The molecular landscape of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Surgical resection of early, localised disease provides the only chance for potentially curative treatment; however, most patients with PDAC present with advanced disease and are not suitable for surgery. Genomic analyses of PDAC tumour lesions have identified a small number of recurrent alterations that are detected across most tumours, and beyond that a large number that either occur at a low (<5%) prevalence or are patient-specific in nature. This molecular heterogeneity has presented a significant challenge for the characterisation of tumour subtypes and effective molecular biomarkers, which have not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC. These challenges are compounded by the overall lack of tumour biopsies for sequencing, the invasive nature of tissue sampling and the confounding effects of low tumour cellularity in many PDAC biopsy specimens, which have limited the applications of molecular profiling in unresectable patients and for longitudinal tumour monitoring. Further investigation into alternative sources of tumour analytes that can be sampled using minimally invasive methods and used to complement molecular analyses from tissue sequencing are required.

Molecular profiling of ctDNA in pancreatic cancer: Opportunities and challenges for clinical application.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality within the next decade, with limited effective treatment options and a dismal long-term prognosis for patients. Genomic profiling has not yet manifested clinical benefits for diagnosis, treatment or prognosis in PDAC, due to the lack of available tissues for sequencing and the confounding effects of low tumour cellularity in many biopsy specimens. Increasing focus is now turning to the use of minimally invasive liquid biopsies to enhance the characterisation of actionable PDAC tumour genomes. Circulating tumour DNA (ctDNA) is the most comprehensively studied liquid biopsy analyte in blood and can provide insight into the molecular profile and biological characteristics of individual PDAC tumours, in real-time and in advance of traditional imaging modalities. This can pave the way for identification of new therapeutic targets, novel risk variants and markers of tumour response, to supplement diagnostic screening and provide enhanced scrutiny in treatment stratification. In the roadmap towards the application of precision medicine for clinical management in PDAC, ctDNA analyses may serve a leading role in streamlining candidate biomarkers for clinical integration. In this review, we highlight recent developments in the use of ctDNA-based liquid biopsies for PDAC and provide new insights into the technical, analytical and biological challenges that must be overcome for this potential to be realised.

The accuracy of pre-operative (P)-POSSUM scoring and cardiopulmonary exercise testing in predicting morbidity and mortality after pancreatic and liver surgery: A systematic review.

BACKGROUND: Cardiopulmonary exercise-testing (CPET) and the (Portsmouth) Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity ((P)-POSSUM) are used as pre-operative risk stratification and audit tools in general surgery, however, both have been demonstrated to have limitations in major hepatopancreatobiliary (HPB) surgery. MATERIALS AND METHODS: The aim of this review is to determine if CPET and (P)-POSSUM scoring systems accurately predict morbidity and mortality. Eligible articles were identified with an electronic database search. Analysis according to surgery type and tool used was performed. RESULTS: Twenty-five studies were included in the final review. POSSUM predicted morbidity demonstrated weighted O/E ratios of 0.75(95%CI0.57-0.97) in hepatic surgery and 0.85(95%CI0.8-0.9) in pancreatic surgery. P-POSSUM predicted mortality in pancreatic surgery demonstrated an O/E ratio of 0.75(95%CI0.27-2.13) and 0.94(95%CI0.57-1.55) in hepatic surgery. In both pancreatic and hepatic surgery an anaerobic threshold(AT) of between 9 0.5-11.5 ml/kg/min was predictive of post-operative complications, and in pancreatic surgery ventilatory equivalence of carbon dioxide(˙VE/˙VCO2) was predictive of 30-day mortality. CONCLUSION: POSSUM demonstrates an overall lack of predictive fit for morbidity, whilst CPET variables provide some predictive power for post-operative outcomes. Development of a new HPB specific risk prediction tool would be beneficial; the combination of parameters from POSSUM and CPET, alongside HPB specific markers could overcome current limitations.

Systematic review of the incidence, presentation and management of gastroduodenal artery pseudoaneurysm after pancreatic resection.

