Sarcopaenia, obesity, sarcopaenic obesity and outcomes following hepatic resection for colorectal liver metastases: a systematic review and meta-analysis.

BACKGROUND: Obesity is a risk factor for the development of colorectal cancer. Limited evidence exists about outcomes for obese patients undergoing hepatic resection for colorectal liver metastases (CRLM). Sarcopaenia is characterised by a decline in muscle function and muscle mass. It is associated with poorer outcomes for patients on chemotherapy, but there are limited data for sarcopaenic patients undergoing hepatic resection for CRLM. METHODS: Pubmed, Embase, Cochrane Central, Web of Science, SCOPUS, and CINAHL databases were searched for articles which were selected in accordance with PRISMA guidelines. Primary outcomes were overall survival (OS) and disease-free survival (DFS). A random effects meta-analysis was conducted. RESULTS: Thirteen studies were included incorporating 2936 patients. No significant difference was found between obese and non-obese patients in OS (HR 0.81, CI 0.47-1.39, p = 0.44) or DFS (HR 1.0, CI 0.99-1.01, p = 0.98). Sarcopaenia was associated with worse OS (HR 1.65, CI 1.10-2.48, p = 0.01), and increased major post operative complications (OR 1.91, CI 1.16-3.14, p = 0.01). Only one study examined outcomes for sarcopaenic obese patients. CONCLUSION: Limited evidence exists describing the impact of obesity and sarcopenia on outcomes following hepatic resection for CRLM. Obese patients do not have worse oncological outcomes, whereas sarcopaenia is associated with poorer long-term survival.

Novel en-bloc resection of locally advanced hilar cholangiocarcinoma: the Rex recess approach.

Loco-regional recurrence after potentially curative resection remains a problem in hilar cholangiocarcinoma. Hilar dissection risks local spillage of tumor cells leading to suboptimal disease free survival. We have developed a new technique of radical resection for hilar cholangiocarcinoma based on the distinctive anatomy of the Rex recess of the liver, which has been assessed in two patients with locally advanced hilar cholangiocarcinoma. This technique included a right hepatectomy with en-bloc resection of the hepatoduodenal ligament and portal venous reconstruction to the left portal vein at the Rex recess. Both patients had R0 resection and have been disease-free for 26 and 38 months, respectively.

Pancreatectomy with synchronous vascular resection--an argument in favour.

BACKGROUND: The first case-series of pancreatectomy with synchronous en-bloc vascular resection with the aim to improve pancreatic cancer survival was published in 1977. Advances in surgical techniques, intensive care management and teaching centers with high volume cases have dramatically reduced mortality and morbidity of major pancreatic resections. This has led to a progressively wider use of venous and/or arterial resections during pancreatic surgery in selected patients to achieve negative resection margins. METHODS: We review the current literature and discuss our experience in pancreatectomies with en-bloc vascular resections. RESULTS: Survival of patients with pancreatic cancer who undergo an R0 resection with venous reconstruction is comparable to those who have a standard pancreaticoduodenectomy with no added mortality or morbidity. Conversely, arterial resection is associated with a higher morbidity, mortality and overall poorer survival, perhaps reflecting more advanced disease. CONCLUSIONS: Since the need for vascular resection may not be always apparent on pre-operative imaging, surgeons who perform major pancreatic surgery should be familiar with vascular resection and reconstruction techniques in order to offer to these patients the best chance to prolong survival.

A large upper abdominal mass in an adolescent with high Ca 19.9: a case report.

Mucinous cystic neoplasms of the liver are uncommon cystic lesions of the liver, most commonly seen in women in the fifth decade of life. We present a case of a 16-year-old girl with an incidentally discovered abdominal mass while undergoing a tonsillectomy. Investigation revealed a multiloculated, septated 17 × 17 × 11 cm cystic lesion arising from the left lobe of the liver, with displacement of the remaining upper abdominal viscera. Serum Ca19.9 was significantly elevated at 2256 U/ml (range 0-37), but other bloods including liver function tests, alphafoetoprotein and carcinoembryonic antigen were within normal limits. We proceeded to open formal left hemi-hepatectomy. Histology was consistent with a diagnosis of mucinous cystic neoplasm with low-grade intra-epithelial neoplasia.

Pancreaticoduodenectomy after liver transplantation in patients with primary sclerosing cholangitis complicated by distal pancreatobiliary malignancy.

