Circumferential resection margins and perineal complications after neoadjuvant long-course chemoradiotherapy followed by extralevator abdominoperineal excision of the rectum: Five years of activity at a single institution.

BACKGROUND: Prone extralevator abdominoperineal excision of the rectum (ELAPE) has been introduced to improve the circumferential resection margins (CRM) compared with traditional APER. OBJECTIVE: We present short-term results achieved with prone ELAPE preceded by neoadjuvant chemoradiotherapy during the last 5 years of activity. DESIGN: A retrospective review was conducted. SETTINGS AND PATIENTS: Prone ELAPE operations performed between September 2010 and August 2014 at Leicester Royal Infirmary preceded by neoadjuvant chemoradiotherapy. INTERVENTIONS AND MAIN OUTCOME MEASURES: Data regarding demographics, staging, neoadjuvant therapies, intraoperative perforations, and perineal complications were collected. RESULTS: Seventy-two patients were included. Pretreatment radiological T4 were 25.0%, histological T4 2.8%. Intraoperative perforations occurred in 2.8%, CRM was involved in 11.1%. Perineal complications consisted of superficial wound infections (20.8%), full thickness dehiscences (16.7%), hematomas (9.7%), pelvic collections (6.9%), and perineal hernias (5.6%). CONCLUSIONS: In our experience, prone ELAPE preceded by long-course chemoradiotherapy has been successfully used in the last 5 years to resect low rectal tumors. Perineal wound complications rates are similar to those presented in series using direct perineal closures. J. Surg. Oncol. 2016;114:86-90. © 2016 Wiley Periodicals, Inc.

Prognostic performance of inflammation-based prognostic indices in patients with resectable colorectal liver metastases.

A range of prognostic cellular indices of the systemic inflammatory response, namely the neutrophil-lymphocyte ratio (NLR), derived NLR (dNLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) and prognostic nutritional index (PNI), have been developed and found to have prognostic utility across varied malignancies. The current study is the first to examine the prognostic value of these six inflammatory scores in patients with resectable colorectal liver metastases (CRLM). Data from 302 consecutive patients undergoing surgery for resectable CRLM were evaluated. The prognostic influence of clinicopathological variables and the inflammatory scores NLR, dNLR, PLR, LMR, COP-NLR and PNI upon overall survival (OS) and cancer-specific survival (CSS) were determined by log-rank analysis and univariate and multivariate Cox regression analyses. High preoperative NLR was the only inflammatory variable independently associated with shortened OS (HR 1.769, 95 % CI 1.302-2.403, P < 0.001) or CSS (HR 1.927, 95 % CI 1.398-2.655, P < 0.001) following metastasectomy. When NLR was replaced by dNLR in analyses, high dNLR was independently associated with shortened OS (HR 1.932, 95 % CI 1.356-2.754, P < 0.001) and CSS (HR 1.807, 95 % CI 1.209-2.702, P = 0.004). The inflammatory scores PLR, LMR, COP-NLR and PNI demonstrated no independent association with either overall or cancer-specific survival in the study population. Our findings support high preoperative NLR and dNLR as independent prognostic factors for poor outcome in patients undergoing CRLM resection, with prognostic value superior to other cellular-based systemic inflammatory scores.

Notch3 and HEY-1 as prognostic biomarkers in pancreatic adenocarcinoma.

In order to achieve a better outcome for pancreatic cancer patients, reliable biomarkers are required which allow for improved diagnosis. These may emanate from a more detailed molecular understanding of the aggressive nature of this disease. Having previously reported that Notch3 activation appeared to be associated with more aggressive disease, we have now examined components of this pathway (Notch1, Notch3, Notch4, HES-1, HEY-1) in more detail in resectable (n = 42) and non-resectable (n = 50) tumours compared to uninvolved pancreas. All three Notch family members were significantly elevated in tumour tissue, compared to uninvolved pancreas, with expression maintained within matched lymph node metastases. Furthermore, significantly higher nuclear expression of Notch1, -3 and -4, HES-1, and HEY-1 (all p ≤ 0.001) was noted in locally advanced and metastatic tumours compared to resectable cancers. In survival analyses, nuclear Notch3 and HEY-1 expression were significantly associated with reduced overall and disease-free survival following tumour resection with curative intent, with nuclear HEY-1 maintaining independent prognostic significance for both outcomes on multivariate analysis. These data further support a central role for Notch signalling in pancreatic cancer and suggest that nuclear expression of Notch3 and its target gene, HEY-1, merit validation in biomarker panels for diagnosis, prognosis and treatment efficacy. A peptide fragment of Notch3 was detected in plasma from patients with inoperable pancreatic cancer, but due to wide inter-individual variation, mean levels were not significantly different compared to age-matched controls.

