Alex D. Michaels

Ileal J-Pouch Volvulus Following Total Proctocolectomy for Ulcerative Colitis

Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) allows restoration of continence in select patients with ulcerative colitis but is associated with significant morbidity. Well-known complications following IPAA include pouchitis, anastomotic leak, and small bowel obstruction. Obstruction secondary to ileal pouch volvulus is exceedingly rare. We report a case of ileal pouch volvulus, which occurred secondary to internal hernia. Radiographic and endoscopic identification of volvulus allowed for early operative management and pouch salvage.

Ureteral stents increase risk of postoperative acute kidney injury following colorectal surgery

BackgroundUreteral stents are commonly placed before colorectal resection to assist in identification of ureters and prevent injury. Acute kidney injury (AKI) is a common cause of morbidity and increased cost following colorectal surgery. Although previously associated with reflex anuria, prophylactic stents have not been found to increase AKI. We sought to determine the impact of ureteral stents on the incidence of AKI following colorectal surgery.MethodsAll patients undergoing colon or rectal resection at a single institution between 2005 and 2015 were reviewed using American College of Surgeons National Surgical Quality Improvement Program dataset. AKI was defined as a rise in serum creatinine to ≥ 1.5 times the preoperative value. Univariate and multivariate regression analyses were performed to identify independent predictors of AKI.Results2910 patients underwent colorectal resection. Prophylactic ureteral stents were placed in 129 patients (4.6%). Postoperative AKI occurred in 335 (11.5%) patients during their hospitalization. The stent group demonstrated increased AKI incidence (32.6% vs. 10.5%; p < 0.0001) with bilateral having a higher rate than unilateral stents. Hospital costs were higher in the stent group (

CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response.

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Abstract C19: The role of resident liver macrophages in suppressing the progression of hepatic micrometastases from pancreatic ductal adenocarcinoma

16,091; p < 0.0001), and patients with bilateral stents had the highest costs. Multivariable logistic regression identified predictors of AKI after colorectal surgery including age, procedure duration, and ureteral stent placement.ConclusionsProphylactic ureteral stents independently increased AKI risk when placed prior to colorectal surgery. These data demonstrate increased morbidity and hospital costs related to usage of stents in colorectal surgery, indicating that placement should be limited to patients with highest potential benefit.

The role of liver-directed surgery in patients with hepatic metastasis from primary breast cancer: A multi-institutional analysis

Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types.Predicting the response to chemotherapy is a major goal of cancer research. Here the authors use CRISPR knockout screens in pancreatic ductal adenocarcinoma cells to identify deletions synergistic with MEK inhibitors.

Declining Operative Experience for Junior-Level Residents: Is This an Unintended Consequence of Minimally Invasive Surgery?

Background: The majority of patients with localized pancreatic ductal adenocarcinoma (PDAC) die from metastatic disease, typically of the liver, despite a margin-negative (R0) resection. Therefore, these patients likely harbor occult metastatic disease in the liver at the time of surgery. In this study, we evaluated the role of resident liver macrophages in suppressing the progression of hepatic micrometastases using a murine model of micrometastatic PDAC with patient-derived xenografts (PDXs). Methods and Results: Low-passage, patient-derived KRAS-mutant tumor cells expressing firefly luciferase were injected into the spleens of athymic nude mice resulting in liver metastases, followed by splenectomy to remove the primary tumor. Hepatic tumor burden and metastatic growth kinetics were evaluated by bioluminescent imaging on post-injection days 1, 2, 3, 7, and weekly thereafter. Each of the PDX tumors exhibited a decline in tumor burden over the initial days after injection followed by a period of quiescence with a reproducible, PDX-specific time to proliferative outgrowth ranging from 15 days to greater than 200 days. To assess the role of apoptosis in initial tumor cell clearance and suppression of outgrowth, mouse liver preparations were analyzed for expression of cleaved caspase-3 and cleaved PARP in tumor cells using flow cytometry. There was low expression of both apoptosis markers, suggesting that apoptosis is not a major cell-clearance mechanism. Athymic nude mice lack cell-mediated immunity but have functioning innate immunity. Because there is a large population of resident macrophages in the liver, we hypothesized that macrophages play an important role in the clearance and suppression of hepatic PDAC metastases. To test this, hepatic metastasis outgrowth was assessed following macrophage ablation with liposomal clodronate treatment of mice 48 hours prior to tumor cell injection. Following macrophage ablation, there was a trend toward less robust initial tumor cell clearance and a significantly decreased time to proliferative outgrowth compared with control (13 days vs 26 days, p =0.039). HE PDX 366: 40.4% vs 76.3% clearance at seven days, p =0.024). Average relative hepatic bioluminescence at 21 days was significantly increased for PDX 608 in the NSG mice (14.7 vs 0.355, p =0.014) and there was a trend toward increase for PDX 366 (3.07 vs 0.025, p =0.065). Conclusions: In a preclinical model of hepatic micrometastatic PDAC, resident liver macrophages are implicated in the initial clearance and the suppression of proliferation of tumor cells. Further investigation of the interaction of resident hepatic macrophages and micrometastatic PDAC cells may lead to novel strategies for therapy. Citation Format: Alex D. Michaels, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Sarbajeet Nagdas, Matthew G. Mullen, Edward B. Stelow, J. Thomas Parsons, Todd W. Bauer. The role of resident liver macrophages in suppressing the progression of hepatic micrometastases from pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C19.