BACKGROUND: The aim of this study was to examine the use of pancreaticoduodenectomy for malignancy in patients who have undergone liver transplantation for primary sclerosing cholangitis (PSC). METHODS: Patients who underwent simultaneous or sequential pancreaticoduodenectomy after liver transplantation were identified from a prospective transplant database. Preoperative, perioperative, and follow-up data were collected by review of patients' medical records. RESULTS: Four patients with PSC underwent simultaneous (1) or sequential (3) pancreaticoduodenectomy for the treatment of distal cholangiocarcinoma (2) or pancreatic adenocarcinoma (2). Postoperative complications occurred in two patients (1 pneumonia and 1 wound infection). Tumour resection margins were negative in all cases. Two patients with node-negative tumours were disease-free after 5 years and 23 months, and two patients with node-positive tumours died of recurrence after 5 and 10 months. CONCLUSIONS: Pancreaticoduodenectomy after liver transplantation can be performed with low morbidity in specialist centres with expertise in both liver transplantation and major pancreatic surgery. Patients with resectable disease should be treated aggressively, although long-term results will be dictated by the histological stage of the tumour, particularly lymph node status.

Budd-Chiari syndrome secondary to caval recurrence of renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) involves the inferior vena cava (IVC) in a minority of patients. Less commonly, it presents with Budd-Chiari syndrome. If untreated, the condition progresses towards liver failure and death. METHOD: We report a case of Budd-Chiari syndrome due to infiltration of the IVC and right atrium by recurrence of RCC 7 years after successful treatment by primary resection. RESULTS: Surgery was performed with a combined abdominal and thoracic approach with cardio-pulmonary by-pass and cardioplegia. The tumor was removed and a cadaveric iliac vein graft used to re-establish venous continuity between the right atrium and hepatic veins. CONCLUSIONS: Although it is a complex and high-risk procedure, aggressive surgery performed by an experienced team with liver transplant and cardiothoracic skills may enable resection of apparently advanced caval tumors. The case is discussed in the light of the current literature.

NF-kappaB and p38 MAPK inhibition improve survival in endotoxin shock and in a cecal ligation and puncture model of sepsis in combination with antibiotic therapy.

BACKGROUND: Nuclear factor-kappa B (NF-kappaB) and p38 mitogen-activated protein kinase (MAPK) are critical intracellular signal transduction pathways that mediate the systemic inflammatory response syndrome. Antibiotics induce bacterial lysis, which also contributes to cytokine production and the inflammatory response by activating NF-kappaB and p38 kinase. In this study, we set out to examine the effects of inhibition of p38 MAPK and NF-kappaB translation in in vivo models of sepsis. MATERIALS AND METHODS: Intraperitoneal lipopolysaccharide (30 mg/kg), tail vein injection of bacteria (Staphylococcus aureus + Salmonella Typhimurium, 5 x 10(7) colony forming units/kg) and cecal ligation and puncture (CLP) with or without antibiotics (Augmentin, 100 mg/kg) were the septic models used. Animals received control, SB-202190 (a p38 inhibitor), or SN-50 (an NF-kappaB inhibitor), and mortality was assessed by log-rank analysis. Blood was collected at different time points for cytokine analysis, and splenic tissue was used for cytoplasmic protein extraction to assess kinase activation. RESULTS: SB-202190 and SN-50 resulted in significant survival benefit in the lipopolysaccharide model (P = 0.0006) but not bacterial or CLP models (P = 0.9 and 0.3, respectively). SB-202190 and SN-50, in combination with antibiotic, resulted in a significant survival benefit in the CLP model (P = 0.0001 and 0.006, respectively). Circulating levels of both tumor necrosis factor-alpha and interleukin-6 were significantly reduced at 2 h (P = 0.047 and 0.036, respectively) and Western blot demonstrated down-regulation of p38 kinase 2 h after CLP in animals treated with p38MAPK and SN-50 inhibitors in combination with antibiotics. CONCLUSIONS: We have demonstrated that p-38 and NF-kappaB inhibition improve survival in endotoxin shock, whereas the survival benefit in polymicrobial sepsis requires coexistent antibiotic treatment.

The role of P38 MAPK and PKC in BLP induced TNF-alpha release, apoptosis, and NFkappaB activation in THP-1 monocyte cells.

