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Purpose To determine whether three-dimensional subharmonic aided pressure estimation (SHAPE) and subharmonic imaging can help predict the response of breast cancer to neoadjuvant chemotherapy. Materials and Methods In this HIPAA-compliant prospective study, 17 women (age range, 45-70 years) scheduled to undergo neoadjuvant therapy for breast cancer underwent ultrasonography (US) immediately before therapy and at completion of 10%, 60%, and 100% of chemotherapy. All patients provided written informed consent. At each examination, radiofrequency data were collected from SHAPE and subharmonic imaging during infusion of a US contrast agent. Maximum-frequency magnitude and mean intensity were calculated for SHAPE and subharmonic imaging. The signal differences in the tumor relative to the surrounding area were compared with the final treatment response by using the Student t test. Results Four patients left the study, and data from two patients were discarded because of technical problems. Eight patients completed the entire imaging protocol, and an additional three patients dropped out after the imaging session at completion of 10% of chemotherapy as a result of disease progression (these patients were counted as nonresponders). Patients' imaging outcomes consisted of six responders (tumor volume reduction >90%) and five partial responders or nonresponders. The results at completion of 10% of therapy showed that the subharmonic signal increased more in the tumor than in the surrounding area for responders than in partial responders or nonresponders (mean ± standard deviation, 3.23 dB ± 1.41 vs -0.88 dB ± 1.46 [P = .001], respectively, for SHAPE and 1.32 dB ± 0.73 vs -0.82 dB ± 0.88 [P = .002], respectively, for subharmonic imaging). Moreover, three patients whose tumor measurements initially increased were correctly predicted to be responders with SHAPE and subharmonic imaging after completion of 10% of therapy. Conclusion SHAPE and subharmonic imaging have the potential to help predict response to neoadjuvant chemotherapy for breast cancer as early as completion of 10% of therapy, albeit on the basis of a small sample size. © RSNA, 2017 Online supplemental material is available for this article.

Background: Esophagectomy carries considerable morbidity. Many studies have evaluated factors to predict patients at risk. This study aimed to determine whether the surgical Apgar score (SAS) predicts complications and length of stay (LOS) for patients undergoing esophagectomy., Study Design: We evaluated 212 patients undergoing esophagectomy. Postoperative complications were graded using the Clavien-Dindo scale and the SAS was determined. Association of SAS with incidence of complications was evaluated using the Cochran-Armitage trend test between grouped SAS scores (0-2, 3-4, 5-6, 7-8, 9-10) and each of the outcomes. Correlation of SAS with LOS was evaluated using competing risks proportional hazards regression., Results: The average patient age was 63.5 years (range 31-86), and the average blood loss was 284 mL (range 50-4000). The median LOS was 10 days. There was a significant association between SAS and grade 2 or higher (P = 0.0002) and grade 3 or higher (P < 0.0001) complications. The perioperative mortality rate was 5.2% (n = 11) with lower SAS being associated with greater mortality. LOS was also associated with SAS (P < 0.0001)., Conclusions: We demonstrate that SAS is a significant predictor of complications and LOS for patients undergoing esophagectomy. SAS should be used to identify lower risk patients to prioritize use of critical care beds and hospital resources., (© 2017 Wiley Periodicals, Inc.)

Introduction: The effects of neoadjuvant chemoradiation therapy on lymph node retrieval during esophagectomy for patients with esophageal cancer are unclear. The aim of this study was to quantify lymph node retrieval after R0 esophagectomy and to assess its impact on overall survival in induction therapy patients., Methods: One hundred seventy-four consecutive patients underwent esophagectomy with or without induction therapy from 2008 to 2015 for esophageal cancer. Total lymph nodes, positive lymph nodes, and lymph node ratios were compared between two groups of patients: those treated with either upfront surgery or those treated with neoadjuvant chemoradiation therapy followed by surgery. Comparisons were made using Student's t test. Overall survival was obtained and compared using Kaplan Meier survival curves., Results: Total lymph node counts were less in the induction therapy group (p = 0.027), while positive lymph node counts and lymph node ratios did not differ between groups (p = 0.262 and p = 0.310, respectively). In the neoadjuvant chemoradiation followed by surgery group, overall survival was significantly shorter for patients who had any positive lymph nodes in the pathologic specimen (p = 0.0065)., Conclusions: Total lymph node counts were significantly lower in the induction therapy group, while positive lymph node counts and lymph node ratios did not differ from the upfront surgery group. Although overall survival was not different between groups, it was decreased within the induction therapy cohort among those who had any positive lymph nodes retrieved at surgery. This study confirms that unstratified gross lymph node counts do not substantially relate to prognosis in the heterogeneous population of locally advanced esophageal cancer patients who may or may not have had neoadjuvant chemoradiation.

Objectives: Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates., Methods: Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m/d over 96 h, weekly), paclitaxel (50 mg/m, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29)., Results: A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d., Conclusions: Vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.

Background: It is important to identify, from the patients' perspectives, the different factors that contribute toward psycho-social-spiritual healing., Methods: This was a qualitative study that took place at a large research center, an underserved clinic, and a community hospital. We used a needs assessment questionnaire and open-ended questions to assess the constituents of psycho-social-spiritual healing: (I) how previous life experiences affected patients' present situations in dealing with their illnesses; (II) barriers to palliative care, and (III) benefits of palliative care., Results: Of a total of 30 participants from 3 different study sites, 24 (80%) were receiving inpatient or outpatient palliative care at a research center. Thirteen (43%) participants were female, 10 (33%) were Black/African American, and 16 (53%) reported being on disability. While the initial shock of the diagnosis made participants feel unprepared for their illnesses, many looked to role models, previous work experiences, and spiritual as well as religious support as sources of strength and coping mechanisms. Barriers to palliative care were identified as either external (lack of proper resources) or internal (symptom barriers and perceived self-limitations). The feeling of "being seen/being heard" was perceived by many participants as the most beneficial aspect of palliative care., Conclusions: The needs assessment questionnaire and open-ended questions presented in this study may be used in clinical settings to better help patients achieve psycho-social-spiritual healing through palliative care and to help clinicians learn about the person behind the patient.

Background: Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear., Methods: In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis., Results: Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test); these results must be interpreted with caution. Nonsentinel-node metastases, identified in 11.5% of the patients in the dissection group, were a strong, independent prognostic factor for recurrence (hazard ratio, 1.78; P=0.005). Lymphedema was observed in 24.1% of the patients in the dissection group and in 6.3% of those in the observation group., Conclusions: Immediate completion lymph-node dissection increased the rate of regional disease control and provided prognostic information but did not increase melanoma-specific survival among patients with melanoma and sentinel-node metastases. (Funded by the National Cancer Institute and others; MSLT-II ClinicalTrials.gov number, NCT00297895 .).

Objective: This multicenter study sought to evaluate the accuracy of the American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) surgical risk calculator for predicting outcomes after pancreatoduodenectomy (PD) and to determine whether incorporating other factors improves its predictive capacity., Background: The ACS-NSQIP surgical risk calculator has been proposed as a decision-support tool to predict complication risk after various operations. Although it considers 21 preoperative factors, it does not include procedure-specific variables, which have demonstrated a strong predictive capacity for the most common and morbid complication after PD - clinically relevant pancreatic fistula (CR-POPF). The validated Fistula Risk Score (FRS) intraoperatively predicts the occurrence of CR-POPF and serious complications after PD., Methods: This study of 1480 PDs involved 47 surgeons at 17 high-volume institutions. Patient complication risk was calculated using both the universal calculator and a procedure-specific model that incorporated the FRS and surgeon/institutional factors. The performance of each model was compared using the c-statistic and Brier score., Results: The FRS was significantly associated with 30-day mortality, 90-day mortality, serious complications, and reoperation (all P < 0.0001). The procedure-specific model outperformed the universal calculator for 30-day mortality (c-statistic: 0.79 vs 0.68; Brier score: 0.020 vs 0.021), 90-day mortality, serious complications, and reoperation. Neither surgeon experience nor institutional volume significantly predicted mortality; however, surgeons with a career PD volume >450 were less likely to have serious complications (P < 0.001) or perform reoperations (P < 0.001)., Conclusions: Procedure-specific complication risk influences outcomes after pancreatoduodenectomy; therefore, risk adjustment for performance assessment and comparative research should consider these preoperative and intraoperative factors along with conventional ACS-NSQIP preoperative variables.

