Downstaging of Pancreatic Adenocarcinoma With Either Neoadjuvant Chemotherapy or Chemoradiotherapy Improves Survival.

BACKGROUND: Neoadjuvant chemotherapy (NAC) or chemoradiation (NAC+XRT) is incorporated into the treatment of localized pancreatic adenocarcinoma (PDAC), often with the goal of downstaging before resection. However, the effect of downstaging on overall survival, particularly the differential effects of NAC and NAC+XRT, remains undefined. This study examined the impact of downstaging from NAC and NAC+XRT on overall survival. METHODS: The National Cancer Data Base (NCDB) was queried from 2006 to 2015 for patients with non-metastatic PDAC who received NAC or NAC+XRT. Rates of overall and nodal downstaging, and pathologic complete response (pCR) were assessed. Predictors of downstaging were evaluated using multivariable logistic regression. Overall survival (OS) was assessed with Kaplan-Meier and Cox proportional hazards modeling. RESULTS: The study enrolled 2475 patients (975 NAC and 1500 NAC+XRT patients). Compared with NAC, NAC+XRT was associated with higher rates of overall downstaging (38.3 % vs 23.6 %; p ≤ 0.001), nodal downstaging (16.0 % vs 7.8 %; p ≤ 0.001), and pCR (1.7 % vs 0.7 %; p = 0.041). Receipt of NAC+XRT was independently predictive of overall (odds ratio [OR] 2.28; p < 0.001) and nodal (OR 3.09; p < 0.001) downstaging. Downstaging by either method was associated with improved 5-year OS (30.5 vs 25.2 months; p ≤ 0.001). Downstaging with NAC was associated with an 8-month increase in median OS (33.7 vs 25.6 months; p = 0.005), and downstaging by NAC+XRT was associated with a 5-month increase in median OS (30.0 vs 25.0 months; p = 0.008). Cox regression showed an association of overall downstaging with an 18 % reduction in the risk of death (hazard ratio [HR] 0.82; 95 % confidence interval, 0.71-0.95; p = 0.01) CONCLUSION: Downstaging after neoadjuvant therapies improves survival. The addition of radiation therapy may increase the rate of downstaging without affecting overall oncologic outcomes.

Contemporary Assessment of Need for Palliative Bypass After Aborted Pancreatoduodenectomy Following Neoadjuvant Therapy.

BACKGROUND: Planned pancreatoduodenectomy (PD) for pancreatic adenocarcinoma (PDAC) can be aborted due to intraoperative findings. There is little guidance regarding the need for prophylactic bypass following an aborted PD to prevent symptomatic biliary obstruction or gastric outlet obstruction (GOO) postoperatively. The aim of this study was to characterize postoperative interventions and postsurgical survival in patients following aborted PD. METHODS: Patients with PDAC treated with neoadjuvant therapy and staging laparoscopy prior to planned PD between 2010 and 2015 were reviewed for aborted PDs. Data on postoperative biliary obstruction, GOO, procedural intervention, and postsurgical survival were analyzed. RESULTS: Of 271 planned PDs, 47 (17.3%) were aborted. Thirty-six patients had ≥ 2 months of follow-up data and were included. Six patients underwent hepaticojejunostomy and nine patients underwent gastrojejunostomy at the time of the aborted PD. Sixteen of 30 patients (53%) without a surgical biliary bypass required endoscopic intervention, but none required palliative surgery. Ten of 27 patients (37%) without an operative gastrojejunostomy required intervention, but none required palliative surgery. Endoscopic or percutaneous therapy was required to treat 13/16 (81%) patients who presented with postoperative biliary obstructions and 6/10 (60%) of GOOs. Median survival following aborted PD was 13.3 months (CI 8.9-17.7). There were no differences in survival when comparing patients who developed a biliary obstruction (p = 0.92) or GOO (p = 0.90) to asymptomatic patients. CONCLUSIONS: Following aborted PD, patients commonly develop obstructive symptoms. However, these symptoms can generally be managed without surgical intervention. In asymptomatic patients, preemptive surgical bypasses are not required at the time of aborted PD.

Impact of Hepatic Metastasectomy in the Multimodal Treatment of Metastatic Breast Cancer.

BACKGROUND: Surgical management of hepatic metastases in patients with stage IV breast cancer remains controversial. The purpose of this study was to examine the impact of hepatic metastasectomy on long-term outcomes. METHODS: The 2004-2015 National Cancer Database was queried for all patients diagnosed with stage IV breast cancer with metastases isolated to the liver. Patient demographics, disease-, treatment- and outcome-related data were analyzed. RESULTS: Of 2,895 patients, only 90 (3.1%) underwent hepatic resection. Compared to patients who did not undergo metastasectomy, patients treated with metastasectomy tended to be younger (52 ± 12.7 versus 59.2 ± 14.6; P < 0.001) and have private insurance (74.4% versus 45.3%; P < 0.001). Independent predictors of metastasectomy included younger age (OR 0.98; CI 0.96-0.99; P = 0.01), lobular carcinoma (OR 2.26; CI 1.06-4.82; P = 0.03), and prior surgery of the primary site (partial mastectomy (OR 6.96; CI 3.47-13.95; P < 0.001) or total mastectomy (OR 5.74; CI 3.06-10.76; P < 0.001)). Compared to no metastasectomy, hepatic metastasectomy was independently associated with a 37% reduction in the risk of death (HR 0.63; CI 0.44-0.91; P = 0.01). CONCLUSIONS: Stage IV breast cancer with metastases to the liver is rare and few patients undergo hepatic resection. However, in this select patient population, hepatic metastasectomy was associated with a significant survival advantage when included in the multimodal treatment of synchronous stage IV breast cancer.

Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma.

Immunotherapy has revolutionized the treatment of melanoma, yet survival remains poor for patients with metastatic disease. The autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine has been shown to be safe adjuvant therapy for patients with resected stage III/IV melanoma who complete the primary vaccine series. Here, we describe an open-label trial of patients with metastatic melanoma treated with TLPLDC vaccine in addition to standard of care (SoC) therapies. The TLPLDC vaccine is created by loading autologous tumor lysate into yeast cell wall particles, which are phagocytosed by autologous dendritic cells ex vivo. Patients who recurred while enrolled in a phase IIb trial of adjuvant TLPLDC vaccine (crossover cohort) and patients with measurable metastatic melanoma cohort were offered TLPLDC vaccine along with SoC therapies. Tumor response was measured by RECIST 1.1 criteria. Overall survival (OS) and progression-free survival (PFS) were estimated by intention-to-treat analysis. Fifty-four patients were enrolled (28 in crossover cohort; 26 in metastatic melanoma cohort). The vaccine was well-tolerated with no grade ≥3 adverse events when given with SoC therapies to include checkpoint inhibitors, BRAF/MEK inhibitors, tyrosine kinase inhibitors, intralesional therapy and/or radiation. In the crossover arm, OS was 76.5% and PFS was 57.1% (median follow-up of 13.9 months). In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% (median follow-up 8.5 months). The TLPLDC vaccine is well-tolerated and safe in combination with SoC therapies. Future trials will determine the efficacy of TLPLDC in combination with SoC therapies in metastatic melanoma.

A Phase IIb Randomized Controlled Trial of the TLPLDC Vaccine as Adjuvant Therapy After Surgical Resection of Stage III/IV Melanoma: A Primary Analysis.

BACKGROUND: Melanoma therapy has changed dramatically over the last decade with improvements in immunotherapy, yet many patients do not respond to current therapies. This novel vaccine strategy may prime a patient's immune system against their tumor and work synergistically with immunotherapy against advanced-stage melanoma. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, phase IIb trial of the tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine administered to prevent recurrence in patients with resected stage III/IV melanoma. Patients were enrolled and randomized 2:1 to the TLPLDC vaccine or placebo (empty yeast cell wall particles and autologous dendritic cells). Both intention-to-treat (ITT) and per treatment (PT) analyses were predefined, with PT analysis including patients who remained disease-free through the primary vaccine/placebo series (6 months). RESULTS: A total of 144 patients were randomized (103 vaccine, 41 control). Therapy was well-tolerated with similar toxicity between treatment arms; one patient in each group experienced related serious adverse events. While disease-free survival (DFS) was not different between groups in ITT analysis, in PT analysis the vaccine group showed improved 24-month DFS (62.9% vs. 34.8%, p = 0.041). CONCLUSIONS: This phase IIb trial of TLPLDC vaccine administered to patients with resected stage III/IV melanoma shows TLPLDC is well-tolerated and improves DFS in patients who complete the primary vaccine series. This suggests patients who do not recur early benefit from TLPLDC in preventing future recurrence from melanoma. A phase III trial of TLPLDC + checkpoint inhibitor versus checkpoint inhibitor alone in patients with advanced, surgically resected melanoma is under development. TRIAL REGISTRATION: NCT02301611.

Optimizing physician skill development for medical students: The four-part assessment.

BACKGROUND: Medical student performance has been poorly correlated with residency performance and warrants further investigation. We propose a novel surgical assessment tool to determine correlations with clinical aptitude. METHODS: Retrospective review of medical student assessments from 2013 to 2015. Faculty rating of student performance was evaluated by: 1) case presentation, 2) problem definition, 3) question response and 4) use of literature and correlated to final exam assessment. A Likert scale interrater reliability was evaluated. RESULTS: Sixty student presentations were scored (4.8 assessors/presentation). A student's case presentation, problem definition, and question response was correlated with performance (r = 0.49 to 0.61, p ≤ 0.003). Moderate correlations for either question response or use of literature was demonstrated (0.3 and 0.26, p < 0.05). CONCLUSION: Our four-part assessment tool identified correlations with course and examination grades for medical students. As surgical education evolves, validated performance and reliable testing measures are required.