Sevoflurane-induced hyperglycemia is attenuated by salsalate in obese insulin-resistant mice.

PURPOSE: Perioperative hyperglycemia is common and is associated with significant morbidity. Although patient characteristics and surgery influence perioperative glucose metabolism, anesthetics have a significant impact. We hypothesized that mice that were obese and insulin-resistant would experience greater hyperglycemia in response to sevoflurane anesthesia compared with lean controls. We further hypothesized that sevoflurane-induced hyperglycemia would be attenuated by salsalate pre-treatment. METHODS: Lean and obese male C57BL/6J mice were anesthetized with sevoflurane for 60 min with or without pre-treatment of 62.5 mg·kg-1 salsalate. Blood glucose, plasma insulin, and glucose uptake into different tissues were measured. RESULTS: Under sevoflurane anesthesia, obese mice had higher blood glucose compared to lean mice. Increases in blood glucose were attenuated with acute salsalate pre-treatment at 60 min under anesthesia in obese mice (mean ± standard error of the mean [SEM], delta blood glucose; vehicle 5.79 ± 1.09 vs salsalate 1.91 ± 1.32 mM; P = 0.04) but did not reach statistical significance in lean mice (delta blood glucose, vehicle 4.39 ± 0.55 vs salsalate 2.79 ± 0.71 mM; P = 0.10). This effect was independent of changes in insulin but associated with an approx. 1.7-fold increase in glucose uptake into brown adipose tissue (vehicle 45.28 ± 4.57 vs salsalate 76.89 ± 12.23 µmol·g-1 tissue·hr-1; P < 0.001). CONCLUSION: These data show that salsalate can reduce sevoflurane-induced hyperglycemia in mice. This indicates that salsalate may represent a new class of therapeutics that, in addition to its anti-inflammatory and analgesic properties, may be useful to reduce perioperative hyperglycemia.

RéSUMé: OBJECTIF: L'hyperglycémie périopératoire est fréquente et est associée à une morbidité significative. Bien que les caractéristiques propres au patient et à la chirurgie influencent le métabolisme périopératoire du glucose, les anesthésiques ont un impact significatif. Nous avons émis l'hypothèse que l'hyperglycémie en réponse à une anesthésie à base de sévoflurane serait plus prononcée chez des souris obèses et insulino-résistantes que chez des souris témoins maigres. Nous avons en outre émis l'hypothèse que l'hyperglycémie induite par le sévoflurane serait atténuée par un prétraitement au salsalate. MéTHODE: Des souris mâles C57BL/6J maigres et obèses ont été anesthésiées avec du sévoflurane pendant 60 min avec ou sans prétraitement de 62,5 mg·kg−1 de salsalate. La glycémie, l'insuline plasmatique et l'absorption glycémique ont été mesurées dans différents tissus. RéSULTATS: Sous une anesthésie au sévoflurane, les souris obèses ont affiché une glycémie plus élevée que les souris maigres. Des augmentations de glucose sanguin ont été atténuées lors d'un prétraitement aigu à base de salsalate à 60 min sous anesthésie chez les souris obèses (moyenne ± erreur-type sur la moyenne [ETM], delta glycémique; véhicule 5,79 ± 1,09 vs salsalate 1,91 ± 1,32 mM, P = 0,04), mais elles n'étaient pas statistiquement significative chez les souris maigres (delta glycémique, véhicule 4,39 ± 0,55 vs salsalate 2,79 ± 0,71 mM; P = 0,10). Cet effet était indépendant des changements de l'insuline mais associé à une augmentation d'environ 1,7 fois de l'absorption glycémique dans les tissus adipeux bruns (véhicule 45,28 ± 4,57 vs salsalate 76,89 ± 12,23 µmol·g−1 tissu·h−1; P < 0,001). CONCLUSION: Ces données montrent que le salsalate peut réduire l'hyperglycémie induite par le sévoflurane chez la souris. Ceci indique que le salsalate pourrait constituer une nouvelle classe d'agents thérapeutiques qui, en plus de leurs propriétés anti-inflammatoires et analgésiques, pourraient être utiles pour réduire l'hyperglycémie périopératoire.

