Scoring of tumour response after neoadjuvant therapy in resected pancreatic cancer: systematic review.

BACKGROUND: Preoperative chemo(radio)therapy is used increasingly in pancreatic cancer. Histological evaluation of the tumour response provides information on the efficacy of preoperative treatment and is used to determine prognosis and guide decisions on adjuvant treatment. This systematic review aimed to provide an overview of the current evidence on tumour response scoring systems in pancreatic cancer. METHODS: Studies reporting on the assessment of resected pancreatic ductal adenocarcinoma following neoadjuvant chemo(radio)therapy were searched using PubMed and EMBASE. All original studies reporting on histological tumour response in relation to clinical outcome (survival, recurrence-free survival) or interobserver agreement were eligible for inclusion. This systematic review followed the PRISMA guidelines. RESULTS: The literature search yielded 1453 studies of which 25 met the eligibility criteria, revealing 13 unique scoring systems. The most frequently investigated tumour response scoring systems were the College of American Pathologists system, Evans scoring system, and MD Anderson Cancer Center system, investigated 11, 9 and 5 times respectively. Although six studies reported a survival difference between the different grades of these three systems, the reported outcomes were often inconsistent. In addition, 12 of the 25 studies did not report on crucial aspects of pathological examination, such as the method of dissection, sampling approach, and amount of sampling. CONCLUSION: Numerous scoring systems for the evaluation of tumour response after preoperative chemo(radio)therapy in pancreatic cancer exist, but comparative studies are lacking. More comparative data are needed on the interobserver variability and prognostic significance of the various scoring systems before best practice can be established.

The ageing pancreas: a systematic review of the evidence and analysis of the consequences.

Senior people constitute the fastest growing segment of the population. The elderly are at risk for malnutrition, thought to be caused by reduced food intake or involution of the physiological capacity of the GI tract. Age-related changes are well known in other secretory organs such as liver, kidney and intestine. The pancreas, representing a metabolically active organ with uptake and breakdown of essential nutritional components, changes its morphology and function with age. During childhood, the volume of the pancreas increases, reaching a plateau between 20 and 60 years, and declines thereafter. This decline involves the pancreatic parenchyma and is associated with decreased perfusion, fibrosis and atrophy. As a consequence of these changes, pancreatic exocrine function is impaired in healthy older individuals without any gastrointestinal disease. Five per cent of people older than 70 years and ten per cent older than 80 years have pancreatic exocrine insufficiency (PEI) with a faecal elastase-1 below 200 µg g-1 stool, and 5% have severe PEI with faecal elastase-1 below 100 µg g-1 stool. This may lead to maldigestion and malnutrition. Patients may have few symptoms, for example steatorrhoea, diarrhoea, abdominal pain and weight loss. Malnutrition consists of deficits of fat-soluble vitamins and is affecting both patients with PEI and the elderly. Secondary consequences may include decreased bone mineral density and results from impaired absorption of fat-soluble vitamin D due to impaired pancreatic exocrine function. The unanswered question is whether this age-related decrease in pancreatic function warrants therapy. Therapeutic intervention, which may consist of supplementation of pancreatic enzymes and/or vitamins in aged individuals with proven exocrine pancreas insufficiency, could contribute to healthy ageing.

Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer.

OBJECTIVE: Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery. DESIGN: Gemcitabine metabolites were analysed in LSL-KrasG12D/+ ; LSL-Trp53R172H/+ ; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation. RESULTS: Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2',2'-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5'-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%. CONCLUSIONS: Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.

Trends in indications, complications and outcomes for venous resection during pancreatoduodenectomy.

