Perioperative immunonutrition in hepatectomy: A systematic review and meta-analysis.

BACKGROUNDS/AIMS: The role of immunonutrition (IMN) after liver resections or hepatectomies remains unclear and controversial. We undertook a systematic review to evaluate the effects of IMN on clinical outcomes of patients undergoing hepatectomy. METHODS: Main electronic databases were searched for randomised trials reported clinical outcomes or effects of IMN. The systematic review was conducted in accordance with the PRISMA guideline and meta-analysis was analysed using fixed or random-effects models. RESULTS: Eleven RCTs were identified. A total of 1084 patients (529 IMN and 555 Control) were included in the final pooled analysis. Of these patients, 43% (440/1016) underwent major hepatectomies and the majority are for hepatocellular carcinoma (90%, 956/1055) with Child-Pugh A disease (89%, 793/894). IMN significantly reduced post-operative wound infection (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.43 to 0.96; p=0.03). IMN also had a shorter hospital stay (MD -4.97 days, 95% CI -8.23 to -1.72; p=0.003). There was no statistically significant in other post-operative morbidities and mortality. CONCLUSIONS: Wound infection rate was not significantly different between oral and parenteral IMN group. The length of hospital stay was significantly lower in parenteral IMN group than in oral IMN group. The mortality rates were not affected. Immunonutrition should be recommended routinely as part of the nutritional support in the Enhanced Recovery after Surgery (ERAS) protocol for hepatectomy.

Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids.

BACKGROUND: Pancreatic organoid systems have recently been described for the in vitro culture of pancreatic ductal cells from mouse and human. Mouse pancreatic organoids exhibit unlimited expansion potential, while previously reported human pancreas organoid (hPO) cultures do not expand efficiently long-term in a chemically defined, serum-free medium. We sought to generate a 3D culture system for long-term expansion of human pancreas ductal cells as hPOs to serve as the basis for studies of human pancreas ductal epithelium, exocrine pancreatic diseases and the development of a genomically stable replacement cell therapy for diabetes mellitus. RESULTS: Our chemically defined, serum-free, human pancreas organoid culture medium supports the generation and expansion of hPOs with high efficiency from both fresh and cryopreserved primary tissue. hPOs can be expanded from a single cell, enabling their genetic manipulation and generation of clonal cultures. hPOs expanded for months in vitro maintain their ductal morphology, biomarker expression and chromosomal integrity. Xenografts of hPOs survive long-term in vivo when transplanted into the pancreas of immunodeficient mice. Notably, mouse orthotopic transplants show no signs of tumorigenicity. Crucially, our medium also supports the establishment and expansion of hPOs in a chemically defined, modifiable and scalable, biomimetic hydrogel. CONCLUSIONS: hPOs can be expanded long-term, from both fresh and cryopreserved human pancreas tissue in a chemically defined, serum-free medium with no detectable tumorigenicity. hPOs can be clonally expanded, genetically manipulated and are amenable to culture in a chemically defined hydrogel. hPOs therefore represent an abundant source of pancreas ductal cells that retain the characteristics of the tissue-of-origin, which opens up avenues for modelling diseases of the ductal epithelium and increasing understanding of human pancreas exocrine biology as well as for potentially producing insulin-secreting cells for the treatment of diabetes.

A systematic review of predicted pathogenic PALB2 variants: an analysis of mutational overlap between epithelial cancers.

