Eric H. Jensen

Major cancer surgery in the elderly: results from the American College of Surgeons National Surgical Quality Improvement Program.

Objective:To examine the association between older age and short-term outcomes after major oncologic resections. Summary Background Data:The effect of older age on outcomes from major cancer surgery remains conflicting because of limitations in measuring coexisting comorbidities. Given the critical role of surgery, older patients and their surgeons often question decisions regarding major cancer surgery. Methods:We identified 8781 patients who underwent elective or emergent major thoracic, abdominal, or pelvic resections for neoplasms in the 2005 to 2007 American College of Surgeons National Surgical Quality Improvement Program database. Pre, intra-, and postoperative characteristics were compared by age groups. Multivariable techniques were used to predict adjusted short-term operative outcomes. Results:Older patients were more likely to have preoperative comorbidities and to receive intraoperative blood transfusions, but at the same time have shorter operative times. Increased age was also associated with higher operative mortality (4.83% for ≥75 years vs. 1.09% for ages 40–55 years), a greater frequency of major complications, and more prolonged hospital stays—all of which persisted after multivariable adjustments. Despite its strong association with 30-day operative mortality, the impact of older age was comparable to other preoperative risk-factors predictive of short-term operative outcomes. Conclusions:The present study, which is one of the largest multihospital studies, showed that older age is independently associated with worse short-term outcomes after major oncologic resections. However, the effect of age was not prohibitively worse, and is comparable to the effects of other preoperative risk factors. These findings support the use of risk-based treatment decision-making in older patients.

Biomarkers Predict Outcomes Following Cytoreductive Surgery for Hepatic Metastases from Functional Carcinoid Tumors

BackgroundCytoreductive therapy for metastatic carcinoid provides symptomatic relief and improvement in overall survival. We evaluated whether CgA and 5HIAA could predict symptomatic relief and control of disease progression after cytoreductive surgery.MethodsWe retrospectively reviewed 70 patients who underwent cytoreductive surgery for neuroendocrine hepatic metastases between 1996 and 2005. Twenty-two patients had pre and post-operative CgA and/or 5HIAA levels measured. Reduction of biomarkers following cytoreduction was correlated with patient symptoms and progression of disease following surgery.ResultsOur study consisted of 14 males and 8 females with a mean age of 55 (±12 years). Median follow-up was 18 months (range 5-64 months). Six patients (26.1%) had complete (R0) cytoreduction, while 4 (17.4%) and 13 (56.5%) had microscopic (R1) and gross (R2) disease remaining. All patients reported improvements in their symptoms, with 12 (54.5%) reporting complete resolution (CR) and 10 (45.5%) reporting partial resolution (PR). Reduction of CgA of ≥ 80% was highly predictive of complete resolution of symptoms (P = 0.007) and stabilization of disease (P = 0.034). Reduction of 5HIAA levels of ≥ 80% (or normalization) was predictive of symptomatic relief, but not progression of disease (P = 0.026 and P = 0.725). Five of six patients who had R0 resections had CR and were free of disease at last follow-up (median 24.5 months, range: 11–48, P = 0.002).ConclusionsWe conclude that ≥ 80% reduction in CgA level following cytoreductive surgery for carcinoid tumors is predictive of subsequent symptom relief and disease control. Substantial reduction in CgA is associated with improved patient outcomes, even after incomplete cytoreduction.

American College of Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update

Disclosures outside the scope of this work: Dr. Minei receiv grant support from Irrespet Corp. AtoxBio. Dr. Laronga rec sation for lectures from Genomic Health Inc. and royalties Date. Dr. Jensen is a consultant and paid speaker for Ethico ceives honoraria from CareFusion for their Speaker’s Progr from Irrimax Corp. for consulting and Research Funding honoraria from Surgical Inc. for consultation. Dr. Itani for a multi-institutional study for Sanofi-Pastuer and the Committee Chair. Dr. Dellinger is on the Advisory B Melinta, and Therevance and a grant recipient from Moti trial of iclaprim vs. vancomycin for treatment of skin and so tions. The remaining authors declare no conflicts. Presented at the Surgical Infection Society, Palm Beach, FL

A Critical Analysis of the Surgical Management of Early-Stage Gallbladder Cancer in the United States