Intraoperative pyloric procedures are often performed during esophagectomies to reduce the rates of gastric conduit dysfunction. They include pyloroplasty (PP), pyloromyotomy (PM), and pylorus botulinum toxin type-A injections (BI). Despite these procedures, patients frequently warrant further endoscopic interventions. The aim of this study is to compare intraoperative pyloric procedures and the rates of postoperative endoscopic interventions following minimally invasive esophagectomy (MIE). We identified patients who underwent MIE for esophageal carcinoma and grouped them as 'None' (no intervention), 'PP', 'PM', or 'BI' based on intraoperative pyloric procedure type. The rates of endoscopic interventions for the first six postoperative months were compared. To adjust for variability due to MIE type, the rates of >1 interventions were compared using a zero-inflated Poisson regression analysis. Significance was established at P < 0.05. There were 146 patients who underwent an MIE for esophageal cancer from 2008 to 2015; 77.4% were three-hole MIE, and 22.6% were Ivor- Lewis MIE. BI was most frequent in Ivor-Lewis patients (63.5%), while PP was most frequent (46.9%) in three-hole patients. Postoperative endoscopic interventions occurred in 38 patients (26.0%). The BI group had the highest percentage of patients requiring a postoperative intervention (n = 13, 31.7%). After adjusting for higher rates of interventions in three-hole MIE patients, the BI and None groups had the lowest rates of >1 postoperative interventions. Our data did not show superiority of any pyloric intervention in preventing endoscopic interventions. The patients who received BI to the pylorus demonstrated a trend toward a greater likelihood of having a postoperative intervention. However when adjusted for type of MIE, the BI and None groups had lower rates of subsequent multiple interventions. Further research is needed to determine if the choice of intraoperative pyloric procedure type significantly affects quality of life, morbidity, and overall prognosis in these patients., (© The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with stage II melanoma have a considerable risk for recurrence. Current guidelines are imprecise as to optimal follow-up. We hypothesized that by examining recurrence patterns, we could help to better inform guidelines., Study Design: We queried IRB-approved melanoma databases of Thomas Jefferson University and University of North Carolina, identifying 581 patients with stage II melanoma between 1996 and 2015 with at least 1 year of follow-up. Data included location of first recurrence and how recurrence was detected (ie patient symptom, physician examination, or routine surveillance imaging). Cox regression with backward elimination was used for multivariable analysis., Results: One hundred and seventy-one patients had a recurrence (29.4%), the incidence increased considerably by stage sub-group. Significant predictors of recurrence included male sex (p = 0.003), ulceration (p = 0.03), and stage (p < 0.001). On multivariable analysis, male sex and stage continued to be significant (p < 0.01). For overall survival, regression, ulceration, stage, and age were significant predictors of survival. Stage, regression, and age remained significant by multivariable analysis. Patient symptoms were the most frequent mode of detection (40%), followed by physician examination (30%) and surveillance imaging (26%)-this did not differ significantly by stage. Regional nodes were the most common site of recurrence (30%), followed by lung (27%) and in-transit (18%)., Conclusions: The majority of recurrences in stage II melanoma are detected by patients and their physicians and rarely by routine imaging. As such, clinical follow-up and patient education are critical factors in detection of recurrence. With the prevalence of regional nodal recurrences, ultrasound might prove to be an important strategy in early recurrence detection., (Copyright © 2017 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: DecisionDx-Melanoma * is a 31-gene expression profile test that predicts the risk of metastasis in patients with primary cutaneous melanoma (CM). This study was designed to ascertain clinical management changes determined by the test outcome, which classifies CM patients being at low (Class 1) or high (Class 2) risk for recurrence., Research Design and Methods: Medical charts were reviewed from 156 CM patients from six institutions (three dermatology and three surgical oncology practices) who were consecutively tested between May 2013 and December 2015. Clinical management data that were compiled and compared before and after receipt of the 31-gene expression test result included frequency of physical exams, frequency and modality of imaging, and referrals to surgical and medical oncologists., Results: Forty-two percent of patients were Stage I, 47% were Stage II and 8% were Stage III. Overall, 95 patients (61%) were Class 1 and 61 (39%) were Class 2. Documented changes in management were observed in 82 (53%) patients, with the majority of Class 2 patients (77%) undergoing management changes compared to 37% of Class 1 patients (p < 0.0001 by Fisher's exact test). The majority (77/82, 94%) of these changes were concordant with the risk indicated by the test result (p < 0.0001 by Fisher's exact test), with increased management intensity for Class 2 patients and reduced management intensity for Class 1 patients., Conclusions: Molecular risk classification by gene expression profiling has clinical impact and influences physicians to direct clinical management of CM patients. The vast majority of the changes implemented after the receipt of test results were reflective of the low or high recurrence risk associated with the patient's molecular classification. Because follow-up data was not collected for this patient cohort, the study is limited for the assessment of the impact of gene expression profile based management changes on healthcare resource utilization and patient outcome.

Since the introduction of minimally invasive esophagectomy 25 years ago, its use has been reported in several high volume centers. With only one published randomized control trial and five meta-analyses comparing its outcomes to open esophagectomy, available level I evidence is very limited. Available technical approaches include total minimally invasive transthoracic (Ivor Lewis or McKeown) or transhiatal esophagectomy; several hybrid options are available with one portion of the procedure completed via an open approach. A review of available level I evidence with focus on total minimally invasive esophagectomy is presented. The old debate regarding the superiority of a transthoracic versus transhiatal approach to esophagectomy may have been settled by minimally invasive esophagectomy as only few centers are reporting on the latter being utilized. The studies with the highest level of evidence available currently show that minimally invasive techniques via a transthoracic approach are associated with less overall morbidity, fewer pulmonary complications, and shorter hospital stays than open esophagectomy. There appears to be no detrimental effect on oncologic outcomes and possibly an added benefit derived by improved lymph node retrieval. Quality of life improvements may also translate into improved survival, but no conclusive evidence exists to support this claim. Robotic and hybrid techniques have also been implemented, but there currently is no evidence showing that these are superior to other minimally invasive techniques.

Background: The management of intraductal papillomas on core biopsy continues to be controversial. Papillomas with atypia are typically excised. However, it is unclear whether surgical excision is warranted for benign lesions., Methods: A retrospective review of our institution's pathology and radiology databases from January 2009 through May 2014 identified 119 patients with a diagnosis of benign papilloma without atypia on core biopsy. We determined the rate of carcinoma identification on surgical excision., Results: The average patient age was 52.8 years (range 24-84 years). Indication for core biopsy included: abnormal imaging (n = 106), nipple discharge (n = 21), or palpable mass (n = 24). Seventy-five patients underwent surgical excision after core biopsy. Sixteen patients (21.3 %) had atypia in the excision specimen (combination atypical ductal hyperplasia, n = 11; atypical lobular hyperplasia, n = 8; lobular carcinoma-in situ, n = 3), 15 (93.8 %) of which were in the surrounding breast tissue. Two patients (2.7 %) had malignancy (ductal carcinoma-in situ and micropapillary carcinoma-in situ). As a result of surgical findings, 12 % of patients had a change in management. In comparing those with benign findings on surgical pathology and those whose disease was upstaged, there was no statistically significant difference in family history of breast cancer, indication for core biopsy, mammographic findings, or location of papilloma., Conclusions: Benign papillomas diagnosed on core biopsy are rarely upstaged to malignancy on surgical excision. However, at least 21 % of patients may have atypical findings in the surrounding tissue, which could change clinical management. Surgical excision should be considered in patients with benign papillomas.