Partner and localiser of BRCA2 forms part of a macromolecular complex with BRCA1 and BRCA2, which is critical for the repair of double-strand DNA breaks by homologous DNA recombination. Germline loss-of-function variants in the PALB2 gene may confer an increased lifetime risk of breast, pancreatic, ovarian and other cancers. However, the complete spectrum of predicted pathogenic PALB2 variants associated with each tissue type of cancer remains unknown. A systematic review is performed with the aim of cataloguing predicted pathogenic PALB2 variants in breast, ovary and pancreas cancers. All catalogued predicted pathogenic variants are analysed to assess for overlap and mutational "hotspots" within gene exons. Our results showed that 911 (92.5%) cases were described in breast cancer patients, 49 (5.0%) cases were described in ovarian cancer patients, and 24 (2.4%) cases were described in pancreatic cancer patients. The top five most frequently reported predicted pathogenic PALB2 variants were c.509_510delGA, c.3113G > A, c.1592delT, c.172_175delTTGT, and c.1240C > T, accounting for 57.3% of all cases. Breast and pancreatic cancers share five variants while breast and ovarian cancers share 12 variants. Breast, ovarian and pancreatic cancers share eight common variants. Exons with the highest mutation rates were exons 2 (6.7%), 1 (6.3%) and 3 (5.8%). This systematic review provides a quantitative catalogue of predicted pathogenic PALB2 variants described in cancers. This comprehensive analysis of the PALB2 mutational spectrum represents a useful resource for clinicians overseeing PALB2-related cancer surveillance and provides a valuable resource for future PALB2-specific research.

Development of a Prognostic Model That Predicts Survival After Pancreaticoduodenectomy for Ampullary Cancer.

OBJECTIVES: The aims of this study were to (i) identify independent predictors of survival after pancreaticoduodenectomy for ampullary cancer and (ii) develop a prognostic model of survival. METHODS: Data were analyzed retrospectively on 110 consecutive patients who underwent pancreaticoduodenectomy between 2002 and 2013. Subjects were categorized into 3 nodal subgroups as per the recently proposed nodal subclassification: N0 (node negative), N1 (1-2 metastatic nodes), or N2 (≥3 metastatic nodes). Clinicopathological features and overall survival were compared by Kaplan-Meier and Cox regression analyses. RESULTS: The overall 1-, 3-, and 5-year survival rates were 79.8%, 42.2%, and 34.9%, respectively. The overall 1-, 3-, and 5-year survival rates for the N0 group were 85.2%, 71.9%, and 67.4%, respectively. The 1-, 3-, 5-year survival rates for the N1 and N2 subgroups were 81.5%, 49.4%, and 49.4% and 75%, 19.2%, and 6.4%, respectively (log rank, P < 0.0001). After performing a multivariate Cox regression analysis, vascular invasion and lymph node ratio were the only independent predictors of survival. Hence, a prediction model of survival was constructed based on those 2 variables. CONCLUSIONS: Using data from a carefully selected cohort of patients, we created a pilot prognostic model of postresectional survival. The proposed model may help clinicians to guide treatments in the adjuvant setting.

Negative predictive value of drain amylase concentration for development of pancreatic fistula after pancreaticoduodenectomy.

BACKGROUND: Post-operative pancreatic fistula (POPF) is the major source of morbidity following pancreaticoduodenectomy. A predictive indicator would be highly advantageous. One potential marker is drain amylase concentration (DAC). However, its predictive value has not been fully established. METHODS: 405 patients undergoing pancreaticoduodenectomy at our centre over a 10 year period were reviewed to determine the value of DAC as a predictive indicator for the development of POPF. RESULTS: POPF developed in 58 patients (14%). These patients suffered greater morbidity. Overall 30-day mortality was 1.5%. Male gender (OR: 5.1; p = 0.0082) and age > 70 (OR 2; p = 0.0372) were independent risk factors for POPF, whilst Type 2 diabetes (OR: 0.2321; p = 0.0090) and pancreatic ductal-adenocarcinoma (OR: 0.3721; p = 0.0039) decreased POPF risk. The DACs post-operatively were significantly higher in those developing POPF, but with significant overlap. ROC curves revealed optimal threshold values for differentiating POPF and non-POPF patients. A DAC°<°1400 U/ml on day 1 and <768 U/ml on day 2, although having a poor positive predictive value (32-44%), had a very strong negative predictive value (97-99%). CONCLUSION: Our data suggest that post-operative DAC below the determined optimal threshold values on day 1 and 2 following pancreaticoduodenectomy carries high negative predictive value for POPF development and identifies patients in whom early drain removal, and enhanced recovery may be considered, with simultaneous assessment of operative and clinical factors.

Chromosome instability and carcinogenesis: insights from murine models of human pancreatic cancer associated with BRCA2 inactivation.