BACKGROUND: P38 mitogen activated protein kinase (p38 MAPK) is a critical mediator of the inflammatory response, which makes it a suitable candidate as a novel therapeutic strategy for inflammatory conditions. In this study, we set out to examine the precise role of both protein kinase C (PKC) and P38 MAPK signaling kinases in bacterial lipoprotein (BLP) induced nuclear factor-kappa B (NFkappaB) activation and tumor necrosis factor-alpha (TNFalpha) release in THP-1 monocytic cell line. MATERIALS AND METHODS: THP-1 cells were incubated with BLP(0-1000 ng/mL), phorbol myristate acetate (PMA; 0-100 microg/mL) or a combination of both for 6 and 24 h, with or without pretreatment with SB202190, a specific inhibitor of p38 MAPK and bisindolylmaleimide I, a specific inhibitor of PKC (0-200 microm). Cell supernatants were analyzed for TNF-alpha release and apoptosis. NFkappaB activity was analyzed by electromobility supershift assay. RESULTS: BLP induced TNF-alpha release was significantly reduced by pretreatment with SB202190 at all concentrations (428.7 +/- 5.9 versus 51 +/- 0.8 rhog/mL, P < 0.05). Pretreatment with bis I significantly inhibited TNF-alpha release at higher concentrations (200 microM) (429.7 +/- 5.9 versus 194.9 +/- 42.68 rhog/mL, P < 0.05) but this was much less effective than SB202190. PMA induced TNF-alpha release was not inhibited at 6 h by either SB202190 or bis I, but was significantly so at 24 h (148.5 +/- 9.8 versus 24 +/- 1.7 and 25.1 +/- 4.4 rhog/mL, P < 0.05). BLP or lipopolysaccharide (LPS) did not result in apoptosis in THP-1 cells (P > 0.05) with PMA inducing apoptosis in a time- and dose-dependent manner. In combination with BLP (1000 ng/mL) but not LPS (1000 ng/mL), low dose PMA resulted in a significant increase in apoptosis, 6% +/- 0.5% (Control) versus 9.2% +/- 0.3% (P < 0.05) and 7% +/- 2.2% (Control) versus 7.7% +/- 0.3% (P > 0.05), respectively. This synergistic effect was inhibited by bisindolylmaleimide 100 nm, 8.9% +/- 0.9% (Control) versus 9.8% +/- 0.2% (P > 0.05). PMA and BLP induced rapid nuclear translocation of NFkappaB, which was inhibited by pretreatment with both SB-202190 and bis I, and SB202190 but not bis I, respectively. CONCLUSIONS: P38 is a critical mediator of BLP induced TNF-alpha release and NFkappaB activation, whereas PKC is only partially responsible for its response. P38 and PKC are both critical mediators of PMA induced TNF-alpha release and NFkappaB activation.

Outcome of liver transplantation in hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism. It is an uncommon indication for liver transplantation (LT). It has been suggested that patients who undergo LT for cirrhosis related to HH have higher morbidity and mortality from cardiac, infectious and malignant complications. The purpose of this retrospective review was to determine whether these observations hold true in the current era. We analysed the data of 22 patients who had LT for HH from 1996 to 2007 at our center. Thirteen patients had LT for complications of end-stage liver disease, seven for hepatocellular carcinoma (HCC) and two for subacute liver failure. Cofactors promoting liver disease were identified in 15 patients. Ten patients had iron reduction with venesection before transplantation. Patient and graft survival at 1 and 5 years were 80.7%, and 74% respectively. There were seven deaths after a median follow up of 46 months either because of multiorgan failure, or caused by HCC recurrence. Bacterial infections were the commonest cause of morbidity. Patients with HH remain at a higher risk of developing HCC. Infectious complications are common. Iron reduction with preoperative venesection reduces the risk of cardiac and infection complications postoperatively. Improved survival post-LT reflects changes in selection, disease modification through venesection, and improvement in immunosuppression.

Managing arterial collaterals due to coeliac axis stenosis during pancreaticoduodenectomy.

CONTEXT: Coeliac artery stenosis is a condition affecting a minority of patients undergoing pancreaticoduodenectomy. In such cases, the development of collateral pathways through the blood supply of the pancreatic head provides challenges for surgical management. CASE REPORT: We report a case of coeliac artery stenosis in a patient undergoing pancreaticoduodenectomy. The main blood supply for the coeliac axis was through a single collateral channel, formed by the anterior pancreaticoduodenal arterial arcade. We describe the preservation of this arcade, resection of the redundant artery with primary anastomosis and a review of the literature. CONCLUSION: Management of coeliac artery stenosis during pancreaticoduodenectomy depends on identifying the cause and dealing with it accordingly, intraoperatively.

p38 MAP kinase inhibition promotes primary tumour growth via VEGF independent mechanism.