Objective: To evaluate surgical performance in pancreatoduodenectomy using clinically relevant postoperative pancreatic fistula (CR-POPF) occurrence as a quality indicator., Background: Accurate assessment of surgeon and institutional performance requires (1) standardized definitions for the outcome of interest and (2) a comprehensive risk-adjustment process to control for differences in patient risk., Methods: This multinational, retrospective study of 4301 pancreatoduodenectomies involved 55 surgeons at 15 institutions. Risk for CR-POPF was assessed using the previously validated Fistula Risk Score, and pancreatic fistulas were stratified by International Study Group criteria. CR-POPF variability was evaluated and hierarchical regression analysis assessed individual surgeon and institutional performance., Results: There was considerable variability in both CR-POPF risk and occurrence. Factors increasing the risk for CR-POPF development included increasing Fistula Risk Score (odds ratio 1.49 per point, P < 0.00001) and octreotide (odds ratio 3.30, P < 0.00001). When adjusting for risk, performance outliers were identified at the surgeon and institutional levels. Of the top 10 surgeons (≥15 cases) for nonrisk-adjusted performance, only 6 remained in this high-performing category following risk adjustment., Conclusions: This analysis of pancreatic fistulas following pancreatoduodenectomy demonstrates considerable variability in both the risk and occurrence of CR-POPF among surgeons and institutions. Disparities in patient risk between providers reinforce the need for comprehensive, risk-adjusted modeling when assessing performance based on procedure-specific complications. Furthermore, beyond inherent patient risk factors, surgical decision-making influences fistula outcomes.

Introduction: Laparoscopic resection is rapidly becoming the treatment of choice for small- to medium-sized gastric gastrointestinal stromal tumors (GIST). While long-term oncologic data are available, quality of life outcomes are less known., Methods: Our IRB-approved prospectively maintained database was retrospectively queried (2003-2013) for patients who underwent laparoscopic gastric GIST resection. Demographics along with perioperative and oncologic outcomes were collected and analyzed. Patients were contacted and asked to complete a quality of life survey consisting of Likert scales scored from 1 to 5. Patients also completed the Gastrointestinal Quality of Life Index (GIQLI)., Results: A total of 69 patients were identified and 36 patients (59.0% of eligible patients) responded to the survey. Median follow-up was 39 months. Patients most commonly reported no change in weight, appetite, early satiety, heartburn, persistent cough, dysphagia, and reflux medication dosing postoperatively. The median scores for chest pain and regurgitation were 4, falling in the "worsened" range. 8.33% of patients reported worsened chest pain and 11.11% of patients reported worsened regurgitation postoperatively. The GIQLI scores had a mean of 126.9 (range 77-141)., Conclusion: While some patients reported a worsening in early satiety, most patients reported no change in symptoms postoperatively, and the GIQLI scores remained within the normal range. Laparoscopic resection of gastric GIST provides durable results with minimal effect on longer-term quality of life.

Activating mutations in neuroblastoma RAS viral oncogene homolog (NRAS) are frequent driver events in cutaneous melanoma. NRAS is a guanosine triphosphate-binding protein whose most well-characterized downstream effector is RAF, leading to activation of mitogen-activated protein kinase (MEK)-extracellular signal-regulated protein kinase 1/2 signaling. Although there are no Food and Drug Administration-approved targeted therapies for melanoma patients with a primary mutation in NRAS, one form of targeted therapy that has been explored is MEK inhibition. In clinical trials, MEK inhibitors have shown disappointing efficacy in mutant NRAS patients, the reasons for which are unclear. To explore the effects of MEK inhibitors in mutant NRAS melanoma, we used a high-throughput reverse-phase protein array platform to identify signaling alterations. Reverse-phase protein array analysis of phospho-proteomic changes in mutant NRAS melanoma in response to trametinib indicated a compensatory increase in v-akt murine thymoma viral oncogene homolog signaling and decreased expression of mitogen-inducible gene 6 (MIG6), a negative regulator of epidermal growth factor receptor/v-erb-b2 erythroblastic leukemia viral oncogene homolog receptors. MIG6 expression did not alter the growth or survival properties of mutant NRAS melanoma cells. Rather, we identified a role for MIG6 as a negative regulator of epidermal growth factor-induced signaling and cell migration and invasion. In MEK-inhibited cells, further depletion of MIG6 increased migration and invasion, whereas MIG6 expression decreased these properties. Therefore, a decrease in MIG6 may promote the migration and invasiveness of MEK-inhibited mutant NRAS melanoma, especially in response to epidermal growth factor stimulation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: International Study Group of Pancreatic Fistula (ISGPF) grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following pancreatoduodenectomy (PD); however, their infrequent occurrence has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication., Methods: Data were accrued from 4301 PDs worldwide. Demographics, postoperative management, and microbiological characteristics of grade C POPFs were evaluated. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative and intraoperative variables were compared between grade C POPFs and a 639-case sample of non-grade C POPFs. Risk factors for grade C POPF formation were identified using regression analysis., Results: Grade C POPFs developed in 79 patients (1.8 %). Deaths (90 days) occurred in 2.0 % (N = 88) of the overall series, with 35 % (N = 25) occurring in the presence of a grade C POPF. Reoperations occurred 72.2 % of the time. The rates of single- and multi-system organ failure were 28.2 and 39.7 %, respectively. Mortality rates escalated with pulmonary, renal, and neurologic organ failure, but they were unaffected by reoperation(s). The median number of complications incurred was four (IQR: 2-5), and the median duration of hospital stay was 32 (IQR: 21-54) days. Warning signs for impending grade C POPFs most often presented on postoperative day (POD) 6. Adjuvant chemotherapy might have benefited 55.7 % of grade C POPF patients, yet it was delayed in 25.6 % and never delivered in 67.4 % of these patients. Predictive models for grade C POPF occurrence based on preoperative factors alone and preoperative and intraoperative factors yielded areas under the receiver operating characteristic curve of 0.73 and 0.84 (both P < 0.000001), respectively., Conclusion: This global study represents the largest analysis of grade C POPFs following PD. It describes the severe burden that grade C POPFs incur on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing death and delay/omission of adjuvant therapy. Additionally, aggressive clinical management for these POPFs did not improve or worsen 90-day mortality. Predictive tools developed through these data may provide value in managing this difficult complication.

