Five-year recurrence/survival after pancreatoduodenectomy for pancreatic adenocarcinoma: does pre-existing diabetes matter? Results from the Recurrence After Whipple's (RAW) study.

BACKGROUND: Diabetes mellitus (DM) has a complex relationship with pancreatic cancer. This study examines the impact of preoperative DM, both recent-onset and pre-existing, on long-term outcomes following pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study, a multi-centre cohort of PD for pancreatic head malignancy (2012-2015). Recurrence and five-year survival rates of patients with DM were compared to those without, and subgroup analysis performed to compare patients with recent-onset DM (less than one year) to patients with established DM. RESULTS: Out of 758 patients included, 187 (24.7%) had DM, of whom, 47 of the 187 (25.1%) had recent-onset DM. There was no difference in the rate of postoperative pancreatic fistula (DM: 5.9% vs no DM 9.8%; p = 0.11), five-year survival (DM: 24.1% vs no DM: 22.9%; p = 0.77) or five-year recurrence (DM: 71.7% vs no DM: 67.4%; p = 0.32). There was also no difference between patients with recent-onset DM and patients with established DM in postoperative outcomes, recurrence, or survival. CONCLUSION: We found no difference in five-year recurrence and survival between diabetic patients and those without diabetes. Patients with pre-existing DM should be evaluated for PD on a comparable basis to non-diabetic patients.

Predictors of actual five-year survival and recurrence after pancreatoduodenectomy for ampullary adenocarcinoma: results from an international multicentre retrospective cohort study.

BACKGROUND: Pancreatoduodenectomy (PD) is recommended in fit patients with a resectable ampullary adenocarcinoma (AA). We aimed to identify predictors of five-year recurrence/survival. METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study, a multicentre retrospective study of PD patients with a confirmed head of pancreas or periampullary malignancy (June 1st, 2012-May 31st, 2015). Patients with AA who developed recurrence/died within five-years were compared to those who did not. RESULTS: 394 patients were included and actual five-year survival was 54%. Recurrence affected 45% and the median time-to-recurrence was 14 months. Local only, local and distant, and distant only recurrence affected 34, 41 and 94 patients, respectively (site unknown: 7). Among those with recurrence, the most common sites were the liver (32%), local lymph nodes (14%) and lung/pleura (13%). Following multivariable tests, number of resected nodes, histological T stage > II, lymphatic invasion, perineural invasion (PNI), peripancreatic fat invasion (PPFI) and ≥1 positive resection margin correlated with increased recurrence and reduced survival. Furthermore, ≥1 positive margin, PPFI and PNI were all associated with reduced time-to-recurrence. CONCLUSIONS: This multicentre retrospective study of PD outcomes identified numerous histopathological predictors of AA recurrence. Patients with these high-risk features might benefit from adjuvant therapy.

Malignant biliary strictures in patients with a normal bilirubin and/or normal liver enzymes.

BACKGROUND: To date, no studies have sought to determine the frequency of malignancy in patients presenting with a putative biliary stricture and normal liver function tests (LFTs). The primary aim of this retrospective cohort study was to determine the likelihood of malignancy in patients presenting with a biliary stricture and normal LFTs, a normal bilirubin level either alone or in combination with normal levels of liver enzymes [alkaline phosphatase (ALP) and alanine transaminase (ALT)]. A secondary aim was to determine any clinical/biochemical/sonographic features that may be associated with malignancy. METHODS: Patients presenting over a 10-year period were included. Fifteen variables were analysed to determine their association with malignant disease. RESULTS: Eight hundred and thirty patients with putative biliary strictures were included. Primary hepatopancreaticobiliary (HPB) cancers presented with a normal bilirubin and normal liver enzymes (ALP and ALT) in 6% of cases. Patients with a putative biliary stricture and a normal bilirubin level whose final diagnoses were pancreatic cancer, ampullary cancer, distal cholangiocarcinoma and hilar cholangiocarcinoma represented 21%, 13%, 7% and 9% of individuals diagnosed with these pathologies, respectively. Hypoalbuminaemia and isolated intrahepatic duct dilatation on ultrasound were significantly associated with malignancy in patients with normal bilirubin and completely normal LFTs. CONCLUSIONS: This study has shown that patients with a putative biliary stricture and completely normal LFTs are unlikely to have a primary HPB malignancy. Those presenting with a normal bilirubin level, but deranged liver enzymes (ALP and/or ALT), are more likely to have malignant disease, and this should necessitate a higher degree of clinical suspicion.