Multiagent neoadjuvant chemotherapy and tumor response are associated with improved survival in pancreatic cancer.

BACKGROUND: Neoadjuvant therapy (NT) for borderline resectable pancreatic cancer (BRPC) has evolved to include multi-agent regimens and chemoradiation. We report our experience and compare outcomes of initially resectable pancreatic cancer (IRPC) vs BRPC receiving NT across two eras of chemotherapy regimens. METHODS: Data were collected retrospectively on pancreaticoduodenectomy patients between January 2008 and October 2015. Outcomes and survival were compared based on patient, laboratory and treatment factors. RESULTS: 195 patients were included and 133 had IRPC and 62 BRPC. IRPC operations were shorter (449 min vs 520 min, p = 0.003), had less blood loss (663 ml vs 954 ml, p = 0.002) and involved fewer vascular resections (29% vs 76%, p = 0.002). The rate of R0 resection was identical (82%, p = 1) and the IRPC group had higher node-positive ratio (19.3% vs 7.2% p < 0.0001). 15 patients received a single agent regimen while 47 received multi-agent regimens with 90% receiving radiation.Survival was similar between BRPC and IRPC (log-rank p = 0.7). Histopathologic response (CAP grade 0 or 1) was not associated with survival (p = 0.13), but completion of ≥4 cycles of multi-agent pre-operative chemotherapy (p = 0.001) and complete response to NT (p = 0.04) were significant predictors of survival. CONCLUSIONS: BRPC patients treated with NT have similar morbidity and survival to their IRPC counterparts. Pathologic response and modern NT are associated with improved survival.

Evaluation of quality of life following placement of self-expanding plastic stents as a bridge to surgery in patients receiving neoadjuvant therapy for esophageal cancer.

PURPOSE: To determine whether self-expanding plastic stent (SEPS) placement significantly improves quality of life and maintains optimal nutrition while allowing full-dose neoadjuvant therapy (NAT) in patients with esophageal cancer. PATIENTS AND METHODS: A prospective, dual-institution, single-arm, phase II (http://ClinicalTrials.gov: NCT00727376) evaluation of esophageal cancer patients undergoing NAT prior to resection. All patients had a self-expanding polymer stent placed prior to NAT. The European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OG25, Functional Assessment of Cancer Therapy-Anorexia, and Functional Assessment of Cancer Therapy-General surveys were administered prior to stenting, within 1 week post-stent placement, and at the completion of neoadjuvant therapy. RESULTS: Fifty-two patients were enrolled; 3 (5.8%) had stent migrations requiring replacement. There were no instances of esophageal erosion or perforation. All patients received some form of neoadjuvant therapy. Thirty-six (69%) received chemoradiation; 34 (93%) of these patients received the planned dose of chemotherapy, and 27 (75%) received the full planned dose of radiotherapy. There were 16 (31%) patients receiving chemotherapy alone; 12 (74%) of patients in the chemotherapy-alone group completed the planned dose of therapy. CONCLUSION: Placement of SEPS appears to provide significant improvement in quality of life related to dysphagia and eating restriction in patients with esophageal cancer undergoing neoadjuvant therapy. Consideration of SEPS instead of percutaneous feeding tube should be initiated as a first line in dysphagia palliation and NAT nutritional support.

Incomplete thermal ablation of hepatocellular carcinoma: effects on tumor proliferation.