BACKGROUND: Pancreatoduodenectomy with superior mesenteric-portal vein resection has become a common procedure in pancreatic surgery. The aim of this study was to compare standard pancreatoduodenectomy with pancreatoduodenectomy plus venous resection at a high-volume centre, and to examine trends in management and outcome over a decade for the latter procedure. METHODS: This retrospective observational study included all patients undergoing pancreatoduodenectomy with or without venous resection at Oslo University Hospital between January 2006 and December 2015. Trends were evaluated by assessing preoperative clinical and radiological characteristics, as well as perioperative outcomes in three time intervals (early, intermediate and late). RESULTS: A total of 784 patients had a pancreatoduodenectomy, of whom 127 (16·2 per cent) underwent venous resection. Venous resection resulted in a longer operating time (median 422 versus 312 min; P = 0·001) and greater estimated blood loss (EBL) (median 700 versus 500 ml; P = 0·004) than standard pancreatoduodenectomy. The rate of severe complications was significantly higher for pancreatoduodenectomy with venous resection (37·0 versus 26·3 per cent; P = 0·014). The overall burden of complications, evaluated using the Comprehensive Complication Index (CCI), did not differ (median score 8·7 versus 8·7; P = 0·175). Trends in venous resection over time showed a significant reduction in EBL (median 1050 versus 375 ml; P = 0·001) and duration of hospital stay (median 14 versus 9 days; P = 0·011) between the early and late periods. However, despite an improvement in the intermediate period, severe complication rates returned to baseline in the late period (18 of 43 versus 9 of 42 versus 20 of 42 patients in early, intermediate and late periods respectively; P = 0·032), as did CCI scores (median 20·9 versus 0 versus 20·9; P = 0·041). CONCLUSION: Despite an initial improvement in severe complications for venous resection during pancreatoduodenectomy, this was not maintained over time. Every fourth patient with venous resection needed relaparotomy, most frequently for bleeding.

Multidetector CT of pancreatic ductal adenocarcinoma: Effect of tube voltage and iodine load on tumour conspicuity and image quality.

OBJECTIVES: To compare a low-tube-voltage with or without high-iodine-load multidetector CT (MDCT) protocol with a normal-tube-voltage, normal-iodine-load (standard) protocol in patients with pancreatic ductal adenocarcinoma (PDAC) with respect to tumour conspicuity and image quality. METHODS: Thirty consecutive patients (mean age: 66 years, men/women: 14/16) preoperatively underwent triple-phase 64-channel MDCT examinations twice according to: (i) 120-kV standard protocol (PS; 0.75 g iodine (I)/kg body weight, n = 30) and (ii) 80-kV protocol A (PA; 0.75 g I/kg, n = 14) or protocol B (PB; 1 g I/kg, n = 16). Two independent readers evaluated tumour delineation and image quality blindly for all protocols. A third reader estimated the pancreas-to-tumour contrast-to-noise ratio (CNR). Statistical analysis was performed with the Chi-square test. RESULTS: Tumour delineation was significantly better in PB and PA compared with PS (P = 0.02). The evaluation of image quality was similar for the three protocols (all, P > 0.05). The highest CNR was observed with PB and was significantly better compared to PA (P = 0.02) and PS (P = 0.0002). CONCLUSION: In patients with PDAC, a low-tube-voltage, high-iodine-load protocol improves tumour delineation and CNR leading to higher tumour conspicuity compared to standard protocol MDCT. KEY POINTS: • Low-tube-voltage high-iodine-load MDCT improves pancreatic cancer conspicuity compared to a standard protocol. • The pancreas-to-tumour attenuation difference increases significantly by reducing the tube voltage. • The radiation exposure dose decreases by reducing the tube voltage.

Pathology reporting of pancreatic cancer following neoadjuvant therapy: challenges and uncertainties.

An increasing number of studies investigate the use of neoadjuvant treatment for ductal adenocarcinoma of the pancreas. While a strong rationale supports this approach, study results are difficult to interpret and compare due to marked variance in multiple aspects of study design and performance. Divergence in pathology examination and reporting as a cause for heterogeneity and incomparability of study results has not been brought into this discussion yet, despite the fact that several key outcome measures for neoadjuvant treatment are pathology-based. This article discusses areas of controversy and difficulty regarding the evaluation of the extent of residual tumour tissue, grading of tumour regression and assessment of the margins, and explains the important clinical implications of the present uncertainty and divergence in pathology practice.

Impact of intrapancreatic or extrapancreatic bile duct involvement on survival following pancreatoduodenectomy for common bile duct cancer.

