?

BACKGROUND: Melanoma liver metastasis is most often fatal, with a 4- to 6-month median overall survival (OS). Over the past 20 years, surgical techniques have improved in parallel with more effective systemic therapies. We reviewed our institutional experience of hepatic melanoma metastases. STUDY DESIGN: Overall and disease-specific survivals were calculated from hepatic metastasis diagnosis. Potential prognostic factors including primary tumor type, depth, medical treatment response, location, and surgical approach were evaluated. RESULTS: Among 1,078 patients with melanoma liver metastases treated at our institution since 1991, 58 (5.4%) received surgical therapy (resection with or without ablation). Median and 5-year OS were 8 months and 6.6 %, respectively, for 1,016 nonsurgical patients vs 24.8 months and 30%, respectively, for surgical patients (p < 0.001). Median OS was similar among patients undergoing ablation (with or without resection) relative to those undergoing surgery alone. On multivariate analysis of surgical patients, completeness of surgical therapy (hazard ratio [HR] 3.4, 95% CI 1.4 to 8.1, p = 0.007) and stabilization of melanoma on therapy before surgery (HR 0.38, 95% CI 0.19 to 0.78, p = 0.008) predicted OS. CONCLUSIONS: In this largest single-institution experience, patients selected for surgical therapy experienced markedly improved survival relative to those receiving only medical therapy. Patients whose disease stabilized on medical therapy enjoyed particularly favorable results, regardless of the number or size of their metastases. The advent of more effective systemic therapy in melanoma may substantially increase the fraction of patients who are eligible for surgical intervention, and this combination of treatment modalities should be considered whenever it is feasible in the context of a multidisciplinary team.

Small bowel carcinoid: Location isn't everything!

AIM: To investigate the prognostic significance of the primary site of disease for small bowel carcinoid (SBC) using a population-based analysis. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was queried for histologically confirmed SBC between the years 1988 and 2009. Overall survival (OS) and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method and compared using Log rank testing. Log rank and multivariate Cox regression analyses were used to identify predictors of survival using age, year of diagnosis, race, gender, tumor histology/size/location, tumor-node-metastasis stage, number of lymph nodes (LNs) examined and percent of LNs with metastases. RESULTS: Of the 3763 patients, 51.2% were male with a mean age of 62.13 years. Median follow-up was 50 mo. The 10-year OS and DSS for duodenal primaries were significantly better when compared to jejunal and ileal primaries (P = 0.02 and < 0.0001, respectively). On multivariate Cox regression analysis, after adjusting for multiple factors, primary site location was not a significant predictor of survival (P = 0.752 for OS and P = 0.966 DSS) while age, number of primaries, number of LNs examined, T-stage and M-stage were independent predictors of survival. CONCLUSION: This 21-year, population-based study of SBC challenges the concept that location of the primary lesion alone is a significant predictor of survival.

Leptin and nonessential amino acids enhance porcine preimplantation embryo development in vitro by intracytoplasmic sperm injection.

Intracytoplasmic sperm injection (ICSI) has been considered one of the strong assisted reproductive technologies for producing transgenic animals as well as treating infertility in animals and humans. However, in porcine ICSI, embryos produced by in vitro methods show low pregnancy rates with high abnormal offspring and blastocyst formation rate as well as quality are poor compared with those in other species. For these reasons, developing a protocol for porcine ICSI is essential to efficiently generate transgenic pigs. Since amino acids were introduced to embryo development because of their beneficial effects, many embryologists have been using nonessential amino acid (NEAA) in culture medium for embryonic development in pig and other species. Leptin also has been shown to be beneficial in embryonic development for increasing rate of cleavage and blastocyst development. However, the effects of NEAA and leptin were not fully understood in the development of porcine ICSI-derived embryos. Here we investigated the optimization of NEAA and leptin supplementation in culture medium to improve developmental competence and quality of preimplantation embryos after ICSI in pig. The proportion of embryos that developed to the blastocyst stage was significantly greater when 1% vol/vol NEAA (24.6%) or 100 ng/mL leptin (27.1%) was supplemented in the culture medium compared with other concentrations or no supplement. When NEAA and leptin (24.8%) were supplemented together, blastocyst formation was significantly higher than other single supplementation groups. We also evaluated the effects of different supplementation periods of NEAA or leptin on the preimplantation embryonic development after ICSI. Both NEAA and leptin showed that supplementation for the entire 7 days significantly increased the blastocyst formation rate compared with the other groups of supplementation for the first 4 days and for the subsequent 3 days. A second goal of our research was to evaluate the quality of developed blastocysts after ICSI. The supplementation of 100 ng/mL leptin in culture medium made blastocysts express less of the proapoptosis genes BAX and BAK and more of the antiapoptosis genes BCL-XL and BCL-2 after the ICSI procedure. Furthermore, terminal deoxynucleotidyl transferase dUTP nick end labeling index, fragmentation, and total apoptosis were significantly decreased and the total cell number was significantly increased when the ICSI-derived embryos were cultured to blastocyst stage in the presence of the combination of NEAA and leptin. These results suggest that NEAA and leptin could improve not only the quantity but also quality of ICSI-derived porcine embryos during in vitro culture with the optimal concentration of each reagent.