Background: Gastroduodenal artery (GDA) pseudoaneurysm is a serious complication following pancreatic resection, associated with high morbidity and mortality rates. This review aimed to report the incidence of GDA pseudoaneurysm after pancreatic surgery, and describe clinical presentation and management. Methods: MEDLINE and Embase were searched systematically for clinical studies evaluating postoperative GDA pseudoaneurysm. Incidence was calculated by dividing total number of GDA pseudoaneurysms by the total number of pancreatic operations. Additional qualitative data related to GDA pseudoaneurysm presentation and management following pancreatic resection were extracted and reviewed from individual reports. Results: Nine studies were selected for systematic review involving 4227 pancreatic operations with 55 GDA pseudoaneurysms, with a reported incidence of 1·3 (range 0·2-8·3) per cent. Additional data were extracted from 39 individual examples of GDA pseudoaneurysm from 14 studies. The median time for haemorrhage after surgery was at 15 (range 4-210) days. A preceding complication in the postoperative period was documented in four of 21 patients (67 per cent), and sentinel bleeding was observed in 14 of 20 patients (70 per cent). Postoperative complications after pseudoaneurysm management occurred in two-thirds of the patients (14 of 21). The overall survival rate was 85 per cent (33 of 39). Conclusion: GDA pseudoaneurysm is a rare yet serious cause of haemorrhage after pancreatic surgery, with high mortality. The majority of the patients had a preceding complication. Sentinel bleeding was an important clinical indicator.

Antecedentes: El pseudoaneurisma (PA) de la arteria gastroduodenal (gastroduodenal artery, GDA) es una complicación grave después de la resección pancreática que conlleva elevadas tasas altas de morbilidad y mortalidad. Esta revisión tiene como objetivo estudiar la incidencia de PA de la GDA tras cirugía pancreática y describir la forma de presentación clínica y el tratamiento. Métodos: Se realizó una búsqueda sistemática en MEDLINE y EMBASE de los estudios clínicos que analizasen el PA postoperatorio de la GDA. Se calculó la incidencia dividiendo el número total de PA de GDA por el número total de intervenciones pancreáticas. De los informes de cada caso, se extrajeron los datos cualitativos relacionados con la forma de presentación y el tratamiento del PA de la GDA tras la resección pancreática. Resultados: Para la revisión sistemática se seleccionaron nueve estudios con 4.227 intervenciones sobre el páncreas y 55 PA de la GDA (incidencia 1,30% (rango 0,22­8,33%). Se obtuvieron, además, datos individuales de 39 casos de PA de la GDA en 14 estudios. La hemorragia se presentó, como mediana, el día 15 (rango: 4­210) del postoperatorio. Fue precedida de una complicación postoperatoria en el 66,7% de los casos y se observó una hemorragia centinela en el 70,0% de los pacientes. En dos tercios de los pacientes hubo complicaciones postoperatorias después del tratamiento del PA y la supervivencia global fue del 84,6%. Conclusión: Los PA de la GDA son una causa poco frecuente, pero grave, de hemorragia después de la cirugía pancreática, con una elevada mortalidad. La mayoría de los pacientes presentaron alguna complicación previa. La hemorragia centinela fue un indicador clínico de importancia.

Switchable CAR-T cells mediate remission in metastatic pancreatic ductal adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a disease of unmet medical need. While immunotherapy with chimeric antigen receptor T (CAR-T) cells has shown much promise in haematological malignancies, their efficacy for solid tumours is challenged by the lack of tumour-specific antigens required to avoid on-target, off-tumour effects. Switchable CAR-T cells whereby activity of the CAR-T cell is controlled by dosage of a tumour antigen-specific recombinant Fab-based 'switch' to afford a fully tunable response may overcome this translational barrier. DESIGN: In this present study, we have used conventional and switchable CAR-T cells to target the antigen HER2, which is upregulated on tumour cells, but also present at low levels on normal human tissue. We used patient-derived xenograft models derived from patients with stage IV PDAC that mimic the most aggressive features of PDAC, including severe liver and lung metastases. RESULTS: Switchable CAR-T cells followed by administration of the switch directed against human epidermal growth factor receptor 2 (HER2)-induced complete remission in difficult-to-treat, patient-derived advanced pancreatic tumour models. Switchable HER2 CAR-T cells were as effective as conventional HER2 CAR-T cells in vivo testing a range of different CAR-T cell doses. CONCLUSION: These results suggest that a switchable CAR-T system is efficacious against aggressive and disseminated tumours derived from patients with advanced PDAC while affording the potential safety of a control switch.