BACKGROUND: The clinicopathological factors that influence survival following pancreatoduodenectomy (PD) for common bile duct (CBD) cancer are not well known. This study aimed to investigate the effect of tumour involvement of the intrapancreatic versus extrapancreatic CBD on margin status, overall (OS) and disease-free (DFS) survival. METHODS: This was a retrospective study of patients who underwent PD for CBD cancer between 2001 and 2009. Pathological examination was performed according to a previously described standardized protocol based on axial slicing. Clinicopathological data and outcome in terms of margin status, DFS and OS were compared between cancers involving exclusively the intrapancreatic CBD (CBDin) and those involving the extrapancreatic CBD, in isolation or combined with invasion of the intrapancreatic part of the duct (CBDex). RESULTS: A total of 66 patients were enrolled. Most CBD cancers were locally advanced (97 per cent pathological (p) T3, 76 per cent pN1). Microscopic margin involvement (R1) was more frequent in CBDex than in CBDin cancers (34 of 39 versus 13 of 27; P = 0.001), more often multifocal (P < 0.001) and more frequently affected the periductal margin (P = 0.005). Venous resection was more often required for CBDex cancers (P = 0.009). CBDex cancers were associated with worse OS (median 21 versus 28 months; P = 0.020) and DFS (14 versus 31 months; P = 0.015), but the rate and site of recurrence did not differ. Metastasis to more than two lymph nodes was an independent predictor of OS and DFS. CONCLUSION: CBDex cancer is associated with a higher rate of R1 resection and venous resection after PD, and has a worse outcome than CBDin cancer.

Resection margins in pancreatic cancer.

The R1 rate and prognostic significance of microscopic margin involvement differ consistently between published series. This divergence results from a lack of consensus regarding various aspects of margin status assessment. Central to the controversies is the lack of clarity about what 'R1' exactly stands for. The current UICC definition--residual microscopic tumor--is possibly too general and invites divergent interpretations. Adherence to different diagnostic criteria for microscopic margin involvement and divergent terminology for the various margins of pancreatoduodenectomy specimens add to the confusion. Furthermore, recent studies demonstrated that the dissection technique and extent of tissue sampling influence the accuracy of margin assessment. Axial specimen slicing, extensive tissue sampling, and multicolored margin inking result in a significantly higher, more accurate R1 rate than when using traditional grossing techniques. Only when international consensus on these various aspects is reached will pathology data on margin involvement be reliable and can multicenter clinical trials produce compelling evidence that allows improved pancreatic cancer treatment.

Resection margin involvement and tumour origin in pancreatic head cancer.

BACKGROUND: Assessment of the origin of adenocarcinoma in pancreatoduodenectomy specimens (pancreatic, ampullary or biliary) and resection margin status is not performed in a consistent manner in different centres. The aim of this review was to identify the impact of such variations on patient outcome. METHODS: A systematic literature search for articles on pancreatic, ampullary, distal bile duct and periampullary cancer was performed, with special attention to data on resection margin status, pathological examination and outcome. RESULTS: The frequent reclassification of tumour origin following slide review, and the wide variation in published incidence of pancreatic (33-89 per cent), ampullary (5-42 per cent) and distal bile duct (5-38 per cent) cancers indicate that the histopathological distinction between the three cancer groups is less accurate than generally believed. Recent studies have shown that the wide range of rates of microscopic margin involvement (R1) in pancreatoduodenectomy specimens (18-85, 0-27 and 0-72 per cent respectively for pancreatic, ampullary and distal bile duct cancers) is mainly caused by differences in pathological assessment rather than surgical practice and patient selection. As a consequence of the existing inconsistency in reporting of these data items, the clinical significance of microscopic margin involvement in each of the three cancer groups remains unclear. CONCLUSION: Inaccurate and inconsistent distinction between pancreatic, ampullary and distal bile duct cancer, combined with inaccuracies in resection margin assessment, results in obfuscation of key clinicopathological data. Specimen dissection technique plays a key role in the quality of the assessment of both tumour origin and margin status. Unless the pathological examination is meticulous and standardized, comparison of results between centres and observations in multicentre trials will remain of limited value.

Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs).

These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.

Biliary papillomatosis in three Caucasian patients in a Western centre.

INTRODUCTION: Biliary papillomatosis (BP) is a rare condition with a strong potential for malignant transformation and cases from Western centres are sparse.(1) We discuss the presentation, investigation and management of this condition in three Caucasian patients and present a review of the existing literature on BP. PATIENTS AND METHODS: The case notes of three Caucasian patients with BP who presented to our tertiary referral centre were reviewed. Their case histories, investigations and managements are presented. A search of MEDLINE, PubMed and Cochrane databases was performed to review relevant literature around BP. DISCUSSION: BP is a rare condition characterised by multiple papillary adenomas involving the biliary tree which lead to recurrent attacks of cholangitis. It is a low-grade neoplasm with high malignant potential and should be regarded as a pre-malignant lesion.

The roles of cell surface attachment molecules and coagulation Factor X in adenovirus 5-mediated gene transfer in pancreatic cancer cells.