Chromosomal instability is a hallmark of human cancer cells, but its role in carcinogenesis remains poorly resolved. Insights into this role have emerged from studies on the tumour suppressor BRCA2, whose inactivation in human cancers causes chromosomal instability through the loss of essential functions of the BRCA2 protein in the normal mechanisms responsible for the replication, repair and segregation of DNA during cell division. Humans who carry heterozygous germline mutations in the BRCA2 gene are highly predisposed to cancers of the breast, ovary, pancreas, prostate and other tissues. Here, we review recent studies that describe genetically engineered mouse models (GEMMs) for pancreatic cancer associated with BRCA2 mutations. These studies not only surprisingly show that BRCA2 does not follow the classical Knudson "two hit" paradigm for tumour suppression, but also highlight features of the interplay between TP53 inactivation and carcinogenesis in the context of BRCA2 deficiency. Thus, the models reveal novel aspects of cancer evolution in carriers of germline BRCA2 mutations, provide new insights into the tumour suppressive role of BRCA2, and establish valuable new preclinical settings for testing approaches to pancreatic cancer therapy; together, these features emphasize the value of GEMMs in cancer research.

Molecular pathogenesis of hepatic adenomas and its implications for surgical management.

INTRODUCTION: Hepatic adenomas (HAs) are benign tumors of the liver, which can be solitary or multiple, and have a definite risk of malignant degeneration. DISCUSSION: The pathogenesis and natural history of this disease entity were previously unknown. Recent research into the molecular pathogenesis of this condition has provided evidence for the malignant transformation of some of these adenomas. In the current article, we discuss the current evidence on the molecular biology underlying malignant transformation of hepatic adenomas and the implications for the surgical management of this disease.

Laparoscopic adrenalectomy: auditing the 10 year experience of a single centre.

BACKGROUND: Laparoscopic adrenalectomy (LA) is the gold standard for benign adrenal resection, and has been performed at our centre since 2000. We present a retrospective audit of our ten-year experience, and discuss the learning curve. METHODS: Creating a retrospective database, clinical and outcome data were collected for all resections performed over a ten-year period (2000-2010). Patients were chronologically divided into an 'early' (first 40 cases) and 'late' (subsequent cases) group to provide an insight into the learning curve. RESULTS: Over this period, 134 laparoscopic resections were performed, predominantly for benign adenomas (80.3%), with 48% of patients having primary hyperaldosteronism. There was almost equal sex distribution and mean age was 50.2 years, with a median BMI of 28.2. The mean operating time for left and right procedures were 127 and 124 min respectively, with 56.7% of resections being left sided. Our rate of conversion to open was 3.9%. Median length of stay was 4 days post-operatively. There was no mortality and 8.7% patients experienced a surgical complication. Analysis of the grouped data demonstrated a statistically significant reduction in open conversion rate (p = 0.017) and operative time (p = 0.011) in the 'late' group. Among the two groups there was no statistically significant difference in the length of stay and surgical complication rate. All results were comparable to published series in the literature. CONCLUSION: LA has proven to be a safe procedure with a low complication rate at our centre. Our data provide evidence that operative time and conversion rate improves with experience.

Extra-hepatic portal vein aneurysm: A case report, overview of the literature and suggested management algorithm.

INTRODUCTION: Portal venous aneurysms are a rare finding. The reported incidence is on the rise with increasing use of modern imaging techniques in clinical practice. However, there is still much to be elicited regarding their aetiology, natural history, and management. PRESENTATION OF CASE: An 80-year-old woman presented with abdominal pain and nausea. Investigations showed a hypoechoic area in the region of the head of pancreas on ultrasound, which was found to be a portal venous aneurysm on CT. In view of her multiple comorbidities, a conservative approach was taken. DISCUSSION: Portal venous aneurysms represent approximately 3% of all venous aneurysms with a reported prevalence of 0.43%. They may be congenital, due to failure of complete regression of the right vitelline vein, or acquired secondary to portal hypertension. The primary presentation of portal vein aneurysm is abdominal pain, followed by incidental detection on imaging, with a minority of patients presenting with gastrointestinal bleeding. Complications of PVA include thrombosis, biliary tract obstruction, inferior vena cava obstruction, and duodenal compression. On the whole PVAs are stable and have a low risk of complications with 88% of patients showing no progression of aneurysm size or complications on subsequent follow up scans. CONCLUSION: We recommend that portal venous aneurysms be assessed using colour Doppler ultrasonography in the first instance with CT scans reserved for indeterminate cases or symptomatic patients. Due to the slow progression of such aneurysms, surgery is recommended only for symptomatic patients or those with complications secondary to portal venous aneurysms.