Do some patients receive unnecessary parenteral nutrition after pancreatoduodenectomy? Results from an international multicentre study.

Backgrounds/Aims: After pancreatoduodenectomy (PD), an early oral diet is recommended; however, the postoperative nutritional management of PD patients is known to be highly variable, with some centers still routinely providing parenteral nutrition (PN). Some patients who receive PN experience clinically significant complications, underscoring its judicious use. Using a large cohort, this study aimed to determine the proportion of PD patients who received postoperative nutritional support (NS), describe the nature of this support, and investigate whether receiving PN correlated with adverse perioperative outcomes. Methods: Data were extracted from the Recurrence After Whipple's study, a retrospective multicenter study of PD outcomes. Results: In total, 1,323 patients (89%) had data on their postoperative NS status available. Of these, 45% received postoperative NS, which was "enteral only," "parenteral only," and "enteral and parenteral" in 44%, 35%, and 21% of cases, respectively. Body mass index < 18.5 kg/m2 (p = 0.03), absence of preoperative biliary stenting (p = 0.009), and serum albumin < 36 g/L (p = 0.009) all correlated with receiving postoperative NS. Among those who did not develop a serious postoperative complication, i.e., those who had a relatively uneventful recovery, 20% received PN. Conclusions: A considerable number of patients who had an uneventful recovery received PN. PN is not without risk, and should be reserved for those who are unable to take an oral diet. PD patients should undergo pre- and postoperative assessment by nutrition professionals to ensure they are managed appropriately, and to optimize perioperative outcomes.

Patterns, timing and predictors of recurrence following pancreaticoduodenectomy for distal cholangiocarcinoma: An international multicentre retrospective cohort study.

INTRODUCTION: Patients undergoing pancreaticoduodenectomy for distal cholangiocarcinoma (dCCA) often develop cancer recurrence. Establishing timing, patterns and risk factors for recurrence may help inform surveillance protocol strategies or select patients who could benefit from additional systemic or locoregional therapies. This multicentre retrospective cohort study aimed to determine timing, patterns, and predictive factors of recurrence following pancreaticoduodenectomy for dCCA. MATERIALS AND METHODS: Patients who underwent pancreaticoduodenectomy for dCCA between June 2012 and May 2015 with five years of follow-up were included. The primary outcome was recurrence pattern (none, local-only, distant-only or mixed local/distant). Data were collected on comorbidities, investigations, operation details, complications, histology, adjuvant and palliative therapies, recurrence-free and overall survival. Univariable tests and regression analyses investigated factors associated with recurrence. RESULTS: In the cohort of 198 patients, 129 (65%) developed recurrence: 30 (15%) developed local-only recurrence, 44 (22%) developed distant-only recurrence and 55 (28%) developed mixed pattern recurrence. The most common recurrence sites were local (49%), liver (24%) and lung (11%). 94% of patients who developed recurrence did so within three years of surgery. Predictors of recurrence on univariable analysis were cancer stage, R1 resection, lymph node metastases, perineural invasion, microvascular invasion and lymphatic invasion. Predictors of recurrence on multivariable analysis were female sex, venous resection, advancing histological stage and lymphatic invasion. CONCLUSION: Two thirds of patients have cancer recurrence following pancreaticoduodenectomy for dCCA, and most recur within three years of surgery. The commonest sites of recurrence are the pancreatic bed, liver and lung. Multiple histological features are associated with recurrence.

Serious complications of pancreatoduodenectomy correlate with lower rates of adjuvant chemotherapy: Results from the recurrence after Whipple's (RAW) study.