Transduction of 11 pancreatic cancer cell lines with a replication-deficient adenovirus 5 expressing enhanced green fluorescent protein (Ad5EGFP) was analyzed and variable EGFP levels were observed, ranging from <1% to ∼40% of cells transduced, depending on the cell line. Efficient Ad5EGFP transduction was associated mainly with higher levels of cell surface Coxsackie and adenovirus receptor (CAR) but not with expression of α(v)ß(3) and α(v)ß(5) integrins and was fiber dependent. Reduction of CAR by RNA interference resulted in a corresponding decrease in Ad5EGFP transduction. Pre-treatment of Ad5EGFP with blood coagulation Factor X increased virus entry even in the presence of low CAR levels generated by RNA interference, suggesting a potential alternative route of Ad5 entry into pancreatic cancer cells. Immunohistochemistry carried out on 188 pancreatic ductal adenocarcinomas and 68 matched controls showed that CAR was absent in 102 (54%) of adenocarcinomas, whereas moderate and strong staining was observed in 58 (31%) and 28 (15%) cases, respectively. Weak or absent CAR immunolabeling correlated with poor histological differentiation of pancreatic cancer. In normal tissue, strong immunolabeling was detected in islet cells and in the majority of inter- and intralobular pancreatic ducts.

Evolution of idiopathic fibrosing pancreatitis--MRI features.

Here, the clinical and imaging features of idiopathic fibrosing pancreatitis are described, including a description of the evolution of MRI features in a patient treated successfully with biliary stenting alone. Thus, not all masses of the pancreatic head in the paediatric population need to be managed surgically.

Analysis of pancreas tissue in a child positive for islet cell antibodies.

AIMS/HYPOTHESIS: Type 1 diabetes is caused by an immune-mediated process, reflected by the appearance of autoantibodies against pancreatic islets in the peripheral circulation. Detection of multiple autoantibodies predicts the development of diabetes, while positivity for a single autoantibody is a poor prognostic marker. The present study assesses whether positivity for a single autoantibody correlates with pathological changes in the pancreas. METHODS: We studied post mortem pancreatic tissue of a child who repeatedly tested positive for islet cell antibodies (ICA) in serial measurements. Paraffin sections were stained with antibodies specific for insulin, glucagon, somatostatin, interferon alpha, CD3, CD68, cyclooxygenase-2 (COX-2), beta-2-microglobulin, coxsackie B and adenovirus receptor (CAR), natural killer and dendritic cells. Apoptosis was detected using Fas-specific antibody and TUNEL assay. Enterovirus was searched for using immunohistochemistry and in situ hybridisation, as well as enterovirus-specific RT-PCR from serum samples. RESULTS: The structure of the pancreas did not differ from normal. The number of beta cells was not reduced and no signs of insulitis were observed. Beta-2-microglobulin and CAR were strongly produced in the islets, but not in the exocrine pancreas. Enterovirus protein was detected selectively in the islets by two enterovirus-specific antibodies, but viral RNA was not found. CONCLUSIONS/INTERPRETATION: These observations suggest that positivity for ICA alone, even when lasting for more than 1 year, is not associated with inflammatory changes in the islets. However, it is most likely that the pancreatic islets were infected by an enterovirus in this child.

The impact of spontaneous tumour perforation on outcome following colon cancer surgery.

OBJECTIVE: The impact of spontaneous tumour perforation on survival following surgery for colon cancer is unclear. This study compares survival outcomes for patients with perforated colonic cancer with stage-matched nonperforated cancer. METHOD: A prospective histological database was searched for all patients undergoing resection for adenocarcinoma of the colon between 1996 and 2002. Patients with T4 cancer were selected and classified into those with spontaneous perforation at the tumour site and those with nonperforated tumour. Patients with synchronous colonic and rectal cancers, familial polyposis, inflammatory bowel disease, iatrogenic or remote colonic perforation were excluded. Histological variables were combined with clinical data obtained by case note review. Data were analysed for differences in demographics, histological variables, operative mortality, disease-free and overall survival. Multivariate analysis of factors predictive of overall survival in both groups was performed. RESULTS: Of 960 patients identified, 52 patients had spontaneous tumour perforation and 82 patients served as the T-stage matched control group. Overall survival at 2 years was 47% and 54% and at 5 years was 28% and 33% for perforated and nonperforated cancers respectively. Patients with perforated cancers were more likely to present with metastatic disease and undergo emergency surgery with a higher 30-day mortality. There was a trend towards reduced overall survival in the perforated group (P = 0.06), but no difference in disease-free survival (P = 0.43). On multivariate testing, 'emergency surgery' and 'age >75 years' were the only independent predictors of mortality in the perforated and nonperforated group respectively. CONCLUSION: Both perforated and nonperforated T4 colon cancers have a poor prognosis. Spontaneous perforation of the cancer is associated with reduced overall survival, due to higher 30-day mortality, but in itself does not appear to significantly impact on disease-free survival. Rather, it is the advanced oncological stage at which perforated cancers present that determines outcome.