BackgroundRadical resection is recommended for selected patients with gallbladder (GB) cancer. We sought to determine whether radical resection improves survival for patients with early-stage cancer and to evaluate surgeon compliance with current treatment recommendations.Patients and methodsPatients with stage 0, I, or II GB cancer who underwent surgical resection were identified from the Surveillance, Epidemiology, and End Results (SEER) tumor registry from 1988 through 2004. Patients were classified by surgical procedure performed (simple vs. radical resection) and adjuvant treatment given (radiation therapy [RT] vs. no RT). Unadjusted and adjusted overall survival (OS) and cancer-specific survival (CSS) were compared.ResultsOf the 4,631 patients who underwent surgery for early-stage GB cancer from 1988 through 2004, 4,188 (90.4%) underwent cholecystectomy alone and 443 (9.6%) underwent radical surgery including hepatic resection. The proportion of patients having radical surgery for T1b, T2, and T3 cancers was 4.5%, 5.6%, and 16.3%, respectively. For patients with T1b/T2 cancer, radical resection was associated with significant improvement in adjusted CSS (p = 0.01) and OS (p = 0.03). For patients with T3 cancers, we noted no improvement in CSS or OS. Survival for patients with node-positive disease (stage 2b) was universally poor and not improved by radical resection. For all patients who underwent radical resection, node negativity, female sex, age <70, low grade, and RT predicted improved CSS and OS.ConclusionsDespite a significant survival advantage for patients with T1b/T2 GB cancer who undergo radical resection, this treatment is significantly underutilized. Ensuring delivery of recommended surgical treatment is vital to improving outcomes for patients with this disease.

Lymph node evaluation is associated with improved survival after surgery for early stage gallbladder cancer

BACKGROUND Guidelines for the current National Comprehensive Cancer Network recommend radical cholecystectomy, including hepatic resection and portal lymph node (LN) dissection, for patients with early stage gallbladder (GB) cancer. We sought to determine the survival benefit conferred by adequate LN evaluation. METHODS We used the surveillance, epidemiology and end results (SEER) neoplasm registry to identify patients who had an operation for GB cancer between 1988 and 2004. Patients were classified by stage of disease, operative procedure performed (cholecystectomy alone or radical resection), number of LNs evaluated (0, 1, >1), and receipt of radiation (RT). We included patients with T1B, T2, and T3 neoplasms who were LN positive or negative. Patients with T4 neoplasms and those with metastatic disease were excluded. Multivariate analysis included adjustment for age, race, sex, neoplasm grade, stage, operation performed, receipt of RT, and neoplasm registry. RESULTS We identified 4,614 patients who underwent operative treatment for stage 1-2B GB (including T1B-T3 and LN positive or negative) cancer between 1988 and 2004. Of 4,614 patients, 9.6% (442) had radical resection, whereas 90.4% (4,172) had cholecystectomy alone. Among patients undergoing radical resection, 56% had LNs evaluated as compared with 28% of patients after cholecystectomy. For patients with T1B and T2 neoplasms who underwent radical resection, pathologic evaluation of at least 1 LN was associated with a significant improvement in median overall survival (OS) compared with those who had no LN evaluated (123 months vs 22 months; P < .0001). Radical resection with no LN evaluation provided similar OS compared with cholecystectomy alone (22 months vs 23 months; P = NS). For patients with T3 neoplasms, radical resection, including pathologic evaluation of at least 1 LN, was also associated with improved OS compared with radical resection with no LN evaluation (12 months vs 7 months; P = .0014). Again, individuals who had radical resection without LN evaluation had similar OS compared with those who had cholecystectomy alone (7 months vs 6 months; P = NS). Individuals who had radical resection with LN evaluation were more likely to receive RT than those who had radical resection without LN evaluation (33.1% vs 19.1%; P = .002). In multivariate analysis (including adjustment for RT), however, LN evaluation was still associated with a decrease in mortality compared with no LN evaluated (HR = 0.611; 95% CI = 0.484, 0.770). The pathologic evaluation of additional LN (>1) did not provide any additional benefit compared with the evaluation of a single node (HR = 0.795; 95% CI = 0.571, 1.107). Radical resection alone (without LN evaluation) did not provide any benefit over cholecystectomy alone (HR = 1.098; 95% CI = 0.971, 1.241). CONCLUSION LN evaluation is a critical component of radical resection for GB cancer. In the absence of LN evaluation, radical resection provides no benefit over cholecystectomy alone.

Therapeutic pancreatic endoscopy after Whipple resection requires rendezvous access

Chronic pancreatic complications after pancreaticoduodenectomy, including strictured pancreaticojejunostomy and pancreatic fistulas, may be amenable to endoscopic therapy. To date there is no published series focusing on pancreatic endotherapy in this group of patients. We report our experience performing pancreatic therapeutic endoscopic retrograde cholangiopancreatography (ERCP) in 10 patients after pancreaticoduodenectomy. All patients had evidence of pancreatic anastomotic obstruction by endoscopic ultrasound (EUS) or secretin-enhanced magnetic resonance cholangiopancreatography. Technical endoscopic success and clinical outcomes were measured. Technically successful endoscopic access and therapy was ultimately achieved by ERCP in eight of the 10 patients. Although a duodenoscope or pediatric colonoscope could be advanced up the afferent limb in all patients, initial unassisted pancreatic cannulation and therapy was successful in only one patient. Rendezvous techniques, either percutaneous or EUS-guided, were required for endoscopic access in the other 9 patients. Complications included moderate pancreatitis with retroperitoneal air after percutaneous rendezvous access in 1 patient, and fever in 1 patient. Therapeutic pancreatic ERCP for chronic complications after Whipple pancreaticoduodenectomy is feasible but quite challenging. Endoscopic access through a stenotic pancreaticojejunal anastomosi generally requires either EUS or percutaneous rendezvous assistance.

