Review of Safety Data for Adenovirus 5 as a Delivery Vector for Intratumoral Cancer Gene Therapy.

With efficient transduction across most cell types and larger packaging capacity, Adenovirus 5 (Ad5) makes an attractive choice as a viral vector. However, a reported past mortality and known immunogenicity cast doubt on the safety of its use. An online database search was performed for all clinical trials administering intratumoral injection of gene therapy packaged in Ad5, being conducted in the United States, and using the Common Terminology Criteria for Adverse Events (CTCAE). Studies with unclear adverse events (AE) were excluded. The primary outcome collected was grade ≥3 (AE). Analyses were performed using Fisher's exact test. Thirty-nine prospective clinical trials across a variety of cancers were identified: 14 studies of therapeutic Ad5 alone, 12 with chemotherapy, 16 with radiation, and 11 with surgery. There were 3 mortalities out of 756 patients (0.4%), which were most likely unrelated to Ad5: 1 due to hypoxic encephalopathy, 1 due to splenic vein thrombus, and 1 due to disease progression. In trials that reported total AE (grades 1-5), there were 284 (10.3%) grade ≥3 AE out of 2,745 total AE in 477 patients. The overall life-threatening (grade 4) AE rate was 1.4% (34/2,425 AE in 428 patients). Overall, the most frequent grade ≥3 AE were lymphopenia (20.6% in 14 trials, 209 patients), dyspnea (8.7% in 11 trials, 208 patients), and neutropenia (8.6% in 12 trials, 174 patients). The most frequent grade 4 AE were neutropenia (4.6%), lymphopenia (3.3%), and leukopenia (3.1% in 13 trials, 192 patients). Our analyses demonstrated relative overall safety of Ad5 and warrant re-evaluation for the use of Ad5 as a delivery vector for gene therapy products.

A cost analysis of sorafenib for desmoid tumors.

INTRODUCTION: A recent randomized trial demonstrated that sorafenib improved progression free survival (PFS) in patients with desmoid tumors despite many patients experiencing stable disease or spontaneous regression without treatment. Utilizing these trial data, we performed a cost analysis of sorafenib efficacy through two years of treatment. METHODS: Current Medicare Part D rates for sorafenib were utilized (dose 400 mg/day, cost $309/day). Annual costs per progression and objective response were calculated. Radiologic progression and response were defined using RECIST criteria. Patients with disease progression were separately analyzed in two groups: both clinical and radiologic (CAR), and radiologic alone. RESULTS: 84 previously randomized patients were analyzed (placebo: 35, sorafenib: 49). At one year, sorafenib was associated with a 43% absolute risk reduction (ARR) of CAR progression and number-needed-to-treat (NNT) of 2.3 patients/year, costing $259,406. At two years, ARR was 48% and NNT of 2.1 patients/year, costing $473,697. When evaluating only patients with RECIST defined radiologic progression, sorafenib patients experienced ARR of 13.9% with NNT 7.2 and estimated costs of $812,052 at one year. Two-year ARR was 17.5% with NNT 5.7 and estimated costs $1,285,052. Sorafenib patients experienced improved RECIST partial response rates at 1 and 2 years of 14.7% and 14.3%, with NNT 6.8 and 6.9, and costs of $766,938 and $1,556,433; respectively. CONCLUSION: For the treatment of desmoid tumors, Sorafenib led to improved PFS, but at a significant cost per patient. Favorable RECIST outcomes were less likely and costlier. Patients should be informed of possible benefits of treatment versus potential financial burden.

The disclosure slide-Informative or obligatory, 5 years of SSO Cancer Symposium oral presentations.