Rapidly accelerated fibrosarcoma (RAF) inhibitors are first-line treatments for patients harboring V600E/K mutant BRAF melanoma. Although RAF inhibitors produce high response rates, the degree of tumor regression is heterogeneous. Compensatory/adaptive responses to targeted inhibitors are frequently initiated by the activation of growth factor receptor tyrosine kinases, including ErbB3, and factors from the tumor microenvironment may play an important role. We have shown previously that mutant v-raf murine sarcoma viral oncogene homolog B1 (BRAF) melanoma cells have enhanced activation of ErbB3 following RAF inhibition. However, the source of neuregulin 1 (NRG1), the ligand for ErbB3, is unknown. In this study, we demonstrate that NRG1 is highly expressed by dermal fibroblasts and cancer-associated fibroblasts (CAFs) isolated from mutant BRAF melanomas. Conditioned medium from fibroblasts and CAFs enhanced ErbB3 pathway activation and limited RAF inhibitor cytotoxicity in V600 mutant BRAF-harboring melanomas. Targeting the ErbB3/ErbB2 pathway partially reversed the protective effects of fibroblast/CAF-derived NRG1 on cell growth properties of RAF inhibitor-treated melanoma cells. These findings support the idea that NRG1, acting in a paracrine manner, promotes resistance to RAF inhibitors and emphasize that targeting the ErbB3/ErbB2 pathway will likely improve the efficacy of RAF inhibitors for mutant BRAF melanoma patients., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Purpose: To evaluate the rate of gastrointestinal (GI) toxicity of neoadjuvant chemoradiation with capecitabine, oxaliplatin, and intensity modulated radiation therapy (IMRT) in cT3-4 rectal cancer., Methods and Materials: Patients with localized, nonmetastatic T3 or T4 rectal cancer <12 cm from the anal verge were enrolled in a prospective, multi-institutional, single-arm study of preoperative chemoradiation. Patients received 45 Gy with IMRT in 25 fractions, followed by a 3-dimensional conformal boost of 5.4 Gy in 3 fractions with concurrent capecitabine/oxaliplatin (CAPOX). Surgery was performed 4 to 8 weeks after the completion of therapy. Patients were recommended to receive FOLFOX chemotherapy after surgery. The primary endpoint of the study was acute grade 2 to 5 GI toxicity. Seventy-one patients provided 80% probability to detect at least a 12% reduction in the specified GI toxicity with the treatment of CAPOX and IMRT, at a significance level of .10 (1-sided)., Results: Seventy-nine patients were accrued, of whom 68 were evaluable. Sixty-one patients (89.7%) had cT3 disease, and 37 (54.4%) had cN (+) disease. Postoperative chemotherapy was given to 42 of 68 patients. Fifty-eight patients had target contours drawn per protocol, 5 patients with acceptable variation, and 5 patients with unacceptable variations. Thirty-five patients (51.5%) experienced grade ≥ 2 GI toxicity, 12 patients (17.6%) experienced grade 3 or 4 diarrhea, and pCR was achieved in 10 patients (14.7%). With a median follow-up time of 3.98 years, the 4-year rate of locoregional failure was 7.4% (95% confidence interval [CI]: 1.0%-13.7%). The 4-year rates of OS and DFS were 82.9% (95% CI: 70.1%-90.6%) and 60.6% (95% CI: 47.5%-71.4%), respectively., Conclusion: The use of IMRT in neoadjuvant chemoradiation for rectal cancer did not reduce the rate of GI toxicity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Genomic research has generated much new knowledge into mechanisms of human disease, with the potential to catalyze novel drug discovery and development, prenatal and neonatal screening, clinical pharmacogenomics, more sensitive risk prediction, and enhanced diagnostics. Genomic medicine, however, has been limited by critical evidence gaps, especially those related to clinical utility and applicability to diverse populations. Genomic medicine may have the greatest impact on health care if it is integrated into primary care, where most health care is received and where evidence supports the value of personalized medicine grounded in continuous healing relationships. Redesigned primary care is the most relevant setting for clinically useful genomic medicine research. Taking insights gained from the activities of the Institute of Medicine (IOM) Roundtable on Translating Genomic-Based Research for Health, we apply lessons learned from the patient-centered medical home national experience to implement genomic medicine in a patient-centered, learning health care system., (© 2015 Annals of Family Medicine, Inc.)

Around the world, innovative genomic-medicine programs capitalize on singular capabilities arising from local health care systems, cultural or political milieus, and unusual selected risk alleles or disease burdens. Such individual efforts might benefit from the sharing of approaches and lessons learned in other locales. The U.S. National Human Genome Research Institute and the National Academy of Medicine recently brought together 25 of these groups to compare projects, to examine the current state of implementation and desired near-term capabilities, and to identify opportunities for collaboration that promote the responsible practice of genomic medicine. Efforts to coalesce these groups around concrete but compelling signature projects should accelerate the responsible implementation of genomic medicine in efforts to improve clinical care worldwide., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Minimally invasive esophagectomy (MIE) is increasingly being used to treat patients with cancer of the esophagus and gastroesophageal junction. We previously reported that oncologic efficacy may be improved with MIE compared with open or hybrid esophagectomy (OHE). We compared survival of patients undergoing MIE and OHE., Study Design: Our contemporary series of patients who underwent MIE (2008 to 2013) was compared with a cohort undergoing OHE (3-hole [n = 39], Ivor Lewis [n = 16], hybrid [n = 13], 2000 to 2013). Summary statistics were calculated by operation type; Kaplan-Meier methods were used to compare survival. Cox regression was used to assess the impact of operation type (MIE vs OHE) on mortality, adjusting for age, sex, total lymph nodes, lymph node ratio (LNR), neoadjuvant chemoradiotherapy (CRT), and stage., Results: The MIE (n = 104) and OHE (n = 68) groups were similar with respect to age and sex. The MIE group tended to have higher BMI, earlier stage disease, and was less likely to receive CRT. The MIE group experienced lower operative mortality (3.9% vs 8.8%, p = 0.35) and significantly fewer major complications. Five-year survival between groups was significantly different (MIE, 64%, OHE, 35%, p < 0.001). Multivariate analysis demonstrated that patients undergoing OHE had a significantly worse survival compared with MIE independent of age, LNR, CRT, and pathologic stage (hazard ratio 2.00, p = 0.019)., Conclusions: This study supports MIE for EC as a superior procedure with respect to overall survival, perioperative mortality, and severity of postoperative complications. Several biases may have affected these results: earlier stage in the MIE group and disparity in timing of the procedures. These results will need to be confirmed in future prospective studies with longer follow-up., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Pannexin1 (Panx1), a channel-forming glycoprotein is expressed in neonatal but not in aged mouse skin. Histological staining of Panx1 knockout (KO) mouse skin revealed a reduction in epidermal and dermal thickness and an increase in hypodermal adipose tissue. Following dorsal skin punch biopsies, mutant mice exhibited a significant delay in wound healing. Scratch wound and proliferation assays revealed that cultured keratinocytes from KO mice were more migratory, whereas dermal fibroblasts were more proliferative compared with controls. In addition, collagen gels populated with fibroblasts from KO mice exhibited significantly reduced contraction, comparable to WT fibroblasts treated with the Panx1 blocker, probenecid. KO fibroblasts did not increase α-smooth muscle actin expression in response to TGF-β, as is the case for differentiating WT myofibroblasts during wound contraction. We conclude that Panx1 controls cellular properties of keratinocytes and dermal fibroblasts during early stages of skin development and modulates wound repair upon injury.

Objectives: To investigate the use of contrast-enhanced ultrasound imaging (US) for detection of secondary lymph nodes (LNs) in a naturally occurring melanoma swine model compared to surgery and pathologic assessment., Methods: Twenty-seven Sinclair swine were studied. The perfluorobutane microbubble contrast agent Sonazoid (GE Healthcare, Oslo, Norway) was administered (1.0 mL total dose) around the melanoma, and contrast-enhanced US was used to localize contrast-enhanced sentinel lymph nodes (SLNs). Then Sonazoid (dose, 0.25-1.0 mL) was injected into the SLNs to detect contrast-enhanced efferent lymphatic channels and secondary LNs. After peritumoral injection of blue dye, a surgeon (blinded to the contrast-enhanced US results) performed a radical LN dissection. Contrast-enhanced US was used to guide removal of any enhanced secondary LNs left after radical LN dissection. Clustered conditional logistic regression analyzed the benefit of contrast-enhanced US-directed secondary LN dissection over radical LN dissection using pathologic findings as the reference standard., Results: A total of 268 secondary LNs were resected, with 59 (22%) containing metastases. Contrast-enhanced US detected 92 secondary LNs; 248 were identified by radical LN dissection; and 68 were identified by both methods. Metastases were detected in 20% (51 of 248) and 40% (37 of 92) of the secondary LNs identified by radical LN dissection and contrast-enhanced US, respectively. Thus, secondary LNs detected by contrast-enhanced US were nearly 5 times more likely to contain metastases than secondary LNs removed by radical LN dissection (odds ratio, 4.8; P < .0001). Twenty-two of the 180 secondary LNs (12%) identified only by radical LN dissection contained metastases, whereas contrast-enhanced US identified 20 secondary LNs after the surgeon completed the radical LN dissection, of which 8 (40%) contained metastases., Conclusions: Secondary LNs can be detected by using contrast-enhanced US after injection of Sonazoid into SLNs. Secondary LNs detected with contrast-enhanced US are significantly more likely to contain metastases than those removed by radical LN dissection., (© 2014 by the American Institute of Ultrasound in Medicine.)