AJCC Cancer Staging Manual 7th edition criteria for colon cancer: do the complex modifications improve prognostic assessment?

BACKGROUND: The 7th edition of the AJCC Cancer Staging Manual (AJCC-7) includes substantial changes for colon cancer (CC), which are particularly complex in patients with stage II and III disease. We used a national cancer database to determine if these changes improved prediction of survival. STUDY DESIGN: The database of the Surveillance, Epidemiology and End Results Program was queried to identify patients with pathologically confirmed stage I to III CC diagnosed between 1988 and 2008. Colon cancer was staged by the 6(th) edition of the AJCC Cancer Staging Manual (AJCC-6) and then restaged by AJCC-7. Five-year disease-specific survival and overall survival were compared. RESULTS: After all exclusion criteria were applied, AJCC-6 and AJCC-7 staging was possible in 157,588 patients (68.9%). Bowker's test of symmetry showed that the number of patients per substage was different for AJCC-6 and AJCC-7 (p < 0.001). The Akaike information criteria comparison showed superior fit with the AJCC-7 model (p < 0.001). However, although AJCC-7 staging yielded a progressive decrease in disease-specific survival and overall survival of patients with stage IIA (86.3% and 72.4%, respectively), IIB (79.4% and 63.2%, respectively), and IIC (64.9% and 54.6%, respectively) CC, disease-specific survival and overall survival of patients with stage IIIA disease increased (89% and 79%, respectively). Subset analysis of patients with >12 lymph nodes examined did not affect this observation. CONCLUSIONS: The AJCC-7 staging of CC does not address all survival discrepancies, regardless of the number of lymph nodes examined. Consideration of other prognostic factors is critical for decisions about therapy, particularly for patients with stage II CC.

Isolation of canine mesenchymal stem cells from amniotic fluid and differentiation into hepatocyte-like cells.

Recent findings have demonstrated that amniotic fluid cells are an interesting and potential source of mesenchymal stem cells (MSCs). In this study, we isolated MSCs from canine amniotic fluid and then characterized their multilineage differentiation ability. Canine amniotic fluid stem (cAFS) cells at passage 5 had a fibroblast-like morphology instead of forming colonies and were positive for pluripotent stem cell markers such as OCT4, NANOG, and SOX2. Flow cytometry analysis showed the expression of MSC surface markers CD44, CD29, and CD90 on the cAFS cells. In addition, these cells were cultured under conditions favorable for adipogenic, chondrogenic, and osteogenic induction. The results of this experiment confirmed the mesenchymal nature of cAFS cells and their multipotent potential. Interestingly, although the cells exhibited a fibroblast-like morphology after hepatogenic induction, reverse transcription-polymerase chain reaction revealed that the expression of several hepatic genes, such as albumin, tyrosine aminotransferase, and alpha-1 antiproteinase, increased following maturation and differentiation. These findings indicated that cAFS cells have functional properties similar to those of hepatocytes. Taken together, the results of our study demonstrated that cAFS cells with mesenchymal characteristics can be successfully isolated from canine amniotic fluid and possess functional properties characteristic of hepatocytes. The findings of our work suggest that cAFS cells have the potential to be a resource for cell-based therapies in a canine model of hepatic disease.