Molecular targeted therapies for pancreatic cancer.

BACKGROUND Pancreatic cancer cells express different mutations that increase the aggressiveness and confer resistance to conventional chemotherapy and radiotherapy. Molecules that selectively bind and inhibit these mutations are effective in other solid tumors and are now emerging as a complementary therapy in pancreatic cancer. The objective of this review is to describe the effect of drugs that inhibit specific mutations present in pancreatic cancer with special emphasis on clinical trials. DATA SOURCES We reviewed the English-language literature (MedLine) addressing the role of drugs that target mutations present in pancreatic cancer. Both preclinical and clinical studies were included. CONCLUSIONS Preclinical evidence supports the combination of conventional approved therapies plus drugs that block epidermal growth factor receptor and vascular growth endothelial factor or induce apoptosis. However, most of the current clinical evidence is limited to small phase I trials evaluating the toxicity and safety of these regimens. The results of additional randomized trials that are still undergoing will clarify the role of these drugs in pancreatic cancer.

Sorafenib and triptolide as combination therapy for hepatocellular carcinoma

INTRODUCTION Sorafenib is the only drug approved by the Food and Drug Administration for metastatic hepatocellular carcinoma (HCC). Triptolide, a diterpene triepoxide, exhibits antineoplastic properties in multiple tumor cell types. In this study, we examined the effects of these agents and their combination on HCC in vitro and in vivo models. METHODS HuH-7 and PLC/PRF/5 cells were treated with triptolide (50 nM), sorafenib (1.25 or 2.5 μM), or a combination of both. Cell viability assay (CCK-8), caspase 3&7 activation, and nuclear factor κB assays were performed. For in vivo studies, 40 mice were implanted with subcutaneous HuH7 tumors and divided into four treatment groups (n = 10); saline control, sorafenib 10 mg/kg PO daily (S), Minnelide (a prodrug of triptolide) 0.21 mg/kg intraperitoneally7 daily (M), and combination of both (C). Tumor volumes were assessed weekly. RESULTS The combination of triptolide and sorafenib was superior to either drug alone in inducing apoptosis and decreasing viability, whereas triptolide alone was sufficient to decrease nuclear factor κB activity. After 2 weeks of treatment, tumor growth inhibition rates were S = 59%, M = 84%, and C = 93%, whereas tumor volumes in control animals increased by 9-fold. When crossed over to combination treatment, control mice tumor growth volumes plateaued over the following 4 weeks. CONCLUSION The combination of sorafenib and triptolide is superior to single drug treatment in increasing cell death and apoptosis in vitro. Combining sorafenib with Minnelide inhibited tumor growth with greater efficacy than single-agent treatments. Importantly, in vivo combination treatment allowed for using a lesser dose of sorafenib (10 mg/kg), which is less than 10% of currently prescribed dose for HCC patients. Therefore, combination treatment could have translational potential in the management of HCC.

Gene expression profiling of colorectal mucinous adenocarcinomas

PURPOSE: Although mucinous adenocarcinomas represent 6% to 19% of all colorectal adenocarcinomas, little is known about the genome-wide alterations associated with this malignancy. We have sought to characterize both the gene expression profiles of mucinous adenocarcinomas and their clinicopathologic features. METHODS: Tumors from 171 patients with primary colorectal cancer were profiled using the Affymetrix HG-U133Plus 2.0 GeneChip with characterization of clinicopathologic data. Gene ontology software was used to identify altered biologic pathways. RESULTS: Twenty (11.7%) mucinous adenocarcinomas and 151 (89.3%) nonmucinous adenocarcinomas were identified. Mucinous adenocarcinomas were more likely to be diagnosed with lymph node (LN) metastases (75% vs 51%, P = .04) and at a more advanced stage (85% vs 54%, P = .006) but long-term survival (5-y survival 58.9% vs 58.7%, P = NS) was similar. Mucinous adenocarcinomas displayed 182 upregulated and 135 downregulated genes. The most upregulated genes included those involved in cellular differentiation and mucin metabolism (eg, AQP3 + 4.6, MUC5AC +4.2, MUC2 + 2.8). Altered biologic pathways included those associated with mucin substrate metabolism (P = .002 and .02), amino acid metabolism (P = .02), and the mitogen-activated protein kinase cascade (P = .02). DISCUSSION: Using gene expression profiling of mucinous adenocarcinomas, we have identified the differential upregulation of genes involved in differentiation and mucin metabolism, as well as specific biologic pathways. These findings suggest that mucinous adenocarcinomas represent a genetically distinct variant of colorectal adencarcinoma and have implications for the development of targeted therapies.

Appendiceal carcinoid tumors: Predictors of lymph node metastasis and the impact of right hemicolectomy on survival

Given the lack of population‐based data in the literature, we sought to (1) identify predictors of appendiceal carcinoid tumor nodal metastasis to distinguish which patients would most likely benefit from hemicolectomy and (2) compare survival after hemicolectomy versus appendectomy alone.