INTRODUCTION: Local recurrence after thermal ablation of hepatocellular carcinoma (HCC) is common, problematic, and poorly understood. The continued effects of the heat sink around major vessels have been hypothesized to increase local ablation failure and possibly enhance the growth of the incompletely ablated malignancy. The aim of this study was to evaluate the critical temperature to which incomplete ablation would occur. METHODS: Established murine (Hep-6L), rodent (Hep-4IIE), and human (Hep-G2) HCC cells were cultivated and then exposed to variable 2° temperatures from 37 °C-54 °C and incubated at 37 °C for 72 h. After incubation, 3-(4, 5-dimthyl-thiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays were used to measure proliferation, metabolic activity, and apoptosis. RESULTS: Reliable cell death occurred in all three cell lines by microscopy and MTT assay after treatment at temperatures above 48 °C. However, in the 72 h after treatment, we observed successive recovery or maintenance of cellular proliferation at each time endpoint at ≤47 °C. This effect was present across all cell lines at 45 °C, and was most pronounced in the Hep-6L and Hep-4IIE cell lines (P < 0.05). Hep-G2 cells demonstrated maintenance of proliferation by MTT assay over the 72 h following treatment at 45 °C. TUNEL assays were strongly positive at temperatures ≥48 °C. TUNEL positivity suggests death via apoptotic mechanisms as opposed to coagulative processes seen at higher temperatures. Cells treated at these higher temperatures had a statistically significant (P < 0.05) higher apoptotic index as measured by TUNEL positivity, despite being morphologically similar by light microscopy. CONCLUSIONS: Cellular proliferation and resistance to apoptosis are significantly increased after incomplete thermal ablation, with a 2° difference in complete versus incomplete ablation.

The Surgeon's Risk of SARS-CoV-2 Infection During the Initial Peak of the COVID-19 Pandemic in New Orleans.

Surgeons who care for patients with active SARS-CoV-2 infection represent a unique population of health care providers whose risk of infection has not been elucidated. The objective of this study was to examine SARS-CoV-2 seroprevalence among surgeons who cared for patients with active SARS-CoV-2 infection compared to other employees within our health care system and also the general public of New Orleans. 105 surgeons at our facilities provided direct surgical care to patients with active SARS-CoV-2 infection and underwent voluntary antibody testing. 2/105 (1.9% CI .2%-6.7%) tested positive for SARS-CoV-2 antibodies. 13 343 hospital employees underwent antibody testing and 1066/13 343 (8.0% CI 7.5%-8.5%) tested positive (1.9% vs. 8.0%; P = .03). We saw a significantly lower SARS-CoV-2 seroprevalence among surgeons who directly cared for infected patients versus other hospital employees. When compared to community seroprevalence (6.9% CI 6.0%-8.0%), seroprevalence among our surgeons is also significantly lower (1.9% vs. 6.9%; P = .04).

recurrence following hepatectomy for metastatic colorectal cancer: development of a model that predicts patterns of recurrence and survival.

BACKGROUND: While several prognostic models have been developed to predict survival of patients who undergo hepatectomy for metastatic colorectal cancer (mCRC), few data exist to predict survival after recurrence. We sought to develop a model that predicts survival for patients who have developed recurrence following hepatectomy for mCRC. METHODS: A retrospective analysis was performed on data from consecutive patients that underwent hepatectomy for mCRC. Clinicopathologic data, recurrence patterns, and outcomes were analyzed. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed. An integer-based model was created to predict the patterns of recurrence and survival after recurrence. RESULTS: This analysis included 280 patients with a median follow-up of 50.1 months. Of these, 53% underwent major hepatectomy and 87% had negative margins. Recurrent disease developed in 63% of patients. After hepatectomy, factors associated with short disease-free interval (DFI) and overall survival (OS) included CEA > 200 ng/ml (P < 0.0005), >1 metastasis (P < 0.0005), and a high Fong score (P < 0.0005). After recurrence, the pattern of recurrence was a strong predictor of OS (P < 0.0005). Independent predictors of the pattern of recurrence on multivariate analysis include CEA > 200 ng/ml, tumor size >5 cm, and >1 liver metastasis. A simple predictive scoring system was developed from the beta coefficients of this analysis that correlated with recurrence pattern (P < 0.0005). CONCLUSIONS: After hepatectomy, survival of patients with recurrent mCRC is strongly predicted by the patterns of recurrence, and the recurrence pattern can be predicted with a simple model. This can also be extended to create a scoring system that estimates expected survival.