ADAM12 is a circulating marker for stromal activation in pancreatic cancer and predicts response to chemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma that harbors tumor-promoting properties. No good biomarkers exist to monitor the effect of stromal targeting therapies or to predict response. We set out to identify such non-invasive markers for PDAC stroma and predict response to therapy. Gene expression datasets, co-culture experiments, xenografts, and patient samples were analyzed. Serum samples were measured from a cohort of 58 resected patients, and 87 metastatic or locally advanced PDAC patients. Baseline and follow-up levels were assessed in 372 additional metastatic PDAC patients who received nab-paclitaxel with gemcitabine (n = 184) or gemcitabine monotherapy (n = 188) in the phase III MPACT trial. Increased levels of ADAM12 were found in PDAC patients compared to healthy controls (p < 0.0001, n = 157 and n = 38). High levels of ADAM12 significantly associated with poor outcome in resected PDAC (HR 2.07, p = 0.04). In the MPACT trial survival was significantly longer for patients who received nab-paclitaxel and had undetectable ADAM12 levels before treatment (OS 12.3 m vs 7.9 m p = 0.0046). Consistently undetectable or decreased ADAM12 levels during treatment significantly associated with longer survival as well (OS 14.4 m and 11.2 m, respectively vs 8.3, p = 0.0054). We conclude that ADAM12 is a blood-borne proxy for stromal activation, the levels of which have prognostic significance and correlate with treatment benefit.

Complications of biliary-enteric anastomoses.

INTRODUCTION Biliary-enteric anastomoses are performed for a range of indications and may result in early and late complications. The aim of this study was to assess the risk factors and management of anastomotic leak and stricture following biliary-enteric anastomosis. METHODS A retrospective analysis of the medical records of patients who underwent biliary-enteric anastomoses in a tertiary referral centre between 2000 and 2010 was performed. RESULTS Four hundred and sixty-two biliary-enteric anastomoses were performed. Of these, 347 (75%) were performed for malignant disease. Roux-en-Y hepaticojejunostomy or choledocho-jejunostomy were performed in 440 (95%) patients. Perioperative 30-day mortality was 6.5% (n=30). Seventeen patients had early bile leaks (3.7%) and 17 had late strictures (3.7%) at a median of 12 months. On univariable logistic regression analysis, younger age was a significant risk factor for biliary anastomotic leak. However, on multivariable analysis only biliary reconstruction following biliary injury (odds ratio [OR]=6.84; p=0.002) and anastomosis above the biliary confluence (OR=4.62; p=0.03) were significant. Younger age and biliary reconstruction following injury appeared to be significant risk factors for biliary strictures but multivariable analysis showed that only younger age was significant. CONCLUSIONS Biliary-enteric anastomoses have a low incidence of early and late complications. Biliary reconstruction following injury and a high anastomosis (above the confluence) are significant risk factors for anastomotic leak. Younger patients are significantly more likely to develop an anastomotic stricture over the longer term.

Resection rate, hospital procedure volume and survival in pancreatic cancer patients in England: Population-based study, 2005-2009.

OBJECTIVE: We assessed the association between population resection rates, hospital procedure volume and death rates in pancreatic cancer patients in England. DESIGN: Patients diagnosed with pancreatic cancer were identified from a linked cancer registration and Hospital Episode Statistics dataset. Cox regression analyses were used to assess all-cause mortality according to resection quintile and hospital volume, adjusting for sex, age, deprivation and comorbidity. RESULTS: There were 31,973 pancreatic cancer patients studied, 2580 had surgery. Increasing resection rates were associated with lower mortality among all patients (χ(2)(1df) = 176.18, ptrend < 0.001), with an unadjusted hazard ratio (HR) of 0.78 95%CI [0.75 to 0.81] in the highest versus the lowest resection quintile. Adjustment changed the estimate slightly (HR 0.82, 95%CI [0.79 to 0.85], (χ(2)(1df) = 99.44, ptrend < 0.001)). Among patients that underwent surgery, higher procedure volume was associated with lower mortality (HR = 0.88 95%CI [0.75-1.03] in hospitals carrying out 30+ versus <15 operations a year, shared frailty model, χ(2)(1df) = 1.82, ptrend = 0.177). CONCLUSION: Higher population resection rates were associated with lower mortality. The association with hospital procedure volume was less clear possibly due to small number of patients who underwent surgery. Nevertheless these results suggest survival is higher in hospitals that carry out a greater number of operations a year, particularly those doing 30+ operations, supporting the benefit of centralising perioperative expertise in specialist centres. Ensuring people are increasingly diagnosed when they are suitable candidates for surgery, and have access to these specialist centres may lead to an increase in the proportion of patients that undergo surgical resection which could plausibly increase survival of pancreatic cancer patients.