BACKGROUND: The surgical insult induces an inflammatory response that activates P38 MAP kinases and solid tumours can also release cytokines. Therfore inhibition of these pathways may reduce tumour growth We set out to examine the effects of P38-MAPK inhibition on apoptosis, proliferation, VEGF release and cell cycle effects in-vitro and on primary tumour growth in-vivo. METHODS: 4T-1 cells (2 x 105 cells/well) were incubated, in 24 well plates with control, 25, 50 or 100 ng/ml of SB-202190 for 24 hours. Cells were subsequently asessed for apoptosis, proliferation, VEGF release and cell cycle analysis. Balb-c mice each received 1 x 106 4T 1 cells subcutaneously in the flank and were then randomised to receive control or SB202190 (2.5 microM/kg) by intraperitoneal injection daily. Tumour size was measured alternate days and at day 24 animals were sacrificed and serum VEGF assessed. RESULTS: P38-MAPK inhibition in-vitro resulted in a significant reduction in proliferation (75.2 +/- 8.4% vs. 100 +/- 4.3%, p < 0.05) and G1 cell cycle phase(35.9 +/- 1.1% vs. 32.5 +/- 0.6%, p < 0.05) but no significant changes in apoptosis or VEGF levels. In-vivo, P38-MAPK inhibition resulted in an increase in primary tumour growth (155.6 +/- 34.9 vs. 86.7 +/- 18.2 mm3, p < 0.05). P38-MAPK inhibition also lowered circulating VEGF levels but this difference was not significant (101.9 +/- 27.1 etag/ml compared to 158.6 +/- 27.1 etag/ml) CONCLUSION: These findings demonstrate that P38-MAPK inhibition in-vitro reduces proliferation and G1 cell cycle phase as well as promoting primary tumour growth in-vivo. These effects would appear to be independent of VEGF.

Cancer of the uncinate process of the pancreas: surgical anatomy and clinicopathological features.

BACKGROUND: The clinicopathological features of uncinate process pancreatic cancer (UPPC) are poorly described. Furthermore the anatomy of the uncinate process and its division during surgery are central to pancreaticoduodenectomy for UPPC. We set out to describe the embryology and anatomy of the uncinate process and the clinicopathological features of UPPC. DATA SOURCES: All published case series of UPPC were reviewed and included in this review. RESULTS: The true incidence of UPPC is difficult to quantify, with the reported incidence ranging from 2.5% to 10.7% of pancreatic cancer. There are 5 published series of UPPC including 117 patients, 72 males and 45 females, aged from 45-53 years to 61-84 years. The median survival was 5 or 5.5 months in 3 of the series, 12.1 months in another based only on potentially resectable lesions and 17 months in another based only on resected cases. CONCLUSIONS: The number of reported series of UPPC is limited, with vague symptoms as the predominant presenting features of the disease. The prognosis is poor with synchronous venous resection demonstrating a survival advantage.

Inhibition of nuclear factor-kappaB and p38 mitogen-activated protein kinase does not always have adverse effects on wound healing.

BACKGROUND: Inflammatory stimuli that activate p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) contribute to inflammation and fibroblast function, which are necessary components of incision and wound healing. Inhibition of these signal transduction pathways may provide novel strategies to prevent sepsis but may interfere with healing. We examined the effects of inhibiting p38 activation and NF-kappaB translation on incision healing in a dorsal slit model. METHODS: Male MF-1 mice were randomized into three treatment groups: Control (0.1% dimethylsulfoxide [vehicle]); SB-202190 (2.5 mcM/kg), an inhibitor of p38 MAPK; and SN-50 (10 mcg/kg), an inhibitor of the p50 subunit of NF-kappaB. Animals first underwent a dorsal slit incision, which was closed with interrupted non-absorbable sutures. Animals were sacrificed at three or seven days, and the incision sites were excised for histologic examination (hematoxylin and eosin and Van Gieson stains) and assessment of breaking strengths by tensiometry. Blood was collected for cytokine analysis. Analysis of variance was used to interpret the data. RESULTS: Neither SB202190 nor SN-50 significantly impaired incision strength at day three (control 0.84 +/- 0.2 N vs. SN-50 0.78 +/- 0.2 N and SB-202190 0.93 +/- 0.2 N) or day seven (0.73 +/- 0.2 N vs. 0.66 +/- 0.2 N and 0.66 +/- 0.2 N, respectively). Circulating concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were low on day three with no significant differences between groups (p = 0.7 and 0.4). On day seven, there were no differences in circulating IL-6 (p = 0.08); however, the blood concentrations of TNF-alpha were significantly higher in the SB-202190-treated group (p = 0.003). Histologic analysis did not demonstrate any differences in inflammatory infiltrate or collagen deposition in the incision sites and correlated with the tensiometry findings. CONCLUSIONS: Inhibition of p38 and NF-kappaB does not affect healing adversely. These results suggest that these agents do not affect the inflammation required for normal healing and could be used safely for treating inflammatory and septic conditions in clinical practice.