Impact of post-operative complications on quality of life after pancreatectomy.

CONTEXT: Pancreatectomies for malignant and benign diseases are increasingly being performed worldwide. Recent studies, that have evaluated quality of life in pancreatectomy, have reported conflicting outcomes. OBJECTIVE: This study was undertaken to analyze the quality of life changes reported by patients with pancreatic cancer undergoing pancreatectomy. DESIGN: Post-hoc analysis was performed of a clinical trial examining the safety of intraoperative autotransfusion during oncologic resections. MAIN OUTCOME MEASURES: Perioperative (90-day) complications were graded prospectively using a validated 5-point scale. Quality of life parameters were recorded prospectively by a single trained interviewer preoperatively, at the first post-operative outpatient visit, and at 6 weeks, 3 months, and 6 months follow-up using the EORTC QLQ-C30 and FACT-An instruments. RESULTS: Pancreatectomy for adenocarcinoma was performed in 34 patients with a median follow-up of 2 years (range: 1-1.5 years). Major (grade≥3) complications occurred in 12 (35.3%) of patients. Early (<6 month) recurrence was noted in 2 patients (5.9%). Increased severity of fatigue, pain, dyspnea, and loss of appetite over baseline were noted at initial follow-up (P<0.05); however, symptom scores normalized at 6-week follow-up, and remained stable at 6 months. No significant difference was noted in quality of life metrics between patients with or without major complications (P>0.11). A significant (P=0.023) decline in cognitive function vs. baseline was noted at 6-month follow-up after pancreatectomy. Using a repeated-measures generalized linear model, neither age, nor complication occurrence, nor adjuvant therapy, nor early recurrence accounted for this cognitive decline (P>0.10). CONCLUSION: Quality of life metrics tend to normalize to preoperative levels after pancreatectomy at 6 weeks post-operatively. The occurrence of major complications does not predict a decreased quality of life. The decrease in self-reported cognitive function at six months in this cohort merits further study.

Differences between bipolar compression and ultrasonic devices for parenchymal transection during laparoscopic liver resection.

OBJECTIVES: In laparoscopic liver resection, multiple options for parenchymal transection techniques exist; however, none have emerged as superior. The aim of this study was to compare operative characteristics and outcomes between bipolar compression and ultrasonic devices used for parenchymal transection during laparoscopic liver resection. METHODS: A review of a prospective hepatopancreatobiliary database from December 2002 to August 2009 identified 54 patients who underwent laparoscopic liver resection with parenchymal division using either a bipolar compression (n= 35) or an ultrasonic (n= 19) device. Operative data, histology and 90-day complication rates were compared between the groups using analysis of variance (anova) and Pearson's chi-squared test. RESULTS: The two groups did not differ significantly in terms of age, body mass index, parenchymal steatosis/inflammation or number of segments resected. A shorter time of parenchymal transection was noted for the bipolar compression device (median: 35 min; range: 20-65 min) vs. the ultrasonic device (median: 55 min; range: 29-75 min) (P < 0.001). Median total operative time was also shorter using the bipolar compression device (130 min) than the ultrasonic device (180 min) (P= 0.050). No significant differences between device groups were noted for estimated blood loss, complications of any type or liver-specific complications. CONCLUSIONS: Bipolar compression devices may offer advantages over ultrasonic devices in terms of decreased transection time and total operative time. No differences in postoperative complications in laparoscopic liver resection emerged between patients operated using the devices.

Hepatectomy after hepatic arterial therapy with either yttrium-90 or drug-eluting bead chemotherapy: is it safe?

