Stephen W. Behrman

A Randomized Prospective Multicenter Trial of Pancreaticoduodenectomy With and Without Routine Intraperitoneal Drainage

Objective:To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. Background:Some surgeons have abandoned the use of drains placed during pancreas resection. Methods:We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. Results:There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. Conclusions:This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.

Improved outcome with femur fractures: early vs. delayed fixation.

Prior studies documented that early fixation of femur fractures results in a decreased incidence of adult respiratory distress syndrome (ARDS), fat embolism syndrome, and pneumonia. This study evaluates the impact of magnitude of injury on pulmonary complications and length of ICU and hospital stays in 339 trauma patients with femur fracture undergoing early (n = 121) vs. late (n = 218) operative fixation. Groups were similar with respect to transfusions, hypotension, and associated injuries, but more patients over age 50 years underwent early fixation. Patients were categorized according to Injury Severity Score (ISS): 1) less than 15 (n = 202), 2) 16-35 (n = 104), and 3) greater than 36 (n = 33). Delayed fixation significantly increased the incidence of pulmonary shunt in ISS (3) patients and of pneumonia in patients older than 50. Late fixation resulted in significantly longer hospital stays in all groups and more ICU days in the ISS (3) group. We believe that early femur fixation should be performed on all patients. Pulmonary complications were decreased and health care costs reduced.

Chemoresistance in Prostate Cancer Cells Is Regulated by miRNAs and Hedgehog Pathway

Many prostate cancers relapse due to the generation of chemoresistance rendering first-line treatment drugs like paclitaxel (PTX) ineffective. The present study aims to determine the role of miRNAs and Hedgehog (Hh) pathway in chemoresistant prostate cancer and to evaluate the combination therapy using Hh inhibitor cyclopamine (CYA). Studies were conducted on PTX resistant DU145-TXR and PC3-TXR cell lines and clinical prostate tissues. Drug sensitivity and apoptosis assays showed significantly improved cytotoxicity with combination of PTX and CYA. To distinguish the presence of cancer stem cell like side populations (SP), Hoechst 33342 flow cytometry method was used. PTX resistant DU145 and PC3 cells, as well as human prostate cancer tissue possess a distinct SP fraction. Nearly 75% of the SP cells are in the G0/G1 phase compared to 62% for non-SP cells and have higher expression of stem cell markers as well. SP cell fraction was increased following PTX monotherapy and treatment with CYA or CYA plus PTX effectively reduced their numbers suggesting the effectiveness of combination therapy. SP fraction cells were allowed to differentiate and reanalyzed by Hoechst staining and gene expression analysis. Post differentiation, SP cells constitute 15.8% of total viable cells which decreases to 0.6% on treatment with CYA. The expression levels of P-gp efflux protein were also significantly decreased on treatment with PTX and CYA combination. MicroRNA profiling of DU145-TXR and PC3-TXR cells and prostate cancer tissue from the patients showed decreased expression of tumor suppressor miRNAs such as miR34a and miR200c. Treatment with PTX and CYA combination restored the expression of miR200c and 34a, confirming their role in modulating chemoresistance. We have shown that supplementing mitotic stabilizer drugs such as PTX with Hh-inhibitor CYA can reverse PTX chemoresistance and eliminate SP fraction in androgen independent, metastatic prostate cancer cell lines.

Pancreatic adenocarcinoma, version 2.2017: Clinical practice guidelines in Oncology

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

miRNA profiling in pancreatic cancer and restoration of chemosensitivity

Pancreatic cancers relapse due to small but distinct population of cancer stem cells (CSCs) which are in turn regulated by miRNAs. The present study identifies a series of miRNAs which were either upregulated (e.g. miR-146) or downregulated (e.g. miRNA-205, miRNA-7) in gemcitabine resistant MIA PaCa-2 cancer cells and clinical metastatic pancreatic cancer tissues. Gemcitabine resistant MIA PaCa-2 cells possessed distinct ALDH-positive CSC fraction expressing stem cell markers OCT3/4 and CD44 and chemoresistance marker class IIIβ-tubulin (TUBB3) which decreases on transfection with miR-205 resulting in the restoration of chemosensitivity to gemcitabine.