Audit of local recurrence following breast conservation surgery with 5-mm target margin and hypofractionated 40-Gray breast radiotherapy for invasive breast cancer.

INTRODUCTION: The risk of ipsilateral breast tumour recurrence (IBTR) following breast conservation surgery (BCS) for invasive breast cancer (IBC) and radiotherapy is dependent on patient-, tumour- and treatment-related variables. In the Cambridge Breast Unit, breast conserving surgery has been performed with a target radial margin of 5 mm for IBC, in combination with 40-Gy hypofractionated (15 fractions) breast radiotherapy, since 1999. PATIENTS AND METHODS: An audit was performed of cases treated between 1999 and 2004. A total of 563 patients underwent BCS for invasive breast cancer with 90.4% receiving radiotherapy (RT) and 60.4% of patients receiving boost RT (3 fractions of 3-Gy). RESULTS: After a median follow-up of 58 months, five of the 563 (0.9%) patients developed IBTR. The 5-year actuarial IBTR rate was 1.1%. In terms of distant disease recurrence (DDR), 29 of the 563 (5.2%) had DDR during follow-up, giving a 5-year actuarial DDR rate of 5.4%. The 5-year breast cancer specific survival was 95%, with the poorer NPI groups having worse breast cancer specific survival (Log-rank, P<0.0001). More importantly, patients with IBTR had a shorter breast cancer-specific survival than those who were IBTR-free (Log-rank, P<0.0001). CONCLUSIONS: Our treatment regimen, combining BCS with a 5-mm target margin and hypofractionated 40-Gy RT, results in an extremely low rate of IBTR, and compares favourably with the target IBTR rate of <5% defined by the Association of Breast Surgeons (ABS) at BASO guidelines.

A lethal case of pneumatosis intestinalis complicated by small bowel volvulus.

Pneumatosis intestinalis (PI) is a condition characterised by gas-filled cystic malformations on the intestinal wall. It is often secondary to an underlying disease process. We describe the case of a 76-year-old gentleman who presented with intermittent abdominal pain, altered bowel habits and weight loss. Barium enema was unremarkable, apart from sigmoid diverticulosis. CT scan found evidence of pneumatosis on small bowel walls with benign pneumoperitoneum. As there was no sign of intra-abdominal crisis, he was initially treated conservatively. Unfortunately, he required re-admission 6 weeks later with symptoms of bowel obstruction and clinical signs of perotinitis. At laparotomy, he was found to have extensive small bowel infarction due to volvulus from 'twisting' around the axis of superior mesenteric vessels. Evidently, this occurred secondary to a congenitally long small bowel mesentery that predisposed him to volvulus. Extensive small bowel resection was performed. The postoperative course was complicated by persistent hypotension, which proved fatal. This case report draws attention to the rare association between PI and small bowel volvulus predisposed by a congenitally long mesentery, which can present initially with a benign picture (intermittent, reversible volvulus), but subsequently be complicated by lethal bowel infarction (irreversible volvulus). This case raises several issues about the management of this rare condition. Clinicians must realise that PI, though often benign, can present with lethal complications, and early recognition of such complications can be life-saving.

A case of gallstone-induced small bowel necrosis masquerading as clinical appendicitis.