BACKGROUND: Financial disclosure (FD) highlights potential conflicts of interest but is often overlooked at academic conferences. METHODS: Retrospective review of 2015-2019 Society of Surgical Oncology Cancer Symposium oral presentation slide and/or verbal FD frequency, duration, and content. RESULTS: Of 963 presentations, 331 (34%) omitted disclosure slide/verbalization. 575 (60%) included a slide, 551 (57%) gave verbal disclosure and 133 (14%) stated relevance. 164 presentations (17%) cited 1 + FD. 2019 had greater median FDs/talk than 2015-2018 (3.50 vs. 2.00; p = .010). Compared to 2015-2018, 2019 yielded shorter median slide display of all disclosures (2.00 s vs. 2.47 s; p = .006), median 1 + FD display (3.37 s vs. 4.81 s; p = .04) and median 1 + FD verbalization (2.81 s vs. 3.66 s; p = .54). 2019 all disclosure verbalization increased (1.97 s vs. 1.14 s; p < .001). Multivariable modeling showed longer display with 2015-2018 (+1.3 s, 95% confidence interval [CI] -0.06 to 2.5 s, p = .04), <4 authors (+3.2 s, 95% CI: 2.1-4.3 s; p < .001) and longer verbalization with 2019 (+0.8 s, 95% CI: 0.2-1.4 s; p = .01), relevance (+1.0 s, 95% CI: 0.4-1.6 s; p = .002), ≤ 4 authors (+0.8 s, 95% CI: 0.3-1.3 s, p < .001) and noncommercial FD (+3.8 s, 95% CI: 2.0-5.0 s; p < .001). The five most cited commercial entities were in 39% of talks. CONCLUSION: Presenters' FDs were brief or omitted. Despite FD increase, disclosure time decreased. Improved FD attention will highlight potential COIs.

Meta-Analysis on the Effect of Pasireotide for Prevention of Postoperative Pancreatic Fistula.

BACKGROUND: A randomized controlled trial of routine administration of pasireotide demonstrated decreased incidence of clinically significant postoperative pancreatic fistula (POPF). Recent studies have not replicated these results. A meta-analysis was performed to evaluate its efficacy in this setting. METHODS: Prospective trials utilizing pasireotide prophylactically after pancreatectomy were reviewed. The primary outcome was clinically significant POPF. Secondary outcomes included length of stay (LOS), readmission rates, and mortality. Study heterogeneity was assessed. RESULTS: Five studies totaling 1571 patients were identified. There was no difference in age, sex, or cancer rates. Pasireotide patients had smaller pancreatic ducts (P < .001) and softer glands (P = .04). For all pancreatectomies, there was no difference in POPF rates (odds ratio [OR] 0.84; 95% CI 0.60-1.16, P = .29). Patients undergoing distal pancreatectomy (OR 0.70; 95% CI 0.30-1.63, P = .41) had similar rates of POPF versus pancreaticoduodenectomy (PD) patients who experienced a lower incidence of POPF (OR 0.60; 95% CI 0.42-0.86, P = .006).Mortality rates and LOS were similar. Readmission rates were decreased with pasireotide (OR 0.61; 95% CI 0.44-0.85). CONCLUSIONS: Routine administration of pasireotide did not decrease POPF rates for all pancreatectomies, but was associated with lower rates for PD, and decreased readmission rates. Further prospective, randomized studies are warranted.

Meta-analysis on the Effect of Pasireotide for Prevention of Postoperative Pancreatic Fistula.

BACKGROUND: A randomized controlled trial (RCT) of routine administration of pasireotide demonstrated decreased incidence of clinically significant postoperative pancreatic fistula (POPF). Recent studies have not replicated these results. A meta-analysis was performed to evaluate its efficacy in this setting. METHODS: Prospective trials utilizing pasireotide prophylactically after pancreatectomy were reviewed. The primary outcome was clinically significant POPF. Secondary outcomes included length of stay (LOS), readmission rates, and mortality. Study heterogeneity was assessed. RESULTS: Five studies totaling 1571 patients were identified. There was no difference in age, sex, or cancer rates. Pasireotide patients had smaller pancreatic ducts (P ≤.001) and softer glands (P = .04). For all pancreatectomies, there was no difference in POPF rates (OR 0.84; 95% CI 0.60-1.16, P = .29). Patients undergoing distal pancreatectomy (OR 0.70; 95% CI 0.30-1.63, P = .41) had similar rates of POPF versus pancreaticoduodenectomy (PD) patients that experienced a lower incidence of POPF (OR 0.60; 95% CI 0.42-0.86, P = .006). Mortality rates and LOS were similar. Readmission rates were decreased with pasireotide (OR 0.61; 95% CI 0.44-0.85). CONCLUSIONS: Routine administration of pasireotide did not decrease POPF rates for all pancreatectomies, but was associated with lower rates for PD and decreased readmission rates. Further prospective, randomized studies are warranted.

Health-Care Workers' Perception of Reimbursement for Complex Surgical Oncology Procedures.