Microcirculatory Flow Changes After Initial Resuscitation of Hemorrhagic Shock with 7.5% Hypertonic Saline/6% Dextran 70

In rabbits, laser Doppler flow probes were placed in the jejunum and on the renal cortex. Pulsed Doppler probes were implanted on the abdominal aorta and superior mesenteric and femoral arteries for measuring blood flow velocity. Cardiac output was measured by thermal dilution. Either 30% or 40% of the calculated blood volume was withdrawn through a carotid catheter. After 30 or 60 minutes, an initial bolus of either lactated Ringers (LR, 16 ml/kg) or 7.5% hypertonic saline/6% dextran 70 (HSD; 4 ml/kg) IV was followed by unlimited IV LR (administered as rapidly as possible) to restore systemic arterial blood pressure to the prehemorrhage levels. With HSD, arterial pressure corrected more rapidly (p less than 0.05), and the initial hemodilution was greater (p less than 0.05), but there were no differences by two hours. With HSD, cardiac output (90%-100% vs. 130%-160% of control; p less than 0.05), plasma Na+ (139-140 mM vs. 146-148 mM; p less than 0.05) and plasma osmolarity (292-295 mOsm vs. 308-310 mOsm; p less than 0.05) were all significantly higher than the values with LR, but there was no effect on blood flow velocities through the infrarenal aorta, femoral artery, or superior mesenteric artery. Renal cortical perfusion (56% vs. 97% of control; p less than 0.05) and jejunal mucosal perfusion (83% vs. 162% of control; p less than 0.05) were significantly higher with HSD. HSD had no detectable effect on bacterial translocation at 24 hours. Thus: 1) HSD restores blood flow more rapidly to the gut mucosal and kidney microcirculations than initial resuscitation with LR; 2) the mechanism could be associated with a transient hemodilution and persistent increases in plasma Na and osmolarity, which reduce hemorrhage-induced cell swelling and blood viscosity changes; and 3) laser Doppler analysis could aid in the diagnosis of reperfusion injury after shock.

Gastric outlet obstruction resulting from peptic ulcer disease requiring surgical intervention is infrequently associated with Helicobacter pylori infection

BACKGROUND Gastric outlet obstruction (GOO) secondary to peptic ulcer disease requiring therapeutic intervention remains a common problem. The incidence of Helicobacter pylori infection in this cohort has not been well defined. Pneumatic dilatation (PD) has been proposed as first-line therapy before surgical intervention. If H pylori infection in patients with GOO is infrequent, PD may not offer permanent control without the need for longterm antacid therapy. STUDY DESIGN The purpose of this study was to examine the incidence of H pylori infection and surgical outcomes in patients undergoing resection for GOO. The records of all patients having resection (vagotomy and antrectomy) for benign disease from 1993 to 1998 for GOO at the University of Tennessee affiliated hospitals were reviewed retrospectively. Smoking history, NSAID use, weight loss, previous ulcer treatment, previous treatment for H pylori, and previous attempts at PD were among the factors examined. H pylori infection was documented by Steiner stain from either preoperative biopsy or, in most patients, final surgical specimens. Surgical complications and patient satisfaction were ascertained from inpatient records, postoperative clinical notes, and, where possible, followup telephone surveys. RESULTS Twenty-four patients underwent surgical resection during the study period. There were 16 men and 8 women, with a mean age of 61 years (range 40 to 87 years). Weight loss was documented in 58% and averaged 27 lb. Five of 24 patients had previous attempts at PD, 3 of whom were H pylori negative. All five had further weight loss after these failed attempts. Of the 24 patients reviewed, only 8 (33%) were H pylori positive. There were no procedure-related deaths. Longterm clinical followup was possible in 16 of 24 patients, and all but one demonstrated dramatic clinical improvement by Visick score. CONCLUSIONS We conclude the following: 1) In this cohort, H pylori infection was present in a minority; 2) previous attempts at PD were unsuccessful, which may be related to the H pylori-negative status of the patients; 3) mortality related to the operation was zero; and 4) patient satisfaction was positive by the Visick scale. Patients with H pylori-negative GOO resulting from peptic ulcer disease should be strongly considered for an early, definitive, acid-reducing surgical procedure.