Cholecysto-duodenal fistula and gallstone ileus are well-recognised complications of gallstone disease. However, small bowel necrosis is a rare complication of gallstone disease. We describe a case of gallstone-induced ileal necrosis presenting with symptoms and signs resembling acute appendicitis. A 79-year-old woman presented to the surgical team with central abdominal pain which subsequently shifted to the right iliac fossa. Clinically, the patient had localised perotinism in the right iliac fossa with high inflammatory markers. Abdominal radiography showed no diagnostic features. Initial clinical impression was that of acute appendicitis. Given that this diagnosis was unlikely in a patient of this age, an abdominal CT scan was performed. The CT scan showed evidence of a large gallstone causing small bowel obstruction in the presence of a cholecysto-duodenal fistula. At surgery, she was found to have an area of necrosis with a pin-point perforation at the site of impaction of the gallstone in the proximal ileum. This occurred secondarily to pressure necrosis from the gallstone impacting at a site where the small bowel diameter narrows in transition from jejunum to ileum. A limited small bowel resection was performed with an uncomplicated postoperative course. This case report draws attention to a rare complication of gallstone disease which presents with a clinical picture similar to acute appendicitis. Preoperative investigation for an elderly patient who presents with an acute abdomen should include an abdominal CT scan to diagnose any rare disease processes which otherwise may not be suspected.

Cancer genetics: a primer for surgeons.

Contemporary ideas of carcinogenesis envisage a series of stochastic genetic changes that confer a selective growth advantage over healthy cells. These changes collectively lead to the disruption of coordinated networks of intercellular communication and cause a fundamental change in cellular behavior, which affects processes, such as proliferation, differentiation, and apoptosis. This progressive dysregulation of cellular function implies that cancer is not a morphologic entity, but a process in which the malignant phenotype is gradually acquired.

High mobility group AT-hook 1 (HMGA1) is an independent prognostic factor and novel therapeutic target in pancreatic adenocarcinoma.

BACKGROUND: High mobility group AT-hook 1 (HMGA1) proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. The authors hypothesized that tumor HMGA1 status represents a novel prognostic marker in pancreatic adenocarcinoma. They also tested the hypothesis that HMGA1 promotes anchorage-independent cellular proliferation and in vivo tumorigenicity. METHODS: Tumor HMGA1 expression was examined by immunohistochemical analysis of tissues from 89 consecutive patients who underwent resection for pancreatic adenocarcinoma. Short-hairpin RNA (shRNA)-mediated RNA interference was used to silence HMGA1 expression in MiaPaCa2 and PANC1 pancreatic cancer cells. Anchorage-independent proliferation was assessed by using soft agar assays. The roles of phosphatidylinositol 3-kinase (PI3-K)/Akt and extracellular signal-regulated kinase (ERK) signaling were investigated by using specific inhibitors and adenoviral dominant-negative/active Akt constructs. In vivo tumorigenicity was assessed by using a nude mouse xenograft model. RESULTS: Tumor HMGA1 expression was detected in 93% of patients with pancreatic adenocarcinoma. Patients with HMGA1-negative tumors had a significantly longer median survival than patients with HMGA1-expressing cancers in univariate analysis (P = .0028) and in multivariate analysis (P<.05). shRNA-mediated HMGA1 silencing resulted in significant reductions in anchorage-independent proliferation in soft agar. Forced HMGA1 overexpression promoted proliferation in soft agar through a process that was dependent on PI3-K/Akt-activited signaling, but not on mitogen-activated protein kinase (MEK)/ERK signaling. Targeted silencing of HMGA1 reduced tumor growth in vivo through reduced proliferation (Ki-67 index) and increased apoptosis (terminal deoxynucleotidyl transferase nick-end labeling). CONCLUSIONS: The current findings suggested that HMGA1 is an independent predictor of poor postoperative survival in patients with pancreatic adenocarcinoma. Furthermore, HMGA1 promotes tumorigenicity through a PI3-K/Akt-dependent mechanism. HMGA1 warrants further evaluation as a prognostic marker and therapeutic target in pancreatic cancer.

HMGA1 is a molecular determinant of chemoresistance to gemcitabine in pancreatic adenocarcinoma.