BACKGROUND: The use of hepatic arterial therapy (HAT) with either yttrium-90 or drug-eluting bead therapy for initially unresectable hepatic malignancies has risen significantly. The safety of hepatic resection after hepatic arterial therapy (HAT) is not established. OBJECTIVE: The present study evaluates the safety profile for hepatic resection after HAT. METHODS: We identified 840 patients undergoing hepatectomy for primary or metastatic lesions. Forty patients underwent HAT before hepatectomy (pre-HAT). A 1:4 case-matched analysis compared three groups: (i) pre-HAT and pre-operative chemotherapy (n=40); (ii) pre-operative chemotherapy (n=160); and (iii) no pre-operative therapy (n=640). Controls were matched for age, resection type, maximal tumour size and magnitude of resection. Morbidity and mortality among groups were compared using a graded complication scale. RESULTS: There were no differences in post-operative complications, grade of complication or liver-specific complications among the groups. A proportional hazards model for all patients did not demonstrate any association between increased complications and either pre-HAT or pre-operative chemotherapy when compared with patients without pre-operative therapy (P=0.7). CONCLUSIONS: Pre-HAT demonstrated similar morbidity, liver-specific morbidity and intra-operative complications when compared with patients undergoing pre-operative chemotherapy alone or without pre-operative chemotherapy. These results suggest that pre-HAT is safe and should not preclude hepatectomy in carefully selected patients.

The prognostic significance of nonsentinel lymph node metastasis in melanoma.

BACKGROUND: We hypothesized that metastasis beyond the sentinel lymph nodes (SLN) to the nonsentinel nodes (NSN) is an important predictor of survival. MATERIALS AND METHODS: Analysis was performed of a prospective multi-institutional study that included patients with melanoma ≥ 1.0 mm in Breslow thickness. All patients underwent SLN biopsy; completion lymphadenectomy was performed for all SLN metastases. Disease-free survival (DFS) and overall survival (OS) were computed by Kaplan-Meier analysis; univariate and multivariate analyses were performed to identify factors associated with differences in survival among groups. RESULTS: A total of 2335 patients were analyzed over a median follow-up of 68 months. We compared 3 groups: SLN negative (n = 1988), SLN-only positive (n = 296), and both SLN and NSN positive (n = 51). The 5-year DFS rates were 85.5, 64.8, and 42.6% for groups 1, 2, and 3, respectively (P < 0.001). The 5-year OS rates were 85.5, 64.9, and 49.4%, respectively (P < 0.001). On univariate analysis, predictors of decreased OS included: SLN metastasis, NSN metastasis, increased total number of positive LN, increased ratio of positive LN to total LN, increased age, male gender, increased Breslow thickness, presence of ulceration, Clark level ≥ IV, and axial primary site (in all cases, P < 0.01). When the total number of positive LN and NSN status were evaluated using multivariate analysis, NSN status remained statistically significant (P < 0.01), while the total number of positive LN and LN ratio did not. CONCLUSIONS: NSN melanoma metastasis is an independent prognostic factor for DFS and OS, which is distinct from the number of positive lymph nodes or the lymph node ratio.

Extracorporeal gastric stapling reduces the incidence of gastric conduit failure after minimally invasive esophagectomy.

Esophageal cancer resection is associated with significant morbidity and mortality. To date, no standardized technique exists. In this study, we analyze our short-term results in 92 minimally invasive resections performed over the past 10 years in an attempt to identify technical factors, which contribute to improved short-term outcomes. A retrospective review of 92 minimally invasive esophagectomies was performed at the Ochsner Clinic Foundation from 1999 through 2009. Data collected included preoperative stage, whether or not preoperative chemoradiation was used, technique of minimally-invasive resection, technique of esophagogastric anastomosis, margin status, anastomotic leak, conduit necrosis, gastric conduit failure of any type, and operative mortality. Gastric stapling was done either laparoscopically (intracorporeal) or through a minilaparotomy (extracorporeal). Ninety-two patients met criteria for this study. There was a significant difference in the incidence of positive gastric margins (P = 0.04), anastomotic leak (P = 0.045), conduit necrosis (P = 0.03), and any gastric conduit failure (P = 0.02) favoring the extracorporeal group. The overall short-term morbidity and operative mortality with minimally invasive esophagectomy is comparable to the results obtained with open techniques. A relatively simple modification of the operative technique-performing extracorporeal stapling of the gastric conduit-led to a significant reduction in the incidence of gastric conduit failures when compared with the intracorporeal stapling technique.