Outcome after surgical resection for duodenal adenocarcinoma in the UK.

BACKGROUND: Factors influencing long-term outcome after surgical resection for duodenal adenocarcinoma are unclear. METHODS: A prospectively created database was reviewed for patients undergoing surgery for duodenal adenocarcinoma in six UK hepatopancreaticobiliary centres from 2000 to 2013. Factors influencing overall survival and disease-free survival (DFS) were identified by regression analysis. RESULTS: Resection with curative intent was performed in 150 (84·3 per cent) of 178 patients. The postoperative morbidity rate for these patients was 40·0 per cent and the in-hospital mortality rate was 3·3 per cent. Patients who underwent resection had a better median survival than those who had a palliative surgical procedure (84 versus 8 months; P < 0·001). The 1-, 3- and 5-year overall survival rates for patients who underwent resection were 83·9, 66·7 and 51·2 per cent respectively. Median DFS was 53 months, and 1- and 3-year DFS rates were 80·8 and 56·5 per cent respectively. Multivariable analysis revealed that node status (hazard ratio 1·73, 95 per cent c.i. 1·07 to 2·79; P = 0·006) and lymphovascular invasion (hazard ratio 3·49, 1·83 to 6·64; P = 0·003) were associated with overall survival. CONCLUSION: Resection of duodenal adenocarcinoma in specialist centres is associated with good long-term survival. Lymphovascular invasion and nodal metastases are independent prognostic indicators.

An unusual cause of gastrointestinal bleeding: duodenal lipoma.

Common causes of chronic upper gastrointestinal bleeding include oesophageal varices, gastroduodenal ulcers and malignancy, and patients mostly present with iron deficiency type anaemia. We present the case of a 60-year-old lady who presented with iron deficiency anaemia and on investigation was found to have a large duodenal polyp requiring surgical excision. On histological examination, the polyp was revealed to be a lipoma. We review the recent literature and formulate a management plan for this rare entity.

Larger hepatic metastases are more frequent with N0 colorectal tumours and are associated with poor prognosis: implications for surveillance.

BACKGROUND: Surgery is the treatment of choice for colorectal cancer liver metastases (CLM). The aim of our study was to analyze which clinical and pathological risk factors can predict recurrence after liver resection. METHODS: Consecutive patients who underwent hepatic resection for CLM were studied retrospectively to identify risk factors influencing cancer recurrence, by univariate and multivariable analyses. RESULTS: 97 patients (2004-2008) with a median age of 64.6 years (inter-quartile range 57.6-72.6) had a median disease free survival of 16.4 months. On univariate analysis the largest metastasis >5 cm (hazard ratio, HR 2.04, 95% CI 1.10-3.80, p = 0.03), presence of extra-hepatic disease (HR 2.39, 95% CI 1.14-5.02, p = 0.02) and a resection margin ≤5 mm (HR 1.91, 95% CI 1.06-3.47, p = 0.03) were significantly associated with a higher risk of recurrence after curative resection for CLM. These were confirmed as independent predictors for recurrence on multivariable analysis. There were significantly more patients with lymph node negative (N0) primary in the group with liver secondary > 5 cm (n = 18, 39%), than in the group with liver secondary £5 cm (n = 7, 14.6%) (p = 0.01). CONCLUSION: We demonstrated a positive correlation between N0 primary tumour and large liver metastases, which have a higher risk of disease recurrence. If validated in larger, independent studies, this study would suggest routine imaging surveillance follow up of even N0 colorectal tumours, until the biology of these tumours is fully understood.

The role of laparoscopy and laparoscopic ultrasound in the preoperative staging of pancreatico-biliary cancers--A meta-analysis.