Pancreatic cancer.

INTRODUCTION: Pancreatic cancer is the fourth most common cause of cancer death in higher-income countries, with 5-year survival only 5% even in people presenting with early-stage cancer. Risk factors include smoking, high alcohol intake, and dietary factors, while diabetes mellitus and previous pancreatitis may also increase the risk. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of surgical treatments in people with pancreatic cancer that is considered suitable for complete tumour resection? What are the effects of adjuvant treatments in people with completely resected pancreatic cancer? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2006 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 31 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: chemoradiotherapy for resected pancreatic cancer, chemoradiotherapy, fibrin glue, fluorouracil-based chemotherapy (adjuvant) for resected pancreatic cancer (with or without surgery), fluorouracil-based chemotherapy (systemic), fluorouracil-based chemotherapy for non-resectable pancreatic cancer, fluorouracil-based combination chemotherapy, fluorouracil-based monotherapy for non-resectable pancreatic cancer, gemcitabine-based chemotherapy (adjuvant) for resected pancreatic cancer, gemcitabine-based chemotherapy (systemic), gemcitabine-based combination chemotherapy, gemcitabine-based monotherapy for non-resectable pancreatic cancer, lymphadenectomy (extended [radical], or standard) in people receiving pancreaticoduodenectomy, pancreatic duct occlusion, pancreaticoduodenectomy (pylorus-preserving), pancreaticoduodenectomy (Whipple's procedure), pancreaticogastrostomy reconstruction, pancreaticojejunostomy, pylorus-preserving pancreaticoduodenectomy, and somatostatin and somatostatin analogues.

Hypertonic saline enhances host response to bacterial challenge by augmenting receptor-independent neutrophil intracellular superoxide formation.

OBJECTIVE: This study sought to determine whether hypertonic saline (HTS) infusion modulates the host response to bacterial challenge. METHODS: Sepsis was induced in 30 Balb-C mice by intraperitoneal injection of Escherichia coli (5 x 107 organisms per animal). In 10 mice, resuscitation was performed at 0 and 24 hours with a 4 mL/kg bolus of HTS (7.5% NaCl), 10 animals received 4 mL/kg of normal saline (0.9% NaCl), and the remaining animals received 30 mL/kg of normal saline. Samples of blood, spleen, and lung were cultured at 8 and 36 hours. Polymorphonucleocytes were incubated in isotonic or hypertonic medium before culture with E. coli. Phagocytosis was assessed by flow cytometry, whereas intracellular bacterial killing was measured after inhibition of phagocytosis with cytochalasin B. Intracellular formation of free radicals was assessed by the molecular probe CM-H(2)DCFDA. Mitogen-activated protein (MAP) kinase p38 and ERK-1 phosphorylation, and nuclear factor kappa B (NFkappaB) activation were determined. Data are represented as means (SEM), and an analysis of variance test was performed to gauge statistical significance. RESULTS: Significantly reduced bacterial culture was observed in the animals resuscitated with HTS when compared with their NS counterparts, in blood (51.8 +/- 4.3 vs. 82.0 +/- 3.3 and 78.4 +/- 4.8, P = 0.005), lung (40.0 +/- 4.1 vs. 93.2 +/- 2.1 and 80.9 +/- 4.7, P = 0.002), and spleen (56.4 +/- 3.8 vs. 85.4 +/- 4.2 and 90.1 +/- 5.9, P = 0.05). Intracellular killing of bacteria increased markedly (P = 0.026) and superoxide generation was enhanced upon exposure to HTS (775.78 +/- 23.6 vs. 696.57 +/- 42.2, P = 0.017) despite inhibition of MAP kinase and NFkappaB activation. CONCLUSIONS: HTS significantly enhances intracellular killing of bacteria while attenuating receptor-mediated activation of proinflammatory cascades.