Development of murine bariatric surgery models: lessons learned.

Roux-en-Y gastric bypass (RYGB) improves comorbidities such as diabetes and hypertension and lowers the risk of obesity-related cancers. To better understand the physiologic and genetic influences of bariatric surgery, a reliable murine model is needed that can be extended to genetically engineered mice. Given the complexity of these procedures, few researchers have successfully implemented these techniques beyond larger rodent models. The purpose of our study was to develop a technically feasible and reproducible murine model for RYGB and sleeve gastrectomy (SG). Mice were converted to liquid diet perioperatively without fasting and housed in groups on raised wire platforms. SG involved significant reduction of stomach volume followed by multilayer repair of the gastrotomy. RYGB procedure consisted of side-to-side, functional end-to-side bowel anastomoses and exclusion of the stomach medial to the gastroesophageal junction. Sham surgeries consisted of enterotomies and gastrotomy followed by primary repair without resection or rerouting. Survival after incorporation of the aforementioned techniques was 100% in the SG group and 41% in the RYGB group at 1 mo after surgery. Only 26% of RYGB mortality was attributed to leak, obstruction, or stricture; the majority of postoperative mortality was due to stress, dumping, or malnutrition. Much of the survival challenge for this surgical model was related to perioperative husbandry, which is to be expected given their small stature and poor response to stress. Utilization of the perioperative and surgical techniques described will increase survival and feasibility of these technically challenging procedures, allowing for a better understanding of mechanisms to explain the beneficial effects of bariatric surgery.

Colorectal cancer lung metastasis treatment with polymer-drug nanoparticles.

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States; the predominant cause for mortality is metastasis to distant organs (e.g., lung). A major problem limiting the success of chemotherapy in metastatic CRC is the inability to target tumor tissues selectively and avoid severe side effects to normal tissues and organs. Here, we demonstrate polymeric nanoparticles (PNPs) entrapping chemotherapeutic agents provide a new therapeutic option for treating CRC that has metastasized to the lung. PNPs assembled from FDA approved biocompatible block copolymer accumulated predominantly in lung tissue. PNPs showed negligible accumulation in liver, spleen and kidneys, which was confirmed by fluorescent nanoparticle imaging and analysis of PI3K inhibition in the organs. PNPs entrapping PI3K inhibitors (i.e., wortmannin and PX866) suppressed CRC lung metastasis growth, and SN-38-loaded PNPs completely eliminated CRC lung metastasis. Our results demonstrate that polymer-drug nanoparticles offer a new approach to reduce toxicity of cancer therapy and has the potential to improve outcomes for patients with lung metastasis.

Failure to operate on resectable gastric cancer: implications for policy changes and regionalization.

BACKGROUND: A significant proportion of patients never receive curative-intent surgery for resectable gastric cancer (GC). The primary aims of this study were to identify disparities and targetable risk factors associated with failure to operate in the context of national trends in surgical rates for resectable GC. METHODS: The National Cancer Database was used to identify patients with resectable GC (adenocarcinoma, clinical stage IA-IIIC, 2004-2013). Multivariate modeling was used to identify predictors of resection and to analyze the impact of surgery on overall survival (OS). RESULTS: Of 46,970 patients with resectable GC, 18,085 (39%) did not receive an appropriate operation. Among unresected patients, 69% had no comorbidities. Failure to resect was associated with reduced median OS (44.4 versus 11.8 mo, hazard ratio [HR]: 2.09, P < 0.001). In the multivariate analysis, the most critical factors affecting OS were resection (HR: 2.09) and stage (reference IA; HR range: 1.16-3.50, stage IB-IIIC). Variables independently associated with no surgery included insurance other than private or Medicare (odds ratio [OR]: 1.60/1.54), nonacademic/nonresearch hospital (OR: 1.16), non-Asian race (OR: 1.72), male (OR: 1.19), older age (OR: 1.04), Charlson-Deyo score >1 (OR: 1.17), residing in areas with median income <$48,000 (OR: 1.23), small urban populations <20,000 (OR: 1.41), and stage (reference IA; OR range: 1.36-3.79, stage IB-IIIC, P < 0.001). CONCLUSIONS: Over one-third of patients with resectable GC fail to receive surgery. Suitable insurance coverage and treatment facility are the most salient (and only modifiable) risk factors for omitting surgery. To mitigate national disparities in surgical care, policymakers should consider improving insurance coverage in underserved areas and regionalization of gastric cancer care.

The Nonwhite Woman Surgeon: A Rare Species.