Resection margins and R1 rates in pancreatic cancer--are we there yet?

The prognosis of pancreatic cancer is poor, even for those patients who undergo surgical resection. The rate of local recurrence is high, despite the fact that in most series complete ('R0') resection is reported to be achieved in the majority of patients. The discrepancy between pathological assessment and clinical outcome indicates that microscopic margin involvement (R1) is frequently underreported, and potential causes for this are discussed in this review. Special emphasis is given to the variation that exists between currently used dissection techniques and their impact on the assessment of the resection margins in pancreatoduodenectomy specimens.

Predictors of malignant potential of cystic lesions of the pancreas.

BACKGROUND: Cystic lesions of the pancreas (CLP) are a diagnostic dilemma, the correct characterisation of which determines surgical management. METHODS: From 1995 to 2005, radiology and pathology records were reviewed for the presence of CLP. CLP were divided into three groups; Group 1: Benign, Group 2: Pre-malignant, and Group 3: Malignant. RESULTS: Seventy-nine of 121 patients were included [Group 1: n=46, Group 2: n=10, Group 3: n=23], with a median age at diagnosis of 68 (31-92) years. The median follow-up period was 24 (14-84) months. On univariate analysis, female gender (p=0.04), jaundice (p<0.01), raised serum ALT concentration (p=0.03), cyst size (> or = 2.5 cm) (p<0.01), and biliary duct dilatation (p<0.01) were associated with malignant potential. Benign cysts were more likely to present incidentally (p<0.01). On multi-variate analysis, cyst size (> or =2.5 cm) was an independent predictor of malignant potential. Sub-group analysis revealed that cysts <2.5 cm in the head of the pancreas with evidence of biliary obstruction (either abnormal liver function; raised ALT [p=0.01], ALP [p=0.01], total bilirubin [p=0.02], and/or biliary duct dilatation [p<0.01]) were associated with malignant potential. CONCLUSION: Cyst size > or =2.5 cm on computer tomography imaging was an independent predictor of pre-malignant and malignant pancreatic cysts. Cyst size and the presence of biliary obstruction predict potentially malignant cysts of the head of the pancreas, which require surgical management.

Retroperitoneal margin involvement by adenocarcinoma of the caecum and ascending colon: what does it mean?

OBJECTIVE: Circumferential margin involvement (CRM) is a powerful predictor of local recurrence, distant metastasis and patient survival in rectal cancer. In this study, we aimed to determine the frequency of retroperitoneal margin involvement in right colon cancer and describe its relationship to tumour stage and outcome of surgical treatment. METHOD: Two hundred and twenty-eight consecutive resections for adenocarcinoma of the ascending colon and caecum were identified between 1998 and 2006. Tumour involvement of the posterior retroperitoneal surgical resection margin (RSRM) was recorded and correlated with tumour stage, grade and clinical outcome. RSRM positive patients were compared with CRM positive rectal tumours resected in the same surgical unit. RESULTS: Nineteen of 228 right hemicolectomies (8.4%) showed tumour involvement of the RSRM (defined as < or = 1 mm). Approximately half of the RSRM positive patients underwent palliative resections because of synchronous distant metastases. Out of nine 'potentially curative' resections where the RSRM was involved, five patients subsequently developed metastatic recurrence and two isolated local recurrence. RSRM positivity was associated with advanced tumour stage and more extensive extramural spread than CRM positive rectal cancers. CONCLUSION: Retroperitoneal surgical resection margin involvement by caecal and ascending colon carcinoma is a marker of advanced tumour stage and associated with a high incidence of synchronous and metachronous distant metastasis. More aggressive surgery to obtain a clear margin or postoperative radiotherapy to the tumour bed is likely to benefit only a minority of patients.