BACKGROUND: Staging laparoscopy (SL) may prevent non-therapeutic laparotomy in patients with otherwise resectable pancreatico-biliary cancers, but evidence is inconclusive. This meta-analysis aims to ascertain the true benefit of SL. METHODS: All studies undertaking SL as a diagnostic sieve were included and data homogenised. Standard meta-analytical tools with emphasis on sensitivity testing and meta-regression to detect the cause for heterogeneity between studies were used. RESULTS: 29 studies satisfied the criteria. 3305 patients underwent SL of which 12 were incomplete. Morbidity (n = 15) and mortality (n = 1) was low. True yield of SL for pancreatic/perpancreatic cancers (PPC) was 25% (95% CI 24-27) with a Diagnostic Odds Ratio (DOR) of 104 (95% CI 48-227). Resection rate improved from 61% to 80%. For proximal biliary cancers (PBC), SL increased the curative resection rate from 27% to 50%, with true yield of 47% (95% CI 42-52) and a DOR 61 (95% CI 19-189). Sub-group analysis for detection of liver and peritoneal lesions demonstrated a sensitivity of 88% (95% CI 83-92) and 92% (95% CI 84-96) for PPC; 83% (95% CI 69-92) and 93% (95% CI 81-99) for PBC, respectively. There was no between-study heterogeneity for peritoneal lesions. However for detection of local invasion, sensitivity was low: 58% (95% CI 51-65) for PPC and only 34% (95% CI 22-47) for PBC. Meta-regression did not reveal any cause for the observed heterogeneity between studies. CONCLUSION: SL offers significant benefit to patients with resectable pancreatico-biliary cancers in avoiding non-therapeutic laparotomy and should be adopted in routine clinical practice in a judicious algorithm.

Aprotinin in severe acute pancreatitis.

Aprotinin, a Kunitz protease inhibitor, has a wide inhibitory action with particular activity against trypsin, chymotrypsin and kallikrein, making it theoretically attractive in ameliorating the effects of acute pancreatitis. Its use in acute pancreatitis has been studied for the last 50 years with disappointing results. In this paper, we review the previous studies and argue that all the studies have not been adequately powered, have inappropriate end-points, but most importantly have not attained adequate plasma and peritoneal levels of aprotinin to produce sufficient inhibitory activity. We hypothesise that a well-powered study with adequate aprotinin dosing may clarify its clinical benefit in severe acute pancreatitis.

Neuroendocrine tumours of the gallbladder: three cases and a review of the literature.

Primary neuroendocrine tumours (NETs) of the gallbladder are rare. In the absence of any randomised controlled trials or prospective case series, we sought trends for clinical presentation and management based on 60 patients from published literature over the last 15 years, as well as three patients from our experience, and categorised them into various subgroups according to the WHO classification for NETs. Well-differentiated NETs have an indolent course and better prognosis. Poorly differentiated neuroendocrine carcinomas, which may be of large-cell or small-cell type and may coexist with other types of carcinoma, have a poor outcome. A variety of surgical and chemotherapeutic approaches have been adopted. Surgical excision appears to prolong life, with chemotherapy perhaps adding a marginal advantage.

Ezrin interacts with cortactin to form podosomal rosettes in pancreatic cancer cells.

BACKGROUND AND AIMS: Pancreatic cancer is a highly invasive malignancy. Ezrin, a plasma membrane-cytoskeletal linker protein, is associated with the invasive behaviour of cancers. The purpose of this study was to elucidate a possible molecular mechanism for the invasive phenotype. METHODS: Using a combination of techniques, such as western blotting, co-immunoprecipitation, confocal and light microscopy, invasion and adhesion assays, organotypic cultures and human samples as well as RNA interference (RNAi) and expression of various mutant ezrin constructs, the dynamic molecular nature of podosomes in pancreatic cancer was dissected out. RESULTS: Podosome and podosomal rosette formation in pancreatic carcinoma (PaCa3) cells is ezrin dependent and associated with adhesion to fibronectin with subsequent digestion of this substrate. Ezrin binds to increasing amounts of cortactin during formation of the podosomal rosette, with the C-terminal region, specifically the actin-binding domain, mediating this molecular linkage. Further, it is shown that phosphorylation of Tyr353 and Thr567 sites on ezrin (conventionally shown to translocate ezrin to the plasma membrane) is not required for podosome formation. The podosomal rosette is revealed to be a highly dynamic and transient structure, which can metamorphose into other cellular processes, such as filopodia or lamellipodia, and thereby enable epithelial cancer cells to "palpate" the underlying substrate and modify their cytoskeletal behaviour accordingly. In human tumour tissues and organotypic cultures, specific subcellular expression of ezrin (basal membranous; cellular processes invading stroma) in pancreatic cancer cells can be correlated with tumour progression and disease-free survival (log-rank test (Mantel-Cox), p = 0.019). CONCLUSION: Podosomes and their rosettes are driven by ezrin-cortactin interaction and this plays a role in pancreatic cancer invasion.