BACKGROUND: As of 2012, 39% of medical student graduates were nonwhite, yet very few nonwhite women graduates chose to become surgeons. METHODS: To better understand issues regarding nonwhite women in surgery, an online survey was sent to surgeons across the United States. Results are based on self-reported data. Mean data are reported. RESULTS: A total of 194 surgeons (42% women) completed the survey; only 12% of responders were nonwhite. Overall, 56% of nonwhite women felt they earned less than what men surgeons earn for equal work. Nonwhite women surgeons earned less than what men surgeons ($224,000 vs. 351,000, p < 0.00002) and white women surgeons ($285,000, p = 0.02) earned. Overall, 96% of nonwhite surgeons believed that racial discrimination currently exists among surgeons. CONCLUSIONS: The few nonwhite women surgeons in the United States recognize that they are paid significantly less than what other surgeons are paid. Inequitable remuneration and a discriminatory work environment encountered by nonwhite women surgeons must be addressed.

Fast left prefrontal rTMS reduces post-gastric bypass surgery pain: findings from a large-scale, double-blind, sham-controlled clinical trial.

BACKGROUND: A single session of left prefrontal rTMS has been shown to have analgesic effects, and to reduce post-operative morphine use. We sought to test these findings in a larger sample, and try and see if multiple sessions had additive analgesic benefit. METHODS: 108 patients undergoing laparoscopic gastric bypass surgery received two sessions of 10 Hz rTMS (110% of motor threshold) over the left dorsolateral prefrontal cortex (one immediately following surgery and one 4 h later). Participants were randomly assigned to receive 2 sessions of real rTMS, 2 sessions of sham, 1 real then 1 sham, or 1 sham then 1 real rTMS treatments. Patients and study staff were blind to rTMS conditions. RESULTS: Unlike previous rTMS trials for post-operative pain, no differences emerged between groups with respect to total patient-controlled analgesia usage (IV hydromorphone). However, despite no difference in IV analgesic usage, subjects that received 2 real rTMS sessions rated both the affective and sensory dimensions of their pain significantly lower than those in the sham­sham group at several time points during the post-surgical/post-rTMS period. CONCLUSIONS: This study suggests that left prefrontal rTMS may produce significant analgesic effects in the perioperative setting. However, further work is needed to understand this effect and attempt to make it clinically useful in light of the lack of effect on PCA hydromorphone use.

A pilot functional MRI study of the effects of prefrontal rTMS on pain perception.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has been shown to effectively treat depression, and its potential value in pain management is emphasized by recent studies. Transcranial magnetic stimulation (TMS)-evoked activity in the prefrontal cortex may be associated with corticolimbic inhibitory circuits capable of decreasing pain perception. The present exploratory pilot study used functional magnetic resonance imaging (fMRI) to examine the effects of left prefrontal rTMS on brain activity and pain perception. DESIGN AND INTERVENTION: Twenty-three healthy adults with no history of depression or chronic pain underwent an 8-minute thermal pain protocol with fMRI before and after a single rTMS session. Participants received 15 minutes of either real (N = 12) or sham (N = 11) 10 Hz rTMS over the left prefrontal cortex (110% of resting motor threshold; 5 seconds on, 10 seconds off). RESULTS: TMS was associated with a 13.30% decrease in pain ratings, while sham was associated with an 8.61% decrease (P = 0.04). TMS was uniquely associated with increased activity in the posterior cingulate gyrus, precuneous, right superior frontal gyrus, right insula, and bilateral postcentral gyrus. Activity in the right superior prefrontal gyrus was negatively correlated with pain ratings (r = -0.65, P = 0.02) in the real TMS group. CONCLUSIONS: Findings suggest that prefrontal rTMS may be capable of activating inhibitory circuits involved with pain reduction.

Prosthetic H-graft portacaval shunts vs transjugular intrahepatic portasystemic stent shunts: 18-year follow-up of a randomized trial.