Perform a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) in patients with brain metastasis. A multi-institutional phase I clinical trial enrolled patients with a histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 to 400 mg daily using a 3+3 trial design. Seventeen patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n = 1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 and 300 mg dose levels. In the 400 mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Both events were most likely related to disease progression rather than treatment; nonetheless, we conservatively classified the death as a dose limiting toxicity. We found Vorinostat administered with concurrent WBRT to be well tolerated to a dose of 300 mg once daily. This is the recommended dose for phase II study.

Connexin 30 (Cx30), a member of the large gap-junction protein family, plays a role in the homeostasis of the epidermis and inner ear through gap junctional intercellular communication (GJIC). Here, we investigate the underlying mechanisms of four autosomal dominant Cx30 gene mutations that are linked to hearing loss and/or various skin diseases. First, the T5M mutant linked to non-syndromic hearing loss formed functional gap junction channels and hemichannels, similar to wild-type Cx30. The loss-of-function V37E mutant associated with Clouston syndrome or keratitis-ichthyosis-deafness syndrome was retained in the endoplasmic reticulum and significantly induced apoptosis. The G59R mutant linked to the Vohwinkel and Bart-Pumphrey syndromes was retained primarily in the Golgi apparatus and exhibited loss of gap junction channel and hemichannel function but did not cause cell death. Lastly, the A88V mutant, which is linked to the development of Clouston syndrome, also significantly induced apoptosis but through an endoplasmic-reticulum-independent mechanism. Collectively, we discovered that four unique Cx30 mutants might cause disease through different mechanisms that also likely include their selective trans-dominant effects on coexpressed connexins, highlighting the overall complexity of connexin-linked diseases and the importance of GJIC in disease prevention.

Background and Objective: Our goal was to evaluate the different subtypes of mucosal melanoma and describe specific variables that predict outcomes., Methods: Prospective review of two tertiary care center databases identified 76 mucosal melanoma patients; 73 with complete records were included. Demographic and clinical data were analyzed. Cox regression determined variables impacting recurrence and survival., Results: In the 73 patients, the mean age was 64 years, and 74% were female. Sixty-seven percent presented with lymph node involvement, and 73% had ulcerated tumors. Major sites affected were nasal/palate/oral (36%), vulvar/vaginal/cervical (48%), and anorectal (15%). Mean overall and disease-free survival were 56.9 and 27.2 months. Variables associated with decreased survival included: lymphovascular invasion (HR17.70, P = 0.0093), Caucasian race (HR3.02, P = 0.0362), nasal/palate/oral sub-group (HR1.85, P = 0.026), Breslow thickness (HR1.23, P = 0.00004), T stage (HR1.34, P = 0.0075), M stage (HR3.03, P = 0.0039), and chemotherapy (HR3.13, P = 0.0002). The worst prognosis was seen in the nasal/palate/oral sub-group, with a median overall survival of 9.7 months and recurrence-free time of 4.5 months. This subtype also demonstrated high lymph node positivity, ulceration, and larger tumor size., Conclusion: The nasal, palate, oral subtype has the worst prognosis compared to other mucosal melanoma locations. Studies are ongoing to evaluate pathologic and genomic variables that may predict outcomes., (© 2013 Wiley Periodicals, Inc.)

Background: Recurrence of pancreatic adenocarcinoma after pancreaticoduodenectomy (PD) can be increased in patients with pancreatic fistula (PF). The purpose of our study was to determine if a relationship exists between PF and tumor recurrence (both peritoneal and local) in patients after PD for pancreatic ductal adenocarcinoma., Study Design: A single-institution, retrospective analysis of 221 patients who underwent PD from January 2001 to December 2009 was conducted. Electronic charts and medical records were queried for tumor characteristics, recurrence, and complications. Presence and grading of PF was determined using the criteria of the International Study Group on Pancreatic Fistula. Data were analyzed using chi-square and Kaplan-Meier survival statistics., Results: There were 114 male and 107 female patients. Mean age was 66 years (range 35 to 91 years). The vast majority (84%) of patients had stage II disease; 143 (65%) had positive lymph nodes (median 2 positive nodes; range 1 to 17 positive nodes). Pancreatic fistula developed in 23 patients (grade A, n = 9; grade B, n = 13; grade C, n = 1; 10.2%). Peritoneal recurrence was noted in 20 patients (9%). Of the 23 patients with PF, peritoneal recurrence developed in 3 (13%). Of the 198 patients without PF, peritoneal recurrence developed in 17 (10%). Local recurrence occurred in 47 patients (21%), 5 (2%) in patients with PF and 42 (21%) in those without PF (p = NS). In Kaplan-Meier survival analysis, there was no significant difference in recurrence-free survival (p = 0.4) and overall survival (p = 0.3) for those with PF vs those without PF., Conclusions: Patients with PF after PD were not found to have a significant increase in local or peritoneal recurrence. Therefore, in this analysis, postoperative PF does not appear to serve as an adverse prognostic marker., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

The antigen processing compartments in antigen-presenting cells (APCs) have well known characteristics of multivesicular bodies (MVBs). However, the importance of MVB integrity to APC function remains unknown. In this study, we have altered the ultrastructure of the MVB by perturbing cholesterol content genetically through the use of a deletion of the lipid transporter Niemann-Pick type C1 (NPC1). Immunofluorescence and electron microscopic analyses reveal that the antigen processing compartments in NPC1(-/-) dendritic cells (DCs) have an abnormal ultrastructure in that the organelles are enlarged and the intraluminal vesicles are almost completely absent and those remaining are completely disorganized. MHC-II is restricted to the limiting membrane of these enlarged MVBs where it colocalizes with the peptide editor H2-DM. Curiously, proteolytic removal of the chaperone protein Invariant chain from MHC-II, degradation of internalized foreign antigens, and antigenic-peptide binding to nascent MHC-II are normal in NPC1(-/-) DCs. Antigen-pulsed NPC1(-/-) DCs are able to effectively activate antigen-specific CD4 T cells in vitro, and immunization of NPC1(-/-) mice reveals surprisingly normal CD4 T cell activation in vivo. Our data thus reveal that the localization of MHC-II on the intraluminal vesicles of multivesicular antigen processing compartments is not required for efficient antigen presentation by DCs.

The incidence of melanoma is increasing rapidly in the United States. Sentinel lymph node biopsy is an important diagnostic tool in the treatment and staging of melanoma. However, many patients with melanoma will have had lymph node surgery for previous melanoma or breast cancer. We set out to examine alterations in drainage patterns in patients with previous axillary dissection for breast cancer. We reviewed four patients with truncal and/or extremity melanomas and examined their lymphoscintigraphy and drainage patterns. Three patients with truncal melanoma mapped to cervical lymph nodes and a fourth patient with an arm melanoma mapped to her previously dissected axilla. Sentinel lymph node mapping is still an important adjunct in patients with melanoma despite previous axillary dissection., (© 2013 Japanese Dermatological Association.)

As the link between obesity and metabolic syndrome and cancer becomes clearer, the need to determine the optimal way to incorporate dietary manipulation in the treatment of cancer patients becomes increasingly important. Metabolic-based therapies, such as caloric restriction, intermittent fasting and a ketogenic diet, have the ability to decrease the incidence of spontaneous tumors and slow the growth of primary tumors, and may have an effect on distant metastases in animal models. Despite the abundance of preclinical data demonstrating the benefit of dietary modification for cancer, to date there are few clinical trials targeting diet as an intervention for cancer patients. We hypothesize that this may be due, in part, to the fact that several different types of diet modification exist with no clear recommendations regarding the optimal method. This article will delineate three commonly used methods of dietary manipulation to assess the potential of each as a regimen for cancer therapy.