A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells.

The receptor for macrophage colony-stimulating factor 1 receptor (CSF1R) is a product of the proto-oncogene c-fms and a member of the class III transmembrane tyrosine kinase receptor family. Earlier, we described increased mRNA expression of CSF1R in human telomerase reverse transcriptase (hTERT) immortalized human ovarian surface epithelial (IOSE) cell lines derived from a single donor. Here, we further describe that CSF1R is upregulated at both the mRNA and protein level in hTERT immortalized human normal OSE cells from two different donors and in hTERT immortalized human pancreatic ductal epithelial cells. CSF1R was not upregulated in hTERT immortalized epithelial clones that subsequently underwent senescence or in immortalized fibroblasts. Upon stimulation by the CSF1R ligand CSF1, the immortalized epithelial cell lines showed rapid internalization of CSF1R with concomitant down-modulation and colocalization of phosphorylated NFkappaBp65 with hTERT protein, hTERT translocation into the nucleus and the binding of c-Myc to the hTERT promoter region. Reducing the expression of CSF1R using short hairpin interfering RNA abolished these effects and also decreased cell survival and the number of population doublings under suboptimal culture conditions. The telomerase inhibitor GRN163L confirmed a role for telomerase in the cleavage of the intracellular domain of CSF1R. On the basis of these findings, we suggest that CSF1R may be a critical factor facilitating hTERT immortalization of epithelial cells.

A comparison of pancreaticoduodenectomy with extended pancreaticoduodenectomy: a meta-analysis of 1909 patients.

AIM: To compare outcomes between pancreaticoduodenectomy (PD) and extended pancreaticoduodenectomy (EPD) from all published comparative studies in the literature. METHODS: Using meta-analytical techniques the present study compared operative details, post-operative adverse events and survival following PD and EPD. Comparative studies published between 1988 and 2005 of PD versus EPD were included. End points were classified into peri-operative details, post-operative complications including 30day mortality, and survival as measured during follow up. A random effect model was employed. RESULTS: Sixteen comparative studies comprising 1909 patients (865 PD and 1044 EPD), including 3 randomized controlled trials with 454 patients (226 PD and 228 EPD) were identified. Tumour size was comparable between the groups (weighted mean difference (WMD) -0.16 cm, p=0.76). Significantly more lymph nodes were harvested from those patients undergoing EPD (WMD p=14 nodes, p< or =0.001). Operative time was longer in EPD (WMD -48.9 min, p<0.001) and there was a trend towards fewer positive resection margins (odds ratio (OR) 1.78, p=0.080). Peri-operative adverse events were similar between the groups with only delayed gastric emptying (OR 0.59, p=0.030) occurring less frequently in the PD group. Peri-operative mortality (OR 1.48, p=0.180) and long-term survival (hazard ratio 0.77, p=0.100) showed a non-significant trend favouring EPD. CONCLUSIONS: EPD is associated with a greater nodal harvest and fewer positive resection margins than PD. However, the risk of delayed gastric emptying is increased and no significant survival benefit has been shown. Better designed, adequately powered studies are required to settle this question.

Impact of hospital volume on outcomes for pancreaticoduodenectomy: a single UK HPB centre experience.