BACKGROUND: Widespread application of transjugular intrahepatic portasystemic shunt (TIPS) continues despite the lack of trials documenting efficacy superior to surgical shunting. Here we present an 18-year follow-up of a prospective randomized trial comparing TIPS with small-diameter prosthetic H-graft portacaval shunt (HGPCS) for portal decompression. STUDY DESIGN: Beginning in 1993, patients were prospectively randomized to undergo either TIPS or HGPCS as definitive therapy for portal hypertension due to cirrhosis. Complications of shunting and long-term outcomes were noted. Failure of shunting was prospectively defined as the inability to place shunt, irreversible shunt occlusion, major variceal rehemorrhage, unanticipated liver transplantation, or death. Survival and shunt failure were compared using Kaplan-Meier curve analysis. Median data are reported. RESULTS: Patient presentation, circumstances of shunting, causes of cirrhosis, severity of hepatic dysfunction (eg, Child's class, Model for End-Stage Liver Disease score), and predicted survival after shunting did not differ between patients undergoing TIPS (n = 66) or HGPCS (n = 66). Survival was significantly longer after HGPCS for patients of Child's class A (91 vs 19 months; p = 0.009) or class B (63 vs 21 months; p = 0.02). Shunt failure occurred later after HGPCS than TIPS (45 vs 22 months; p = 0.04). CONCLUSIONS: Compared with TIPS, survival after HGPCS was superior for patients with better liver function (eg, Child's class A or B). Shunt failure after HGPCS occurred later than after TIPS. Rather than TIPS, application of HGPCS is preferred for patients with complicated cirrhosis and better hepatic function.

A pilot study of the tolerability and effects of high-definition transcranial direct current stimulation (HD-tDCS) on pain perception.

UNLABELLED: Several brain stimulation technologies are beginning to evidence promise as pain treatments. However, traditional versions of 1 specific technique, transcranial direct current stimulation (tDCS), stimulate broad regions of cortex with poor spatial precision. A new tDCS design, called high definition tDCS (HD-tDCS), allows for focal delivery of the charge to discrete regions of the cortex. We sought to preliminarily test the safety and tolerability of the HD-tDCS technique as well as to evaluate whether HD-tDCS over the motor cortex would decrease pain and sensory experience. Twenty-four healthy adult volunteers underwent quantitative sensory testing before and after 20 minutes of real (n = 13) or sham (n = 11) 2 mA HD-tDCS over the motor cortex. No adverse events occurred and no side effects were reported. Real HD-tDCS was associated with significantly decreased heat and cold sensory thresholds, decreased thermal wind-up pain, and a marginal analgesic effect for cold pain thresholds. No significant effects were observed for mechanical pain thresholds or heat pain thresholds. HD-tDCS appears well tolerated, and produced changes in underlying cortex that are associated with changes in pain perception. Future studies are warranted to investigate HD-tDCS in other applications, and to examine further its potential to affect pain perception. PERSPECTIVE: This article presents preliminary tolerability and efficacy data for a new focal brain stimulation technique called high definition transcranial direct current stimulation. This technique may have applications in the management of pain.

Ten sessions of adjunctive left prefrontal rTMS significantly reduces fibromyalgia pain: a randomized, controlled pilot study.

Transcranial magnetic stimulation (TMS) of the prefrontal cortex can cause changes in acute pain perception. Several weeks of daily left prefrontal TMS has been shown to treat depression. We recruited 20 patients with fibromyalgia, defined by American College of Rheumatology criteria, and randomized them to receive 4000 pulses at 10 Hz TMS (n=10), or sham TMS (n=10) treatment for 10 sessions over 2 weeks along with their standard medications, which were fixed and stable for at least 4 weeks before starting sessions. Subjects recorded daily pain, mood, and activity. Blinded raters assessed pain, mood, functional status, and tender points weekly with the Brief Pain Inventory, Hamilton Depression Rating Scale, and Fibromyalgia Impact Questionnaire. No statistically significant differences between groups were observed. Patients who received active TMS had a mean 29% (statistically significant) reduction in pain symptoms in comparison to their baseline pain. Sham TMS participants had a 4% nonsignificant change in daily pain from their baseline pain. At 2 weeks after treatment, there was a significant improvement in depression symptoms in the active group compared to baseline. Pain reduction preceded antidepressant effects. TMS was well tolerated, with few side effects. Further studies that address study limitations are needed to determine whether daily prefrontal TMS may be an effective, durable, and clinically useful treatment for fibromyalgia symptoms.

Feasibility, safety, and effectiveness of transcranial direct current stimulation for decreasing post-ERCP pain: a randomized, sham-controlled, pilot study.