Influence of hepatic parenchymal histology on outcome following right hepatic trisectionectomy.

BACKGROUND: Histological abnormalities in the non-tumour-bearing liver (NTBL) may influence outcome following hepatectomy. Effects will be most pertinent following right trisectionectomy but have yet to be specifically examined in this context. This study aimed to investigate the influence of perioperative factors, including NTBL histology, on outcome following right trisectionectomy. METHODS: Pathological review of the NTBL of 103 consecutive patients undergoing right trisectionectomy between January 2003 and December 2009 was performed using established criteria for steatosis, non-alcoholic steatohepatitis (NASH), sinusoidal injury (SI), fibrosis and cholestasis. Perioperative and pathological factors were correlated with post-operative outcome (morbidity, major morbidity, hepatic insufficiency and mortality). RESULTS: Morbidity, hepatic insufficiency and major morbidity occurred in 37.9 %, 14.6 % and 22.3 % of cases, respectively. Ninety-day mortality rate was 5.8 %. NASH (P = 0.007) and perioperative blood transfusion (P = 0.001) were independently associated with hepatic insufficiency following trisectionectomy. NASH (P = 0.028), perioperative transfusion (P = 0.016), diabetes mellitus (P = 0.047) and coronary artery disease (P = 0.036) were independently associated with major morbidity. Steatosis, SI, fibrosis and cholestasis in the NTBL demonstrated no association with any adverse outcome. CONCLUSION: NASH, but not steatosis or SI, is associated with adverse outcome following right trisectionectomy and caution must be exerted when considering major hepatectomy in patients with NASH.

Preoperative systemic inflammation and infectious complications after resection of colorectal liver metastases.

BACKGROUND: Postoperative complications are associated with a poor long-term prognosis after resection of colorectal liver metastases via an undetermined mechanism. The preoperative systemic inflammatory response, itself a predictor of poor survival, was recently shown to independently predict postoperative infectious complications after primary colorectal cancer resection. OBJECTIVE: To examine the association of postoperative infectious complications with preoperative systemic inflammation and survival in patients undergoing resection of colorectal liver metastases. DESIGN: Retrospective study based on a prospectively updated database. SETTING: A United Kingdom tertiary referral hepatobiliary unit. PATIENTS: A total of 202 consecutive patients with colorectal liver metastases undergoing hepatectomy between January 1, 2000, and April 30, 2006. MAIN OUTCOME MEASURES: Multivariable analyses were performed to correlate preoperative and operative variables with postoperative complications and to correlate complications with long-term survival after metastasectomy. RESULTS: Ninety-day mortality and morbidity were 2.0% and 25.7%, respectively. The preoperative systemic inflammatory response independently predicted the development of infectious complications (P = .009) and major infectious complications (P = .005) after hepatectomy, along with performance of trisectionectomy. Infectious complications were associated with poor long-term survival after metastasectomy but lost independent significance when systemic inflammatory variables were included in multivariable analyses. CONCLUSIONS: The preoperative systemic inflammatory response independently predicts the development of infectious complications after colorectal liver metastases resection. Although infectious complications are associated with adverse long-term prognosis after hepatectomy, they lacked independent prognostic value when systemic inflammatory variables were also considered, suggesting that much of their prognostic value arises from their association with the preoperative systemic inflammatory response.

Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo.

The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva®) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin. Tumor volume was assessed, as was the expression of Ki-67, cleaved caspase-3 and Notch-1. Curcumin in combination with oxaliplatin was able to decrease proliferative capacity of oxaliplatin-resistant p53 wildtype and p53(-/-) cell lines more effectively than oxaliplatin alone. It also decreased markers associated with proliferation. After 21 days of treatment in the xenograft model, the order of efficacy was combination > Meriva > oxaliplatin > control. The decrease in tumor volume when compared to vehicle-treated animals was 53, 35 and 16%, respectively. Ki-67 and Notch-1 immunoreactivity was decreased by the combination when compared to vehicle-treated animals, with cleaved caspase-3 rising by 4.4-fold. Meriva did not adversely affect the DNA-platinating ability of oxaliplatin. Curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting the mode of action of oxaliplatin. Addition of formulated curcumin to oxaliplatin-based chemotherapy regimens has the potential for clinical benefit.

The safety and efficacy of ablative techniques adjacent to the hepatic vasculature and biliary system.