John Chalmers DaCosta was an influential chairman and the first Samuel D. Gross Professor of Surgery at Jefferson Medical College in Philadelphia. He was well known throughout the field as a skilled surgeon, passionate speaker, and exceptional writer. In addition to countless accomplishments during his career, DaCosta was deeply dedicated to the preservation and commemoration of surgical history. This ideology was exemplified when he set out on a mission to recover the old wooden operating table used by many of his iconic mentors including Samuel D. Gross, Joseph Pancoast, and William W. Keen. This table was originally used for surgical demonstrations and anatomy lessons in a lecture room of the Ely Building and later in the great amphitheater of the Jefferson Sansom Street Hospital. It was found forgotten in the basement of the College Building and was promptly refurbished, donned with dedicatory plaques, and returned to its honored position in the medical college. Dr. DaCosta also contributed a detailed article recalling the history of the table and the notable leaders in surgery who taught and practiced on its surface. The old table currently stands proudly in the entranceway of the Department of Surgery where it will remain as a cherished symbol of the early beginnings of surgical practice and education.

Introduction: The incidence of cancer of the esophagus/GE junction is dramatically increasing but continues to have a dismal prognosis. Esophagectomy provides the best opportunity for long-term cure but is hampered by increased rates of perioperative morbidity. We reviewed our large institutional experience to evaluate the impact of postoperative complications on the long-term survival of patients undergoing resection for curative intent., Methods: We identified 237 patients who underwent esophagogastrectomy, with curative intent, for cancer between 1994 and 2008. Complications were graded using the previously published Clavien scale. Survival was calculated using Kaplan-Meier methodology and survival curves were compared using log-rank tests. Multivariate analysis was performed with continuous and categorical variables as predictors of survival, and examined with logistic regression and odds ratio confidence intervals., Results: There were 12 (5 %) perioperative deaths. The average age of all patients was 62 years, and the majority (82 %) was male. Complication grade did not significantly affect long-term survival, although patients with grade IV (serious) complications did have a decreased survival (p = 0.15). Predictors of survival showed that the minimally invasive type esophagectomy (p = 0.0004) and pathologic stage (p = 0.0007) were determining factors. There was a significant difference in overall survival among patients who experienced pneumonia (p = 0.00016) and respiratory complications (p = 0.0004), but this was not significant on multivariate analysis., Conclusions: In this single-institution series, we found that major perioperative morbidity did not have a negative impact on long-term survival which is different than previous series. The impact of tumor characteristics at time of resection on long-term survival is of most importance.

Introduction: Pancreaticoduodenectomy (PD) has a high morbidity rate. Previous work has shown that hypoalbuminemia on postoperative day 1 (POD) to be contributory to post-esophagectomy complications. We set out to determine the impact of blood urea nitrogen (BUN) and albumin on POD 1 for patients undergoing PD., Methods: We examined 446 consecutive patients who underwent PD at the Thomas Jefferson University Hospital between January 1, 2000 and December 31, 2008. Complications were graded using the Clavien scale. We examined the incidence of complications based on POD 1 albumin <2.5 versus ≥2.5 mg/dl, as well as POD 1 BUN <10 vs. ≥10 g/dL., Results: Patients with a BUN <10 had a significantly decreased risk of any complication (p < 0.001), serious complication (p < 0.001), and pancreatic fistula (p = 0.011). On multivariate analysis, BUN ≥ 10 was the most significant predictor of grade III or above complication (p = 0.0019, hazard ration (HR) = 2.7) and pancreatic fistula (p = 0.016, HR = 2.6). POD 1 albumin <2.5 mg/dl was also an independent predictor of serious complication (p = 0.01, HR = 2.3). Patients with both risk factors had a 31 % chance of developing serious complications and 18.5 % risk of developing pancreatic fistula, while those patients with neither risk factor had a 6.5 and 3.6 % risk, respectively., Conclusion: Serum albumin and BUN on POD 1 are important predictors of perioperative morbidity following PD. These low-cost and easily accessible tests can be used as a prognostic tool to predict adverse surgical outcomes.

Tumor cells often use developmental processes to progress toward advanced disease. The E-box transcription factor TWIST1 is essential to epithelial-mesenchymal transition (EMT) and cell migration in the developing neural crest. In melanoma, which derives from the neural crest cell lineage, enhanced TWIST1 expression has been linked to worse clinical prognosis. However, mechanisms underlying TWIST1 expression and whether aberrant TWIST1 levels promote steps in melanoma progression remain unknown. Here, we report that elevated TWIST1 mRNA/protein expression is dependent on extracellular signal-regulated kinase (ERK)1/2 signaling, which is hyperactive in the majority of melanomas. We show that TWIST1 protein levels are especially high in melanoma cell lines generated from invasive, premetastatic stage tumors. Furthermore, TWIST1 expression is required and sufficient to promote invasion through Matrigel and spheroid outgrowth in three-dimensional dermal-mimetic conditions. Alterations to spheroid outgrowth were not as a result of altered cell death, cell-cycle profile, or paradigm EMT protein changes. Importantly, we identify matrix metalloproteinase-1 (MMP-1) as a novel downstream target of TWIST1. We have determined that TWIST1 acts, in a dose-dependent manner, as a mediator between hyperactive ERK1/2 signaling and regulation of MMP-1 transcription. Together, these studies mechanistically show a previously unrecognized interplay between ERK1/2, TWIST1, and MMP-1 that is likely significant in the progression of melanoma toward metastasis.

Introduction: Gastrointestinal stromal tumors (GIST) are uncommon gastric neoplasms, which are typically treated by surgical excision. During the past 10 years, our institution has gained experience in resecting these tumors by minimally invasive methods. The purpose of this study is to review our experience with laparoscopic resection, report our short-term outcomes, and offer our perspective on the technical nuances involved in handling these neoplasms., Methods: We retrospectively queried our prospectively maintained, institutional review board-approved database for all gastric GISTs resected from 2002 to 2012. We analyzed all cases that were resected via laparoscopy. Operative notes were reviewed for the technique employed. Data on tumor location, size, margin status, operative time, and blood loss were collected and analyzed., Results: During the 10-year study period, 104 gastric GISTs were resected. Laparoscopy was attempted in 58 cases with only one conversion to an open procedure. Tumors were separated based on anatomic zones. Forty-seven tumors (82%) were located on the body or fundus of the stomach (18 on the posterior wall and 29 on the anterior wall). Five GISTs (9%) were located at the gastroesophageal junction (GEJ). Five tumors (9%) were located at the antrum. The mean tumor size was 3.8 cm with a mean estimated blood loss of 40 ml. We achieved R0 resection in 100% of the cases. Most tumors (96%) were amenable to wedge resection. Tumors at the extremes of the stomach required variations of technique to achieve resection. Intraoperative endoscopy was selectively utilized., Conclusions: As our experience with gastric GISTs has increased, laparoscopic resection has become our first-line treatment for most small- and moderate-sized tumors. By employing a structured approach to tumors along the entire stomach, laparoscopic resection of these tumors can be performed safely with adequate short-term results.