Perception of physician reimbursement for surgical procedures is not well studied. The few existing studies illustrate that patients believe compensation to be higher than in reality. These studies focus on patient perceptions and have not assessed health-care workers' views. Our study examined health-care workers' perception of reimbursement for complex surgical oncology procedures. An anonymous online survey was distributed to employees at our cancer center with descriptions and illustrations of three oncology procedures-hepatectomy, gastrectomy, and pancreaticoduodenectomy. Participants estimated the Medicare fee and gave their perceived value of each procedure. Participants recorded their perception of surgeon compensation overall, both before and after revealing the Medicare fee schedule. Most of the 113 participants were physicians (33.6%) and nurses (28.3%). When blinded to the Medicare fee schedules, most felt that reimbursements were too low for all procedures (60-64%) and that surgeons were overall undercompensated (57%). Value predictions for each procedure were discordant from actual Medicare fee schedules, with overestimates up to 374 per cent. After revealing the Medicare fee schedules, 55 per cent of respondents felt that surgeons were undercompensated. Even among health-care workers, a large discrepancy exists between perceived and actual reimbursement. Revealing actual reimbursements did not alter perception on overall surgeon compensation.

Long-term survival based on pathologic response to neoadjuvant therapy in esophageal cancer.

BACKGROUND: Neoadjuvant treatment is standard for locally advanced esophageal cancer. However, whether the addition of radiation to neoadjuvant regimen improves survival remains unclear. The aim of this study was to compare survival in locally advanced esophageal cancer treated with neoadjuvant chemotherapy versus chemoradiation. MATERIALS AND METHODS: A prospectively maintained database of esophagectomies (1999-2012) was analyzed. We identified 297 patients with locally advanced esophageal cancer that underwent either neoadjuvant chemotherapy (n = 231) or chemoradiation (n = 66) followed by esophagectomy. Pretreatment and pathologic staging were compared to assess response. Overall survival was recorded. RESULTS: Most patients in the chemotherapy and chemoradiation groups had pretreatment stage III disease (66.7% versus 65.2%; P = 0.44). Median follow-up was 79.3 and 64.9 mo for chemotherapy and chemoradiation cohorts, respectively. Complete response rate was higher in chemoradiation than chemotherapy groups (30.3% versus 13.8%; P < 0.001). Overall survival was similar between complete responders in both groups (median not reached versus 121.1 mo; chemotherapy versus chemoradiation). However, partial responders in the chemotherapy cohort had improved median survival (147.2 mo) versus those in the chemoradiation cohort (83.7 mo, P < 0.03). Within the chemotherapy-only group, partial responders had improved survival compared with nonresponders (P = 0.041); however, there was no difference in survival between partial and complete responders (P = 0.36). CONCLUSIONS: In patients undergoing esophagectomy for locally advanced esophageal cancer, neoadjuvant chemotherapy was associated with an equivalent overall survival, when compared with neoadjuvant chemoradiotherapy. Adding neoadjuvant radiation may enhance complete response rates but does not appear to be associated with improved survival.

Esophagectomy for cancer in octogenarians: should we do it?

PURPOSE: Inconsistent data exists regarding esophagectomy outcomes in octogenarians undergoing transhiatal esophagectomy for esophageal cancer. METHODS: A retrospective review was performed for esophagectomy cancer patients between 2000 and 2012 at our tertiary referral center. Outcome data for octogenarians was compared to younger patients aged 20 to 79 years. A case-matched group of patients younger than 80 years old (n = 33) was included based on the Charlson comorbidity index with the octogenarian group (n = 33). Endpoints included operative morbidity and mortality as well as short- and long-term survival. RESULTS: Thirty-three octogenarians met inclusion criteria. The median age was 82 years, and 79% were male; 76% had adenocarcinoma, 87% had distal esophageal, and 52% had poorly differentiated tumors. Stages 0 through III were observed in 6, 18, 27, and 48% of octogenarians, respectively. Neoadjuvant therapy was administered to 70% of patients, with 48% experiencing downstaging. Transhiatal esophagectomy was performed in 82% of patients, with R0 resection in 94%. The mean hospital stay was 18 days, with morbidity and mortality rates 56 and 9%, respectively, not significantly different from 13-day hospital stay, 45% morbidity, and 9% mortality in younger patients. Cardiac, pulmonary, and surgical site complications occurred in 24, 27, and 6% of octogenarians, respectively. Anastomotic leak occurred in 18% and reoperations in 3%. The median, 3-year survival, and 5-year survival were 21 months, 55.9%, and 37.1%, respectively. Overall survival was worse for octogenarians (p < 0.001). CONCLUSIONS: Postoperative mortality, morbidity, and length of stay in octogenarians are comparable to younger patients, while the overall survival is worse. With appropriate patient selection, good outcomes can be accomplished in octogenarians undergoing esophagectomy for cancer.