Ablative techniques may provide an alternative to resection in treating awkwardly placed hepatic malignancy adjacent to major vascular and biliary structures. The heat-sink effect may reduce efficacy adjacent to major vascular structures. Vascular occlusion improves efficacy but is associated with increased vascular and biliary complications. The safety and efficacy of ablation in these situations remain to be defined. Further studies comparing both safety and efficacy are needed.

Laparoscopic splenectomy: a personal series of 140 consecutive cases.

INTRODUCTION: Laparoscopic splenectomy has emerged as a safe and effective treatment for a variety of haematological conditions. The objective was to review the results from a large personal series from the perspective of outcomes according to operative time, conversion to open operation, complications and mortality. The application of laparoscopic splenectomy to cases of splenomegaly without hand assistance is examined. PATIENTS AND METHODS: A retrospective review of 140 patients undergoing laparoscopic splenectomy at a single university hospital by one surgeon during 1994-2006. Case notes were reviewed and data collected on operative time, conversion to open procedure, morbidity and mortality. Particular reference was made towards the results of cases of splenomegaly. RESULTS: In total 140 laparoscopic splenectomies were performed with a complication rate of 15% and no mortality. The median operative time was 100 min and conversion to open procedure was necessary in 2.1%. Conversion for cases of splenomegaly was only 5.7%. The median hospital stay was 3 days. CONCLUSIONS: Laparoscopic splenectomy is a safe procedure with acceptable morbidity. A laparoscopic approach for splenomegaly is feasible.

Combined biliary and gastric bypass procedures as effective palliation for unresectable malignant disease.

BACKGROUND: Although endoscopic treatment of jaundice is increasingly used in the palliation of unresectable malignant disease, surgical bypass still has a role to play in this setting. This study aimed to reappraise the short-term and long-term results of combined biliary/gastric bypass (hepaticojejunostomy and gastrojejunostomy) as palliation for unresectable malignant disease. METHODS: All patients undergoing simultaneous biliary and gastric bypass procedures for unresectable malignant disease between August 2000 and January 2006 were identified and outcomes reviewed. RESULTS: One hundred and two patients underwent open surgical biliary drainage procedures for palliation of malignant disease. Underlying malignant disease included pancreatic carcinoma (n = 88), duodenal adenocarcinoma (n = 6) and distal cholangiocarcinoma (n = 3). Thirty-one of the patients underwent a planned palliative bypass procedure, the remainder being carried out after unresectable disease was identified at laparotomy. Postoperative mortality and morbidity rates were higher in the group undergoing planned bypass. During follow up, two patients developed recurrent jaundice that required transhepatic stenting and two patients developed late gastric outlet obstruction requiring refashioning of the gastrojejunostomy. CONCLUSION: Combined surgical biliary and gastric bypass achieved effective palliation of jaundice and gastric outlet obstruction until death in >95% of patients in this series. It remains first-line therapy in patients identified as having unresectable disease at laparotomy.

Normothermic perfusion of ischaemic porcine kidneys: an evaluation of ex vivo function and endothelin receptor antagonism.

BACKGROUND: Non-heart-beating donors suffer a period of warm ischaemia (WI) injury, resulting in higher rates of delayed graft function compared with heart-beating donors. Endothelin is believed to play a pathophysiological role in the intense vasospasm associated with WI. This study aimed to investigate renal function using normothermic perfusion and potential therapeutic intervention with endothelin receptor antagonism. METHODS: Porcine kidneys, subjected to varying periods of in situ WI (<10, 30 and 60 minutes), underwent normothermic machine perfusion with a perfluorodecalin perfusate. Intrarenal vascular resistance (IRR) was measured throughout perfusion, and urine and perfusate biochemical analysis was performed after 1 and 3 hours. Endothelin receptor antagonism was tested by administration of BQ-123 and BQ-788. RESULTS: Initial IRR during perfusion increased with WI. IRR reduced to similar levels in all WI groups after 90 minutes of perfusion, but subsequently rose after 150 minutes. BQ-123 considerably increased the initial IRR; however, it abolished the rise seen towards the end of perfusion. BQ-788 had little effect. Renal metabolism and function deteriorated with increasing WI. Perfusion had adverse effects on renal function and metabolism. Endothelin receptor antagonism had little effect on renal function. CONCLUSIONS: This study suggests that ex vivo assessment after normothermic perfusion correlates with warm ischaemic damage. However, endothelin receptor antagonism does not ameliorate the rise in IRR or renal function after kidneys are subjected to a warm ischaemic insult.

Systematic review of minimally invasive pancreatic resection.