Nanoways to overcome docetaxel resistance in prostate cancer

Prostate cancer is the most common non-cutaneous malignancy in American men. Docetaxel is a useful chemotherapeutic agent for prostate cancer that has been available for over a decade, but the length of the treatment and systemic side effects hamper compliance. Additionally, docetaxel resistance invariably emerges, leading to disease relapse. Docetaxel resistance is either intrinsic or acquired by adopting various mechanisms that are highly associated with genetic alterations, decreased influx and increased efflux of drugs. Several combination therapies and small P-glycoprotein inhibitors have been proposed to improve the therapeutic potential of docetaxel in prostate cancer. Novel therapeutic strategies that may allow reversal of docetaxel resistance include alterations of enzymes, improving drug uptake and enhancement of apoptosis. In this review, we provide the most current docetaxel reversal approaches utilizing nanotechnology. Nanotechnology mediated docetaxel delivery is superior to existing therapeutic strategies and a more effective method to induce P-glycoprotein inhibition, enhance cellular uptake, maintain sustained drug release, and improve bioavailability.

Prophylactic octreotide for pancreatoduodenectomy: more harm than good?

BACKGROUND Most accrued evidence regarding prophylactic octreotide for a pancreatoduodenectomy (PD) predates the advent of the International Study Group of Pancreatic Fistula (ISGPF) classification system for a post-operative pancreatic fistula (POPF), and its efficacy in the setting of high POPF risk is unknown. The Fistula Risk Score (FRS) predicts the risk and impact of a clinically relevant (CR)-POPF and can be useful in assessing the impact of octreotide in scenarios of risk. METHODS From 2001-2013, 1018 PDs were performed at four institutions, with octreotide administered at the surgeons discretion. The FRS was used to analyse the occurrence and burden of POPF across various risk scenarios. RESULTS Overall, 391 patients (38.4%) received octreotide. A CR-POPF occurred more often when octreotide was used (21.0% versus 7.0%; P < 0.001), especially when there was advanced FRS risk. Octreotide administration also correlated with an increased hospital stay (mean: 13 versus 11 days; P < 0.001). Regression analysis, controlling for FRS risk, demonstrated that octreotide increases the risk for CR-POPF development. CONCLUSION This multi-institutional study, using ISGPF criteria, evaluates POPF development across the entire risk spectrum. Octreotide appears to confer no benefit in preventing a CR-POPF, and may even potentiate CR-POPF development in the presence of risk factors. This analysis suggests octreotide should not be utilized as a POPF mitigation strategy.

Breakdown of intestinal repair after laparotomy for trauma: incidence, risk factors, and strategies for prevention.

BACKGROUND Breakdown of intestinal repair and enteric leakage after trauma laparotomy can have dire consequences. Factors contributing to these failures when stratified according to location of intestinal injury and method of repair were examined. METHODS We retrospectively reviewed all intestinal injuries occurring in a recent 2-year time span in adult patients surviving for more than 48 hours at a Level I trauma center. Data included Injury Severity Score, Abdominal Trauma Index score, site (stomach, duodenum, small and large intestine), and type of repair (enterorrhaphy vs. resection and anastomosis). Physiologic parameters within 48 hours of repair were assessed. Nonparametric analysis was used with significance assessed at the 95% confidence interval. RESULTS Two hundred twenty-two intestinal repairs in 171 patients were evaluated. All repairs but one were performed at the initial surgery. Eleven (5%) of these failed in 11 patients (6.4%)--four duodenum, four small bowel, and three colon--and were not recognized for an average of 15 days. Breakdown of repair occurred in patients with higher Injury Severity Scores and Abdominal Trauma Index scores (30 vs. 21 and 29 vs. 14, respectively; p < 0.001) and higher intraoperative blood and fluid administration (8.8 vs. 2.2 U and 11.5 vs. 5.1 L, respectively; p < 0.05). This was associated with longer intensive care unit and hospital stays (15.1 vs. 1.9 and 68.4 vs. 10.4 days, respectively; p < 0.001). All small bowel leaks occurred after resection and anastomosis versus enterorrhaphy (p < 0.05). All anastomotic breakdowns (four small bowel, one colon) occurred in the setting of massive blood and fluid administration versus those that did not leak (12.5 vs. 1.7 U and 12.7 vs. 5.8 L, respectively; p < 0.05). Four of 12 duodenal enterorrhaphies failed. All were associated with pancreatic injury versus none without (p < 0.05). The abdominal compartment syndrome occurred in three patients. In each case, breakdown of a small bowel anastomosis occurred. CONCLUSIONS (1) Stomach repair and small bowel and large-bowel enterorrhaphy may be safely accomplished in any setting. (2) Associated pancreatic injury is a risk factor for disruption of duodenorrhaphy. (3) In patients with massive blood and fluid administration, delay of bowel anastomoses should be considered. (4) Disruption of small bowel anastomoses is associated with abdominal compartment syndrome.