PURPOSE: HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. We previously have shown that RNA interference targeting the HMGA1 gene may represent a potential chemosensitizing strategy in pancreatic adenocarcinoma cells. In this study, we tested the hypothesis that HMGA1 promotes chemoresistance to gemcitabine in pancreatic cancer cells. EXPERIMENTAL DESIGN AND RESULTS: Stable short hairpin RNA-mediated HMGA1 silencing in BxPC3 and MiaPaCa2 cells promoted chemosensitivity to gemcitabine, with reductions in gemcitabine IC(50) and increases in gemcitabine-induced apoptosis and caspase-3 activation. In contrast, forced HMGA1 overexpression in MiaPaCa2 cells promoted chemoresistance to gemcitabine, with increases in gemcitabine IC(50) and reductions in gemcitabine-induced apoptosis and caspase-3 activation. Dominant negative Akt abrogated HMGA1 overexpression-induced increases in chemoresistance to gemcitabine. Finally, HMGA1 silencing promoted chemosensitivity to gemcitabine in vivo in a nude mouse xenograft model of pancreatic adenocarcinoma. CONCLUSION: Our findings suggest that HMGA1 promotes chemoresistance to gemcitabine through an Akt-dependent mechanism. Targeted therapies directed at HMGA1 represent a potential strategy for ameliorating chemoresistance in pancreatic adenocarcinoma.

Synchronous colonic carcinomas presenting as an inguinoscrotal hernial mass: a case report.

BACKGROUND: A carcinoma within a hernia in the groin is uncommon, with an incidence of less than 0.5 percent of all excised sacs. This article describes a case of synchronous colonic carcinomas, one of which presented as an inguinoscrotal mass. CASE PRESENTATION: A 69-year old man presented with a large, irreducible left inguinoscrotal hernia and symptoms of obstruction. On examination, there was an 8 cm palpable mass within the hernia sac. CT scan revealed small and proximal large bowel obstruction secondary to a large ingunoscrotal sac and synchronous colonic tumours of the transverse colon and the ascending colon. The former presented as an inguinoscrotal mass. Laparotomy revealed a large tumour mass arising from the transverse colon in the hernia sac. The procedure was followed by an extended right hemicolectomy, during which the second tumour in the ascending colon was also resected. CONCLUSION: This case demonstrates a rare but interesting occurrence of primary transverse colon carcinoma presenting in a hernia sac, in conjunction with a synchronous tumour of the ascending colon. Prognosis is comparable to patients with a solitary tumour of similar pathological staging when the resection is curative. The presence of an inguinal hernia itself does not signify an increased risk of colorectal malignancy. However, in the presence of obstruction, incarceration, and weight loss, malignancy should be suspected. Thorough clinical examination, flexible sigmoidoscopy or radiographic evaluation is necessary preoperatively in such patients. Surgical resection, with or without adjuvant oncological treatment, should be performed as soon as possible, using established techniques with modifications according to involvement of local structures.

HMGA1 is a determinant of cellular invasiveness and in vivo metastatic potential in pancreatic adenocarcinoma.

HMGA1 proteins are architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. We hypothesized that HMGA1 expression is a determinant of cellular invasiveness and metastasis in pancreatic cancer. Stable silencing of HMGA1 in MiaPaCa2 and PANC1 pancreatic adenocarcinoma cells was achieved by transfection of short hairpin RNA-generating vectors. Additionally, stable overexpression of HMGA1 in MiaPaCa2 cells (characterized by low levels of inherent HMGA1 expression) was achieved. HMGA1 silencing resulted in significant reductions in cellular invasiveness through Matrigel; in cellular matrix metalloproteinase-9 (MMP-9) activity, mRNA levels, and gene promoter activity; and in Akt phosphorylation at Ser(473). Conversely, forced HMGA1 overexpression resulted in significant increases in cellular invasiveness; in cellular MMP-9 activity, mRNA levels, and promoter activity; and in Akt phosphorylation at Ser(473). HMGA1 overexpression-induced increases in invasiveness were MMP-9 dependent. The role of phosphatidylinositol-3 kinase (PI3K)/Akt in mediating HMGA1-dependent invasiveness was elucidated by a specific PI3K inhibitor (LY294002) and constitutively active and dominant-negative Akt adenoviral constructs. Akt-dependent modulation of MMP-9 activity contributed significantly to HMGA1 overexpression-induced increases in invasive capacity. Furthermore, HMGA1 silencing resulted in reductions in metastatic potential and tumor growth in vivo and in tumoral MMP-9 activity. Our findings suggest that HMGA1 may be a novel molecular determinant of invasiveness and metastasis, as well as a potential therapeutic target, in pancreatic adenocarcinoma.