INTRODUCTION: Adjuvant chemotherapy (AC) can prolong overall survival (OS) after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, fitness for AC may be influenced by postoperative recovery. We aimed to investigate if serious (Clavien-Dindo grade ≥ IIIa) postoperative complications affected AC rates, disease recurrence and OS. MATERIALS AND METHODS: Data were extracted from the Recurrence After Whipple's (RAW) study (n = 1484), a retrospective study of PD outcomes (29 centres from eight countries). Patients who died within 90-days of PD were excluded. The Kaplan-Meier method was used to compare OS in those receiving or not receiving AC, and those with and without serious postoperative complications. The groups were then compared using univariable and multivariable tests. RESULTS: Patients who commenced AC (vs no AC) had improved OS (median difference: (MD): 201 days), as did those who completed their planned course of AC (MD: 291 days, p < 0.0001). Those who commenced AC were younger (mean difference: 2.7 years, p = 0.0002), more often (preoperative) American Society of Anesthesiologists (ASA) grade I-II (74% vs 63%, p = 0.004) and had less often experienced a serious postoperative complication (10% vs 18%, p = 0.002). Patients who developed a serious postoperative complication were less often ASA grade I-II (52% vs 73%, p = 0.0004) and less often commenced AC (58% vs 74%, p = 0.002). CONCLUSION: In our multicentre study of PD outcomes, PDAC patients who received AC had improved OS, and those who experienced a serious postoperative complication commenced AC less frequently. Selected high-risk patients may benefit from targeted preoperative optimisation and/or neoadjuvant chemotherapy.

Postoperative complications after pancreatoduodenectomy for malignancy: results from the Recurrence After Whipple's (RAW) study.

BACKGROUND: Pancreatoduodenectomy (PD) is associated with significant postoperative morbidity. Surgeons should have a sound understanding of the potential complications for consenting and benchmarking purposes. Furthermore, preoperative identification of high-risk patients can guide patient selection and potentially allow for targeted prehabilitation and/or individualized treatment regimens. Using a large multicentre cohort, this study aimed to calculate the incidence of all PD complications and identify risk factors. METHOD: Data were extracted from the Recurrence After Whipple's (RAW) study, a retrospective cohort study of PD outcomes (29 centres from 8 countries, 2012-2015). The incidence and severity of all complications was recorded and potential risk factors for morbidity, major morbidity (Clavien-Dindo grade > IIIa), postoperative pancreatic fistula (POPF), post-pancreatectomy haemorrhage (PPH) and 90-day mortality were investigated. RESULTS: Among the 1348 included patients, overall morbidity, major morbidity, POPF, PPH and perioperative death affected 53 per cent (n = 720), 17 per cent (n = 228), 8 per cent (n = 108), 6 per cent (n = 84) and 4 per cent (n = 53), respectively. Following multivariable tests, a high BMI (P = 0.007), an ASA grade > II (P < 0.0001) and a classic Whipple approach (P = 0.005) were all associated with increased overall morbidity. In addition, ASA grade > II patients were at increased risk of major morbidity (P < 0.0001), and a raised BMI correlated with a greater risk of POPF (P = 0.001). CONCLUSION: In this multicentre study of PD outcomes, an ASA grade > II was a risk factor for major morbidity and a high BMI was a risk factor for POPF. Patients who are preoperatively identified to be high risk may benefit from targeted prehabilitation or individualized treatment regimens.

Does an extensive diagnostic workup for upfront resectable pancreatic cancer result in a delay which affects survival? Results from an international multicentre study.