BACKGROUND: High hospital volume has a favorable impact on outcomes for complex procedures including pancreaticoduodenectomy (PD); however, the temporal relationship has not been evaluated in a single centre. AIM: To evaluate the impact of UK cancer outcome guidelines (COG) on outcomes for PD in a single UK HPB specialist centre. PATIENTS AND METHODS: All patients with pancreatic pathologies undergoing surgery at our institution from 1999 to 2006 were identified, of which 140 underwent PD. The annual caseload for PD and corresponding outcomes for length of hospital stay, morbidity, mortality and survival were analysed during the period around the implementation of UK COG with an increase in the surgical workload correlating with catchment's population increase from 1.6 to 3.1 million. RESULTS: Between January 1999 and December 2006, 140 patients underwent a PD (M:F 1.06:1; median age 64 (range 34-84) years). Median hospital stay was 16 days (range 7-318). The 30-day mortality was 2.8%, in-hospital mortality was 6.4% and morbidity was 37.1%. Pancreatic leak/fistula rate was 8.6%. Over the 7-year period, PDs per year increased 5.3 fold from 6 procedures in 1999 to 32 in 2006. Analysis of the data for 1999-2002-(pre-COG) and 2003-2006-(post-COG) showed a trend towards decrease in mortality (from 9.7% to 5.0%, p = 0.448: OR = 2.74 (95% CI, 0.58-12.88); Fisher's exact test) and morbidity (from 41.6% to 35.3%; OR = 1.29 (95% CI, 0.74-3.56); p = 0.565). CONCLUSION: With COG implementation within a single UK pancreatic unit, the PD volume and staffing levels increased with a trend towards decreased morbidity and mortality.

Analysis of mortality rates for gallbladder cancer across the world.

AIM: Ethnic background and geographical location are important when measuring the incidence of gallbladder carcinoma leading to variable mortality rates across the world. METHOD: Age standardized mortality rates [ASR(W)] were extracted separately for males and females from a database maintained by the International Agency for Research on Cancer for 50 countries across the world (Europe 32; the Americas 8; and Asia 10) for the period 1992-2002 and log-linear regression was performed to analyse trends in the last decade. RESULT: In the period 1992-2002, declining trends in mortality for both sexes were observed in Germany, Sweden, Japan, USA, and Hungary (p<0.001), and in France, Canada, United Kingdom, The Netherlands, and Hong Kong (p<0.01). Austria, Czechoslovakia, Slovenia, Denmark, Spain, and Israel exhibited decreasing mortality trends more significant in women (p<0.01) than in men (p<0.05). Decreasing female mortality trends were seen in Finland, Italy, and Portugal (p<0.01) and in Georgia, Luxembourg, and Belgium (p<0.05). Iceland, Costa Rica, and Korea were the only countries with an increase in male mortality (p<0.05). CONCLUSIONS: Overall, there was a decline in ASR(W) for gallbladder cancer. Better diagnostic modalities resulting in appropriate staging of gallbladder/biliary cancers, as well as changes in the ICD classification and perhaps increased awareness, may have contributed to these trends.

Analysis of mortality rates for pancreatic cancer across the world.

INTRODUCTION: Pancreas cancer is the fourth commonest cause of cancer-related mortality across the world, with incidence equalling mortality. A recent study has suggested that both the incidence and the mortality of pancreatic cancer are falling in the UK. We investigated whether this trend was being seen all over the world. METHODS: Age-standardized mortality (world) rates [ASR(W)] for pancreatic cancer were extracted separately for males and females from a database maintained by the International Agency for Research on Cancer for 51 countries across the world (Europe, 33 countries; Americas, 8 countries; and Asia, 10 countries) for the period 1992-2002; log-linear regression analysis was performed to analyse trends in the past decade. RESULTS: In the period 1992-2002, the ASR(W) remained static across most countries for both sexes. The highest mortality rates (for both sexes) were seen in Central Europe [range: men (8-12), women (4.5-7)] with trends towards increasing mortality in Romania (p<0.001), along with Albania, Spain and Croatia (p<0.01). Korea in the Far East, too, demonstrated increasing mortality trends for both sexes (men p<0.001, women p<0.01). Increasing mortality trends were also observed among women in France (p<0.001). In Canada, there was a decline in mortality [men (7.5-6.4), women (5.9-5); p<0.01], while for men there was a downward trend in Ireland, the UK, Switzerland, Austria, and Poland [p<0.05]. CONCLUSION: The changes perhaps reflect standardization and consolidation of diagnostic tests for pancreatic cancer in the Western world and further in-depth analysis would be required.