BACKGROUND: Pancreatic resection is associated with a significant morbidity. Efforts to reduce hospital stay and enhance recovery have seen the introduction of minimally invasive surgical techniques. This article reviews the current published literature on the safety and efficacy of minimally invasive surgery of the pancreas. METHODS: An electronic search of the PubMed and Embase databases was performed from 1996 to May 2008 to identify all relevant publications; studies meeting predefined inclusion criteria were retrieved and analyzed using a standardized protocol. Data on the safety and efficacy of minimally invasive surgery of the pancreas were recorded and analyzed. RESULTS: Of 565 abstracts reviewed, 39 studies were identified as eligible for inclusion. There were 37 case series and two case control studies. Compared with open pancreatic surgery, minimally invasive pancreatic resection is similar in terms of morbidity and mortality. Blood loss and length of stay are decreased. CONCLUSIONS: Laparoscopic distal pancreatic resection and enucleation of insulinoma appear to be safe procedures with reduced hospital stay, though morbidity remains significant. The evidence for laparoscopic pancreaticoduodenectomy is in its infancy, but the authors feel it is unlikely that many centers will achieve sufficient case load to make the introduction of minimally invasive resection feasible.

Prognostic molecular markers in cholangiocarcinoma: a systematic review.

The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, with the incidence in United Kingdom (UK) now exceeding 1000 cases per year. It is an aggressive malignancy typified by unresponsiveness to the existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though post-operative disease recurrence is common, with 5-year survival rates of less than 25% following resection. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date, p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.

Phytochemicals as potential chemopreventive and chemotherapeutic agents in hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and the incidence is rising. Surgery, including transplantation resection, is currently the most effective treatment for HCC; however, recurrence rates are high and long-term survival is poor. Identifying novel chemopreventive and chemotherapeutic agents and targeting them to patients at high risk of developing HCC or following curative treatment may go some way towards improving prognosis. This review examines current knowledge regarding the chemopreventive and chemotherapeutic potential of phytochemicals in heptocarcinogenesis. Both in-vitro and animal studies demonstrate that several phytochemicals, including curcumin, resveratrol, green tea catechins, oltipraz and silibinin, possess promising chemopreventive and chemotherapeutic properties. Despite this, very few clinical trials have been performed. Problems regarding validation of biomarkers, agent delivery, side effects and patient selection are barriers that need to be overcome to determine the potential of such agents in clinical practice.

Delayed necrotizing acalculous cholecystitis after multiple trauma.

This is a case report of a necrotizing acalculous cholecystitis 7 weeks after multiple orthopedic trauma successfully treated by operative intervention.

Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt.

BACKGROUND AND OBJECTIVES: Reactivation of the Notch signalling pathway occurs in a range of human malignancies. Previous research suggests that Notch3 is expressed in pancreatic adenocarcinomas, but neither cellular location nor association with clinical parameters has been described. The relationship between Notch3, clinical endpoints, and other proteins with potential to interact with Notch was therefore examined. METHODS: An immunohistochemical study was performed on human pancreatic adenocarcinoma (n = 23) and normal pancreas (n = 12), to assess expression of Notch3, cyclin D1, pAkt, STAT3 and pSTAT3. Immunohistochemical data were then correlated with clinicopathological characteristics. RESULTS: Notch3 was significantly overexpressed in the cytoplasm of 73.9% of tumours. Nuclear expression was not observed in normal pancreatic ductal tissue, but was noted in 43.5% of tumours. No tumour expressing nuclear Notch3 was resectable. There were significant correlations between expression and intracellular location of Notch3 and each of STAT3, pSTAT3 and pAkt, but not cyclin D1. CONCLUSION: The presence of Notch3 in tumour nuclei is likely to represent functional activation of the protein, and is clearly linked to a more aggressive tumour phenotype. The correlation with STAT3, pSTAT3 and pAkt expression has not previously been described and the concurrent intracellular localisation of these proteins suggests a functional relationship between them.

Prognostic molecular markers in hepatocellular carcinoma: a systematic review.

Hepatocellular carcinoma (HCC) is the fifth commonest malignancy worldwide and its incidence is rising. Surgery, including transplantation, remains the only potentially curative modality for HCC, yet recurrence rates are high and long-term survival poor. The ability to predict individual recurrence risk and subsequently prognosis would help guide surgical and chemotherapeutic treatment. As understanding of hepatocarcinogenesis has increased, the myriad of genetic and molecular events that drive the hepatocarcinogenic disease process, including angiogenesis, invasion and metastasis, have been identified. This systematic review examines the evidence from published manuscripts reporting the prognostic potential of molecular biomarkers in hepatocellular carcinoma. In summary, a number of molecular biomarkers with prognostic significance have been identified in hepatocellular carcinoma. Not only might these molecules allow more accurate prediction of prognosis for patients with HCC, but they may also provide targets for potential therapeutic agents.