BACKGROUND: Emerging evidence shows that transcranial direct current stimulation (tDCS), a minimally invasive brain stimulation technique, has analgesic effects in chronic pain patients and in healthy volunteers with experimental pain. No studies have examined the analgesic effects of tDCS immediately after surgical/endoscopic procedures. Endoscopy investigating abdominal pain, especially ERCP, can cause significant postprocedural pain. OBJECTIVE: To test the feasibility, efficacy, and safety of tDCS on post-ERCP pain and analgesia use. DESIGN: Randomized, sham-controlled, pilot study. SETTING: Tertiary-care medical center. PATIENTS: This study involved 21 patients who were hospitalized overnight for ERCP for unexplained right upper quadrant pain. INTERVENTION: Twenty minutes of real 2.0 mA tDCS or sham (anode over left prefrontal cortex; cathode over gut-representation of right sensory cortex) immediately after ERCP. MAIN OUTCOME MEASUREMENTS: Pain (visual analogue scale, McGill pain questionnaire, brief pain inventory), patient-controlled analgesia use, adverse events. RESULTS: Real tDCS was associated with 22% less total hydromorphone use, versus sham. The slope of the cumulative patient-controlled analgesia usage curve was significantly steeper in the sham tDCS group (F [2,13] = 15.96; P = .0003). Real tDCS patients reported significantly less pain interference with sleep (t [17] = 3.70; P = .002) and less throbbing pain (t [16] = 2.37; P = .03). Visual analogue scale pain and mood scores (4 hours post-ERCP) suggested a nonsignificant advantage for real tDCS, despite less hydromorphone use. Side effects of tDCS were limited to mild, self-limited tingling, itching, and stinging under electrodes. LIMITATIONS: Small sample size, variability in chronic pain, and chronic opioid use. CONCLUSION: In this pilot study, tDCS appears to be safe, has minimal side effects, and may reduce postprocedural analgesia requirements and subjective pain ratings. Future studies appear warranted.

Prefrontal cortex transcranial direct current stimulation (tDCS) temporarily reduces food cravings and increases the self-reported ability to resist food in adults with frequent food craving.

This study examined whether a 20-min session of prefrontal transcranial direct current stimulation (tDCS) (anode over the right prefrontal cortex and cathode over the left prefrontal cortex) would reduce food cravings and increase the self-reported ability to resist foods in 19 healthy individuals who reported frequent food cravings. Participants viewed computerized images of food and used computerized visual analogue scales to rate food cravings and inability to resist foods before, during, and after receiving either real or sham tDCS. This study employed a randomized within-subject crossover design; participants received both real and sham tDCS and were blind to the condition. Food cravings ratings were reduced in both conditions, however, the percent change in cravings ratings from pre- to post-stimulation was significantly greater for real stimulation than for sham. The percent change in inability to resist food from pre- to post-stimulation also showed a greater decrease in the real condition than for sham. Post hoc analyses suggest that active prefrontal tDCS acutely and significantly decreased food cravings ratings for sweet foods and carbohydrates more so than sham tDCS. No significant differences were seen in the amount of food ingested between real and sham tDCS. These findings in healthy subjects indicate that tDCS is able to temporarily reduce food cravings and improve the self-reported ability to resist foods.

Fast left prefrontal rTMS acutely suppresses analgesic effects of perceived controllability on the emotional component of pain experience.

The prefrontal cortex may be a promising target for transcranial magnetic stimulation (TMS) in the management of pain. It is not clear how prefrontal TMS affects pain perception, but previous findings suggest that ventral lateral and medial prefrontal circuits may comprise an important part of a circuit of perceived controllability regarding pain, stress, and learned helplessness. Although the left dorsolateral prefrontal cortex is a common TMS target for treating clinical depression as well as modulating pain, little is known about whether TMS over this area may affect perceived controllability. The present study explored the immediate effects of fast TMS over the left dorsolateral prefrontal cortex on the analgesic effects of perceived pain controllability. Twenty-four healthy volunteers underwent a laboratory pain task designed to manipulate perception of pain controllability. Real TMS, compared with sham, suppressed the analgesic benefits of perceived control on the emotional dimension of pain, but not the sensory/discriminatory dimension. Findings suggest that, at least acutely, fast TMS over the left dorsolateral prefrontal cortex may interrupt the perceived-controllability effect on the emotional dimension of pain experience. Although it is not clear whether this cortical area is directly involved with modulating perceived controllability or whether downstream effects are responsible for the present findings, it appears possible that left dorsolateral prefrontal TMS may produce analgesic effects by acting through a cortical perceived-control circuit regulating limbic and brainstem areas of the pain circuit. Despite evidence that prefrontal TMS can have analgesic effects, fast left prefrontal TMS appears to acutely suppress analgesia associated with perceived-control. This effect may be limited to the emotional dimension of pain experience.