Objective: Hemorrhage within a hepatic cyst (hemorrhagic hepatic cyst, HHC) is a complication of liver cysts that is difficult to differentiate from other neoplastic entities on imaging. Even when accurately diagnosed, there has been a lack of consensus on the optimal treatment strategy. After presenting our experience with a patient treated via laparoscopy, we aimed to conduct a review of the literature on HHCs., Methods: A computerized search in Medline, PubMed, Google Scholar, and The Cochrane Collaboration was carried out for journal articles or abstracts published from 1950 to 2011., Results: A total of 24 patients with HHCs were identified from 1983 to 2011. The cohort had an even gender distribution with a mean age of 62.7 years. Most patients presented with abdominal pain (80 %), while three (14 %) patients were asymptomatic at the time of presentation. CT imaging and ultrasound were unable to accurately diagnose HHC, whereas hyperintensity on MRI was a reliable diagnostic tool. Three (13 %) patients were managed conservatively with observation. Seven (30 %) patients had percutaneous transhepatic drainage. Among these, two patients experienced recurrence that required repeat treatment. Two (9 %) patients underwent open unroofing of their HHC and one (4 %) laparoscopically, without recurrences. Seven (30 %) patients underwent hepatic resection, whereas six (26 %) patients had a cyst enucleation for their HHCs. All patients had uneventful recoveries, with a mean follow-up of 25 months., Conclusions: MRI is a reliable diagnostic tool in the setting of an HHC. Laparoscopic unroofing of HHCs may represent a less morbid and safe treatment modality with low recurrence rates. Given the low level of clinical evidence available so far, these results should be interpreted with caution.

Pannexin 1 (Panx1) is a channel-forming glycoprotein expressed in different cell types of mammalian skin. We examined the role of Panx1 in melanoma tumorigenesis and metastasis since qPCR and Western blots revealed that mouse melanocytes exhibited low levels of Panx1 while increased Panx1 expression was correlated with tumor cell aggressiveness in the isogenic melanoma cell lines (B16-F0, -F10, and -BL6). Panx1 shRNA knockdown (Panx1-KD) generated stable BL6 cell lines, with reduced dye uptake, that showed a marked increase in melanocyte-like cell characteristics including higher melanin production, decreased cell migration and enhanced formation of cellular projections. Western blotting and proteomic analyses using 2D-gel/mass spectroscopy identified vimentin and β-catenin as two of the markers of malignant melanoma that were down-regulated in Panx1-KD cells. Xenograft Panx1-KD cells grown within the chorioallantoic membrane of avian embryos developed tumors that were significantly smaller than controls. Mouse-Alu qPCR of the excised avian embryonic organs revealed that tumor metastasis to the liver was significantly reduced upon Panx1 knockdown. These data suggest that while Panx1 is present in skin melanocytes it is up-regulated during melanoma tumor progression, and tumorigenesis can be inhibited by the knockdown of Panx1 raising the possibility that Panx1 may be a viable target for the treatment of melanoma.

Objectives: Pancreaticoduodenectomy (PD) remains a procedure that carries considerable morbidity. Numerous studies have evaluated factors to predict patients at risk. The aim of this study was to determine whether the surgical Apgar score (SAS) predicts perioperative morbidity and mortality., Methods: We examined 553 patients undergoing successful PD between January 2000 and December 2010. Postoperative complications were graded using the Clavien scale, and the SAS (range, 0-10) was determined. The Cochran-Armitage test for trend was used to determine the association between grouped SAS scores (0-2, 3-4, 5-6, 7-8, and 9-10) and each of the outcomes., Results: The average patient age was 64 years, and there was an even distribution of males and females. There were 11 perioperative deaths (2%), 186 grade 2 or higher complications (34%), and 86 major complications (grades 3-5, 16%). Additionally, 61 patients developed pancreatic fistulae (11%). Statistical analysis determined that SAS was a significant predictor of grade 2 or higher complications (p < 0.0001), major morbidity (p = 0.01), and pancreatic fistula (p = 0.04) but not mortality (p = 0.20)., Conclusions: We demonstrate that the SAS is a significant predictor of perioperative morbidity for patients undergoing PD. This score should be used to identify patients at higher risk in order to prioritize use of postoperative critical care beds and hospital resources.

Introduction: The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients., Methods: We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (≤10%, n = 93; 10-≤25%, n = 45; and >25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model., Results: The median survival time of the entire group of patients was 34 months. The median number of positive nodes was 2 (range = 1, 55), and the median number of examined nodes was 22 (range = 5-123). Tumor characteristics of the primary melanoma (such as thickness, ulceration, and primary site) were not significant predictors of survival in this analysis. By univariate analysis, LNR was an important prognostic factor. Patients with LNR 10-25% and >25% had decreased survival compared to those patients with LNR ≤10% (HR = hazard ratio = 2.0 and 3.1, respectively; P ≤ 0.005). The number of positive lymph nodes also impacted on survival (P = 0.001). In multivariate analysis, LNR of 10-25% and >25% predicted survival (HR = 2.5 and 4.0, respectively)., Conclusion: LNR is an important prognostic factor in patients undergoing LND for stage III melanoma. It can be used to stratify patients being considered for adjuvant therapy trials and should be evaluated using a larger prospective database., (Copyright © 2011 Wiley Periodicals, Inc.)

The yield of preoperative PET/CT (PET/CT) for regional and distant metastases for thin/intermediate thickness melanoma is low. Objective of this study is to determine if PET/CT performed for T4 melanomas helps guide management and alter treatment plans. Methods. Retrospective cohort of 216 patients with T4 melanomas treated at two tertiary institutions. Fifty-six patients met our inclusion criteria (T4 lesion, PET/CT and no clinical evidence of metastatic disease). Results. Fifty-six patients (M: 32, F: 24) with median tumor thickness of 6 mm were identified. PET/CT recognized twelve with regional and four patients with metastatic disease. Melanoma-related treatment plan was altered in 11% of the cases based on PET/CT findings. PET/CT was negative 60% of the time, in 35% of the cases; it identified incidental findings that required further evaluation. Conclusion. Patients with T4 lesions, PET/CT changed the treatment plan 18% of the time. Regional findings changed the surgical treatment plan in 11% and the adjuvant plan in 7% of our cases due to the finding of metastatic disease. Additionally 20 patients had incidental findings that required further workup. In this subset of patients, we feel there is a benefit to PET/CT, and further studies should be performed to validate our findings.

Purpose: Lymph node status is an important predictor of survival in pancreatic cancer. We performed a secondary analysis of Radiation Therapy Oncology Group (RTOG) 9704, an adjuvant chemotherapy and chemoradiation trial, to determine the influence of lymph node factors--number of positive nodes (NPN), total nodes examined (TNE), and lymph node ratio (LNR ratio of NPN to TNE)--on OS and disease-free survival (DFS)., Patient and Methods: Eligible patients from RTOG 9704 form the basis of this secondary analysis of lymph node parameters. Actuarial estimates for OS and DFS were calculated using Kaplan-Meier methods. Cox proportional hazards models were performed to evaluate associations of NPN, TNE, and LNR with OS and DFS. Multivariate Cox proportional hazards models were also performed., Results: There were 538 patients enrolled in the RTOG 9704 trial. Of these, 445 patients were eligible with lymph nodes removed. Overall median NPN was 1 (min-max, 0-18). Increased NPN was associated with worse OS (HR=1.06, p=0.001) and DFS (HR=1.05, p=0.01). In multivariate analyses, both NPN and TNE were associated with OS and DFS. TNE>12, and >15 were associated with increased OS for all patients, but not for node-negative patients (n=142). Increased LNR was associated with worse OS (HR=1.01, p<0.0001) and DFS (HR=1.006, p=0.002)., Conclusion: In patients who undergo surgical resection followed by adjuvant chemoradiation, TNE, NPN, and LNR are associated with OS and DFS. This secondary analysis of a prospective, cooperative group trial supports the influence of these lymph node parameters on outcomes after surgery and adjuvant therapy using contemporary techniques., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: The use of induction chemoradiotherapy followed by surgery has been widely used for the treatment of esophageal cancer. The presumed risk of increased postoperative morbidity and mortality with this regimen has led to reluctance to offer this therapy to elderly patients. We compared the perioperative morbidity and mortality of patients 70 years old and older with those of patients younger than 70 who received CRT followed by esophagectomy and sought to identify preoperative risk factors that may predict higher risk of postoperative death or complications., Methods and Materials: We identified 260 patients who underwent preoperative chemoradiotherapy followed by esophagectomy. The association of age with postoperative death and complications was evaluated. The Charlson index, prior cardiac history, and diabetes were identified as preoperative risk factors and were evaluated as potential confounders or effect modifiers., Results: Cardiac disease and the Charlson index were potential modifiers of the effect of age on length of hospital stay (p = 0.08 and p = 0.07, respectively) and postoperative complications (p = 0.1 and p = 0.2) but were not statistically significant. There was a slight nonsignificant decrease in the risk of death in elderly patients after adjustment for the Charlson index (p = 0.2)., Conclusion: No significant differences were detected with respect to morbidity and mortality in elderly patients. The presence of cardiac disease, higher scores on the Charlson index, or diabetes did not significantly influence length of stay, postoperative complications, or postoperative death. Given the potential to improve outcomes, this regimen should not be discounted in elderly patients., (Copyright © 2011. Published by Elsevier Inc.)