Could there be a fine-tuning role for brain-derived adipokines in the regulation of bodyweight and prevention of obesity?

Obesity is one of the most prevalent medical conditions, often associated with several negative stereotypes. Although it is true that weight gain occurs when food intake exceeds energy expenditure, it is important to note that even a 1% mismatch between the two can lead to a substantial weight gain after only a few years. Further, the body appears to balance energy metabolism via an endogenous lipostatic loop in which adipose stores send hormonal signals (e.g. adipokines such as leptin) to the hypothalamus in order to reduce appetite and increase energy expenditure. However, the brain is also a novel site of expression of many of these adipokine genes. This led to the hypothesis that hypothalamic-derived adipokines might also be involved in bodyweight regulation by exerting some effect on the control of appetite or hypothalamic function. When RNA interference (RNAi) was used to specifically silence adipokine gene expression in various in vitro models, this led to increases in cell death, modification of the expression of key signaling genes (i.e. suppressor of cytokine signaling-3; SOCS-3), and modulation of the activation of cellular energy sensors (i.e. adenosine monophosphate-activated protein kinase; AMPK). Subsequently, when RNAi was used to inhibit the expression of brain-derived leptin in adult rats this resulted in minor increases in weight gain in addition to modifying the expression of other adipokine genes (eg. resistin). In summary, although adipokines secreted by adipose tissue appear to the main regulator of lipostatic loop, this review shows that the fine tuning that is required to maintain a stable bodyweight by this system might be accomplished by hypothalamic-derived adipokines. Perturbations in this central adipokine system could lead to alterations in normal hypothalamic function which leads to unintended weight gain.

Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB-IVM1c melanoma.

Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The median age was 72 (range: 32-96) years and 54% of the patients were men. Patients had an ECOG performance status of 0 (68%) or 1 (32%). The median treatment duration was 13.1 (3.0-41.1) weeks. Treatment-related adverse events of greater than or equal to grade 3 were reported in three (7.3%) patients and included vomiting, upper abdominal pain, chills, hyperhidrosis, nausea, pyrexia, and wound infection. Suspected herpetic lesions were swabbed in five (12%) patients. One of the five tested positive for talimogene laherparepvec DNA by qPCR, but this lesion had been injected previously with talimogene laherparepvec. During the study, five patients completed treatment because of complete response per investigators. In the clinical practice setting, talimogene laherparepvec has a safety profile comparable to that observed in previous clinical trials. Talimogene laherparepvec (IMLYGIC) is now approved in the US, European Union, and Australia.

Increased expression of the adipokine genes resistin and fasting-induced adipose factor in hypoxic/ischaemic mouse brain.

Adipose tissue is the primary source of the adipokines resistin and fasting-induced adipose factor (FIAF). We reported that the brain is also a site of adipokine expression, although their function there is unknown. Peripheral resistin and fasting-induced adipose factor are reported to be inflammatory markers, and we hypothesized that they would be induced in the brain by hypoxia/ischaemia. We show that neonatal hypoxia/ischaemia rapidly increased fiaf mRNA in the injured cortex and hippocampus at 2 and 7 days after hypoxia/ischaemia. In contrast, resistin (retn) mRNA was increased in the cortex only at 21 days after hypoxia/ischaemia. As a lipopolysaccharide-induced inflammatory response did not increase brain fiaf and retn mRNA levels, we conclude that brain injury may be responsible for the novel hypoxia/ischaemia-induced changes in adipokine gene expression. In summary, our results indicate that brain injury, or an inflammatory stimulus, regulates the central expression of two genes normally considered to be adipose tissue-specific. These observations add to our previous evidence that the brain is an important site of adipokine gene expression.