Tumor-to-tumor metastasis: report of two cases of renal cell carcinoma metastasizing to microcystic serous cystadenoma of the pancreas.

Metastatic cancer to the pancreas accounts for less than 2% of all pancreatic malignancies. In contrast to other metastatic tumors, renal cell carcinoma (RCC) has a propensity to metastasize as a solitary pancreatic lesion. While symptomatic patients may present with obstructive jaundice, abdominal pain, or gastrointestinal bleeding, the diagnosis of metastatic pancreatic involvement is often made in asymptomatic patients, during follow-up evaluation in the aftermath of an initial diagnosis of renal cell carcinoma. Microcystic serous cystadenoma of the pancreas is an uncommon pancreatic exocrine neoplasm that morphologically resembles conventional (clear cell) RCC, in so far as both tumors are characterized by neoplastic cells with clear cytoplasm, relatively uniform nuclei and scant associated tumor stroma. Herein, we report 2 immunohistochemically confirmed cases of unsuspected metastatic RCC to the pancreas, with the metastatic tumor in each case confined to a preexisting microcystic serous cystadenoma of the pancreas.

Early trauma-hemorrhage-induced splenic and thymic apoptosis is gut-mediated and toll-like receptor 4-dependent.

Immune depression after trauma-hemorrhage has been implicated as an important factor in the pathogenesis of sepsis and septic-organ failure. Although recent studies have implicated immune-cell apoptosis as an important factor in the evolution of this posttrauma immune-suppressed state, neither the initial triggers that induce this response nor the cellular pathways through which these triggering pathways act have been fully defined. Thus, the current study tests the hypothesis that acute splenic and thymic immune-cell apoptosis developing after trauma-hemorrhagic shock (T/HS) is due to gut-derived factors carried in intestinal lymph and that this T/HS lymph-induced immune depressed state is mediated through Toll-like receptor 4 (TLR4). The first set of experiments documented that T/HS caused both thymic and splenic immune-cell apoptosis as measured by TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase-3 immunohistochemistry and that this increase in apoptosis was totally abrogated by mesenteric lymph duct ligation. In subsequent experiments, mesenteric lymph collected from animals subjected to T/HS or trauma-sham shock were injected into TLR4-deficient (TLR4mut) mice or their wild-type (WT) littermates. Trauma-hemorrhagic shock, but not trauma-sham shock, lymph caused splenic apoptosis in the WT mice. However, the TLR4mut mice were resistant to T/HS lymph-induced splenic apoptosis. Furthermore, the WT, but not the TLR4mut mice developed splenic apoptosis after actual T/HS. In conclusion, gut-derived factors appear to initiate a sequence of events that leads to an acute increase in splenic and thymic immune-cell apoptosis, and this process is TLR4-dependent.

Anticoagulants influence the in vitro activity and composition of shock lymph but not its in vivo activity.

Many models of trauma-hemorrhagic shock (T/HS) involve the reinfusion of anticoagulated shed blood. Our recent observation that the anticoagulant heparin induces increased mesenteric lymph lipase activity and consequent in vitro endothelial cell cytotoxicity prompted us to investigate the effect of heparin-induced lipase activity on organ injury in vivo as well as the effects of other anticoagulants on mesenteric lymph bioactivity in vitro and in vivo. To investigate this issue, rats subjected to trauma-hemorrhage had their shed blood anticoagulated with heparin, the synthetic anticoagulant arixtra (fondaparinux sodium), or citrate. Arixtra, in contrast to heparin, did not increase lymph lipase activity or result in high levels of endothelial cytotoxicity. Yet, the arixtra-treated rats subjected to T/HS still manifested lung injury, neutrophil priming, and red blood cell dysfunction, which was totally abrogated by lymph duct ligation. Furthermore, the injection of T/HS mesenteric lymph, but not sham-shock lymph, collected from the arixtra rats into control mice recreated the pattern of lung injury, polymorphonucleocyte (PMN) priming, and red blood cell dysfunction observed after actual shock. Consistent with these observations, citrate-anticoagulated rats subjected to T/HS developed lung injury, and the injection of mesenteric lymph from the citrate-anticoagulated T/HS rats into control mice also resulted in lung injury. Based on these results, several conclusions can be drawn. First, heparin-induced increased mesenteric lymph lipase activity is not responsible for the in vivo effects of T/HS mesenteric lymph. Second, heparin should be avoided as an anticoagulant when studying the biology or composition of mesenteric lymph because of its ability to cause increases in lymph lipase activity that increase the in vitro cytotoxicity of these lymph samples.