Introduction: The prognosis after pancreaticoduodenectomy (PD) for ampullary carcinoma (AC) is superior to that of pancreatic cancer. Decisions regarding adjuvant therapy are influenced by factors such as nodal status, stage, and grade, but the influence of these individual variables on survival is unclear., Methods: A prospective tumor registry database was queried to identify patients who underwent PD for AC at Thomas Jefferson University between Jan 1997 and Apr 2009. The study was conducted with the approval of the institutional review board. Data were collected through review of hospital and departmental charts. Overall survival (OS) was analyzed using univariate and multivariate Cox proportional hazard models. The proportional hazard assumption was verified for the overall model and individual covariates., Results: A total of 61 patients underwent PD for AC at our institution. There were five perioperative deaths (8.2%). Mean age was 70 years (62% male). Median survival time (MST) was 50 months for all patients. Only primary tumor stage, T1/T2 versus T3/T4 (American Joint Committee on Cancer Staging, version 6), was associated with OS in univariate analyses (p = 0.003). The association of nodal status with OS was borderline-significant (p = 0.08), with the MST being 84 months for node-negative and 17 months for node-positive patients. The remaining covariates were not predictors of OS. In the multivariate analysis, only primary tumor stage (HR, 5.1; p < 0.001) and age (HR, 1.04; p = 0.06), but not nodal status or adjuvant therapy, were associated with overall survival., Conclusions: Advanced primary tumor stage and age were associated with inferior OS after PD for AC. Adjuvant therapy did not impact survival. Patients with advanced tumor stage should be considered for clinical trials of adjuvant therapy after PD with novel compounds and optimized radiation therapy strategies.

Morphine, heroin and other commonly abused opioids induce little mu opioid receptor (MOR) trafficking compared to endogenous opioids. We utilized knock-in mice expressing a mutant recycling MOR (RMOR) that desensitizes and is internalized in response to morphine to show that facilitating MOR trafficking not only enhances morphine reward but, despite this, reduces the development of addiction-like behaviours. To demonstrate this, we developed a novel model of the transition from controlled to compulsive drug use that recapitulates many features of human addiction, including persistent drug seeking despite adverse consequences and a decreased preference for alternative rewards. These behaviours emerged spontaneously in wild-type but not RMOR mice, and their intensity predicted the reinstatement of morphine seeking after extended abstinence, while prior morphine intake did not. These results confirm previous findings in the rat that addiction can be dissociated from both reward and consumption. Most importantly, these results demonstrate that one can simultaneously reduce the 'addictiveness' of morphine and enhance its desirable effects by promoting agonist-induced MOR trafficking., (Copyright © 2011 EMBO Molecular Medicine.)

Background: Major morbidity and mortality rates continue to be high in large series of transthoracic esophagectomies. Minimally invasive approaches are being increasingly used. We compare our growing series of minimally invasive (combined thoracoscopic and laparoscopic) esophagectomies (MIEs) with a series of open transthoracic esophagectomies., Study Design: We identified 65 patients who underwent an MIE with thoracoscopy/laparotomy (n = 11), Ivor Lewis (n = 2), or 3-hole approach (n = 52). These patients were compared with 53 patients who underwent open Ivor-Lewis esophagectomy (n = 15) or 3-hole esophagectomy (n = 38) over the past 10 years., Results: The MIE and open groups were similar regarding gender and average age. The majority of patients in the open group underwent neoadjuvant chemoradiation therapy (81%); a significantly smaller (43%) number of patients in the MIE group underwent neoadjuvant therapy (p < 0.0001). Regarding oncologic efficacy, 97% and 94% of patients in both groups underwent R0 resections. Patients undergoing MIE had a significant increase in the number of harvested lymph nodes (median 20 vs 9; p < 0.0001). Length of stay was significantly decreased in patients who underwent MIE (8.5 days vs 16 days; p = 0.002). Finally, there were significantly fewer serious complications (grades 3-5) in the MIE group (19% vs 48%; p = 0.0008)., Conclusions: In this initial report of a single-institution series of MIE, we demonstrate that oncologic efficacy is not compromised and may actually be improved with a significantly increased number of harvested LNs. We also demonstrate that this approach is associated with fewer serious complications and a significant decrease in the length of postoperative hospital stay., (Copyright © 2011 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Enterococci are commensal organisms in the alimentary tract. However, they can cause a variety of life-threatening infections, especially in nosocomial settings. We hypothesized that induction of cell death might enable these facultative pathogenic bacteria to evade the innate immune response and to cause infections of their host. We demonstrate that E. faecium when exposed to lysozyme induces cell death in macrophages in vitro and in vivo. Flow cytometric analyses of J774A.1 macrophages infected with E. faecium revealed loss of cell membrane integrity indicated by uptake of propidium iodide and decrease of the inner mitochondrial transmembrane potential DeltaPsi(m). Inhibition of caspases, treatment of macrophages with cytochalasin D, or rifampicin did not prevent cells from dying, suggesting cell death mechanisms that are independent of caspase activation, bacterial uptake, and intracellular bacterial replication. Characteristics of necrotic cell death were demonstrated by both lack of procaspase 3 activation and cell shrinkage, electron microscopy, and release of lactate dehydrogenase. Pretreatment of E. faecium with lysozyme and subsequently with broad spectrum protease considerably reduced cell death, suggesting that a bacterial surface protein is causative for cell death induction. Moreover, in a mouse peritonitis model we demonstrated that E. faecium induces cell death of peritoneal macrophages in vivo. Altogether, our results show that enterococci, under specific conditions such as exposure to lysozyme, induce necrotic cell death in macrophages, which might contribute to disseminated infections by these facultative pathogenic bacteria.

Background: Pancreatic fistula (PF) is a major source of morbidity following distal pancreatectomy (DP). Our aim was to identify risk factors related to PF following DP and to determine the impact of technique of transection and stump closure., Methods: We performed a retrospective review of 215 consecutive patients who underwent DP. Perioperative and postoperative data were collected and analyzed with attention to PF as defined by the International Study Group of Pancreatic Fistula., Results: PF developed in 36 patients (16.7%); fistulas were classified as Grade A (44.4%), B (44.4%), or C (11.1%). The pancreas was transected with stapler (n = 139), cautery (n = 70), and scalpel (n = 3). PF developed in 19.8% of remnants which were stapled/oversewn and 27.7% that were stapled alone (p = 0.4). Of the 69 pancreatic remnants transected with cautery and oversewn, a fistula developed in 4.3% (p = 0.004 compared to stapled/oversewn; p = 0.006 compared to stapled/not sewn). The median length of postoperative hospital stay was significantly increased in patients who developed PF (10 vs. 6 days, p = 0.002), Conclusion: The method of transection and management of the pancreatic remnant plays a critical role in the formation of PF following DP. This series suggests that transection using electrocautery followed by oversewing of the pancreatic remnant has the lowest risk of PF.