Addition of an iliac/obturator lymph node dissection does not improve nodal recurrence or survival in melanoma.

BACKGROUND: Controversy exists regarding the value and indications for inguinal dissection alone or in combination with an iliac/obturator lymph node dissection for melanoma. STUDY DESIGN: We reviewed patients from a multicenter prospective clinical trial and a single center who underwent inguinal dissection alone or combined with an iliac/obturator dissection for cutaneous melanoma. Analyses were stratified and compared by microscopic or macroscopic (palpable or detected by imaging) disease. RESULTS: The study was composed of 134 patients with a median follow-up of 39 months. Indications for inguinal dissection were microscopic disease in 94 (70%) patients and macroscopic nodal disease in 40 (30%) patients. An iliac/obturator dissection yielded tumor-positive pelvic nodes in 25% vs 55% in the microscopic vs macroscopic groups, respectively (p = 0.10). No risk factors for positive pelvic nodes were identified. For both microscopic and macroscopic disease, addition of an iliac/obturator dissection to an inguinal dissection did not significantly reduce the risk of pelvic nodal recurrence. Five-year overall survival rates for 4 groups were compared: microscopic disease, inguinal dissection alone (72%); microscopic disease, iliac/obturator dissection (68%); macroscopic disease, inguinal dissection alone (51%); and macroscopic disease, iliac/obturator dissection (44%) (p = 0.0163). On survival analysis, addition of an iliac/obturator dissection in either microscopic or macroscopic disease did not affect disease-free survival or regional lymph node recurrence-free survival. CONCLUSIONS: The addition of an iliac/obturator dissection to an inguinal dissection for both microscopic and macroscopic nodal disease did not significantly affect lymph node recurrence rates, disease-free survival, or overall survival.

Negative effects of transfused blood components after hepatectomy for metastatic colorectal cancer.

There has been conflicting evidence regarding negative effects of blood transfusion in oncology patients. This study was undertaken to determine any negative effects of specific blood product transfusion after resection of hepatic colorectal metastases (CRM). Retrospective review of patients undergoing hepatectomy for CRM from 1995 to 2009 at a single institution was performed. Specific attention was paid to the effect of blood transfusion within 30 days of operation on overall survival, disease-free survival (DFS), and complications. To mitigate the bias introduced by complications that require blood transfusion to treat, only nonbleeding complications were considered. Complications were analyzed with univariate and multivariate logistic regression. Survival was analyzed according to Kaplan-Meier and Cox proportional hazards. There were 239 patients included in the study. There were 64 (26.8%) receiving a transfusion of any kind with 25.5 per cent getting red cells (PRBCs), 7.11 per cent getting fresh-frozen plasma, and 3.77 per cent getting platelets. Multivariate analysis revealed only PRBC transfusion to be independently associated with nonbleeding complications (odds ratio, 1.980; 95% confidence interval, 1.094 to 3.582; P = 0.0239). There was no significant adverse effect of transfusion with any product on overall or DFS. PRBC transfusion appears to increase the risk of postoperative complications; thus, strategies to minimize blood use may be warranted.

Hypothalamic kiss1 mRNA and kisspeptin immunoreactivity are reduced in a rat model of polycystic ovary syndrome (PCOS).

An intact hypothalamic kiss1/kisspeptin/kiss1r complex is a prerequisite for reproductive competence, and kisspeptin treatment could be a practical therapeutic approach to some problems of infertility. One such disorder is polycystic ovarian syndrome (PCOS), a common cause of infertility affecting more than 100 million women. A rodent model of PCOS is the prepubertal female rat treated for a prolonged period with dihydrotestosterone (DHT), which induces many of the metabolic characteristics of the syndrome. We hypothesized that hypothalamic kiss1 mRNA levels, and kisspeptin immunoreactivity (ir), would be abnormal in these rats. Prepubertal female rats were exposed to DHT for 60 days. Rats were killed in two groups: at 26 and 60 days of DHT exposure. Kiss1 mRNA was quantified in hypothalamus, pituitary, ovary and visceral adipose tissue. Separate groups of rats provided brain tissue for immunohistochemical analysis of kisspeptin-ir. At 26 days of DHT exposure, hypothalamic kiss1 mRNA was severely depleted. In contrast DHT had no effect on pituitary kiss1 expression but it significantly increased levels of kiss1 mRNA in fat (+9-fold; p<0.01) and in ovary (+3-fold; p<0.05). At 60days, kiss1 expression had reverted to normal in hypothalamus and ovary but remained elevated in fat (+4-fold; p<0.05). Immunohistochemical analysis revealed that after 26 days of exposure to DHT, kisspeptin-ir was almost completely absent in the arcuate nucleus and a large depletion in kisspeptin +ve fibers was also seen in the paraventricular nucleus, supraoptic nucleus and in the anteroventral periventricular area. At 60 days, despite restored normal levels of kiss1 mRNA, hypothalamic kisspeptin-ir remained depleted in the treated rats. In summary Kiss1 gene expression is differentially affected in various tissues by chronic exposure to dihydrotestosterone in a rat model of polycystic ovary syndrome. In hypothalamus, specifically, kiss1 mRNA, and levels of kisspeptin immunoreactivity, are significantly reduced. Since these rats exhibit many of the characteristics of polycystic ovary syndrome, we suggest that atypical kiss1 expression may contribute to the multiple tissue abnormalities observed in women with this disorder. However, and of some importance, our data do not appear to be consistent with the elevated levels of LH seen in women with PCOS; i.e. reduced levels of hypothalamic kiss1 mRNA and kisspeptin immunoreactivity observed in DHT-treated rats are unlikely to produce elevated LH secretion.

Superinduction of leptin mRNA in mouse hypothalamic neurons.

In marked contrast to several other species, including rats and humans, leptin gene expression is undetectable in mouse brain. This unexpected finding may reflect unique energy regulation pathways in the mouse. We investigated possible mechanisms by which leptin (ob) gene expression is suppressed in mouse brain: (a) the possibility that ob mRNA levels might be detectable in vitro through the superinduction of gene expression following protein synthesis inhibition and (b) whether chromatin modification of the ob gene was responsible for this repression. Experiments were conducted on mouse hypothalamic neurons in vitro. Cells were treated with (a) protein synthesis inhibitors: cycloheximide (CHX; 25 µg/ml); puromycin (50 µg/ml); anisomycin (5 µM); (b) trichostatin A (histone deacetylase inhibitor; 500 nM); and (c) 5-aza-2'-deoxycytidine (DNA methylation inhibitor; 5 µM). Following the incubations, cells were harvested for the preparation of RNA and ob mRNA was detected using real-time reverse transcription PCR. Protein synthesis inhibitors induced a rapid increase in ob mRNA levels in mouse hypothalamic neurons in vitro. For example CHX stimulation of ob mRNA was detectable at 60 min after treatment and reached a maximum between 4 and 6 h. A dose-response analysis, with concentrations of CHX of 1, 2, 10, 25, and 50 µg/ml, indicated that CHX was already effective at 1.0 µg/ml, with a maximal effect by 25 µg/ml. In contrast, incubation with trichostatin A and 5-aza-2'-deoxycytidine had no effect and ob mRNA remained undetectable. These data show that leptin gene expression is superinduced in ob-negative mouse hypothalamic neurons following inhibition of protein synthesis. They confirm that the previously reported absence of leptin mRNA in mouse brain is probably because of an active repressive mechanism, although this may not involve chromatin modification.

Ablative therapies for colorectal liver metastases.

Ablative therapies remain a useful adjunct in the multidisciplinary treatment of patients with colorectal liver metastases not amenable to hepatic resection. This review summarizes the rationale, underlying mechanisms, techniques, complications, and outcomes of current and emerging ablative modalities.