Backgrounds/Aims: Pancreatoduodenectomy (PD) is recommended in fit patients with a carcinoma (PDAC) of the pancreatic head, and a delayed resection may affect survival. This study aimed to correlate the time from staging to PD with long-term survival, and study the impact of preoperative investigations (if any) on the timing of surgery. Methods: Data were extracted from the Recurrence After Whipple's (RAW) study, a multicentre retrospective study of PD outcomes. Only PDAC patients who underwent an upfront resection were included. Patients who received neoadjuvant chemo-/radiotherapy were excluded. Group A (PD within 28 days of most recent preoperative computed tomography [CT]) was compared to group B (> 28 days). Results: A total of 595 patents were included. Compared to group A (median CT-PD time: 12.5 days, interquartile range: 6-21), group B (49 days, 39-64.5) had similar one-year survival (73% vs. 75%, p = 0.6), five-year survival (23% vs. 21%, p = 0.6) and median time-todeath (17 vs. 18 months, p = 0.8). Staging laparoscopy (43 vs. 29.5 days, p = 0.009) and preoperative biliary stenting (39 vs. 20 days, p < 0.001) were associated with a delay to PD, but magnetic resonance imaging (32 vs. 32 days, p = 0.5), positron emission tomography (40 vs. 31 days, p > 0.99) and endoscopic ultrasonography (28 vs. 32 days, p > 0.99) were not. Conclusions: Although a treatment delay may give rise to patient anxiety, our findings would suggest this does not correlate with worse survival. A delay may be necessary to obtain further information and minimize the number of PD patients diagnosed with early disease recurrence.

Determination of anthocyanins in the urine of patients with colorectal liver metastases after administration of bilberry extract.

Anthocyanins possess cancer chemopreventive properties in preclinical models. Their clinical pharmacology is only poorly understood. In this pilot study, anthocyanins and their metabolites were analysed in the urine of two patients with colorectal liver metastases. They received a single dose of 1.88 g standardized bilberry extract (mirtoselect) via either nasogastric or nasojejunal tube intra-operatively during liver resection. HPLC-MS/MS and HPLC-UV analysis showed there were more anthocyanins and metabolites in the urine of the patient who received mirtoselect via the stomach than via the jejunum. This result is consistent with information obtained in rodents which suggests the stomach is the predominant site for anthocyanin absorption.

Spontaneous intramural esophageal hematoma.

We report the case of an 80-year-old woman who developed a spontaneous intramural esophageal hematoma and review the available literature. Spontaneous intramural esophageal hematoma (SIOH) is a rare but important condition. Because the cardinal symptom is severe chest pain, the condition is often initially misdiagnosed as an acute cardiac event or aortic dissection. Increased awareness of SIOH may prevent misdiagnosis on the basis of endoscopic and radiological appearances.

An unusual Spigelian hernia involving the appendix: a case report.

INTRODUCTION: Spigelian herniae are uncommon and frequently pose a diagnostic challenge. CASE PRESENTATION: We report the case of a 71-year-old man in whom an ischaemic appendix was found within the sac of a Spigelian hernia during emergency repair. CONCLUSIONS: There are very few reported cases in which an appendix has been found within a Spigelian hernia, in the absence of inflammatory bowel disease. An awareness of the range of viscera which may be encountered in Spigelian herniae is important for safe repair.

A simple, safe technique for the drainage of pancreatic pseudocysts.

BACKGROUND: A number of methods are available for the drainage of pancreatic pseudocysts, including percutaneous, endoscopic and open approaches. In Leicester, we developed a combined radiological and endoscopic technique (predating the use of endoscopic/ultrasound) to allow drainage of pancreatic pseudocysts into the stomach. The aim of the study was to evaluate the long-term results of this approach. METHODS: This is a retrospective study of patients undergoing combined endoscopic/ultrasound-guided percutaneous stenting between 1994 and 2007. Data were extracted from case records and our computerised radiology database. RESULTS: Thirty-seven combined endoscopic/ultrasound-guided procedures were undertaken. Median patient age was 52 years (range 26-84 years). Nineteen pseudocysts were secondary to acute pancreatitis and 18 were in patients with chronic pancreatitis. The diameter of pseudocysts on pre-procedure imaging ranged from 4 to 21 cm (median 11 cm). Median duration of hospital stay was 7 days (range 1-44 days) and 30-day mortality was 0%. Stents were inserted in 70.3% of patients (n= 26). Of those patients stented during the combined procedure, three developed infection of the pseudocyst, necessitating open cystgastrostomy within the first month. During a mean follow-up period of 41 months, two patients developed recurrent pseudocysts which were successfully drained with a further combined procedure (16 and 43 months). Repeat imaging in the remainder of patients failed to show any evidence of a persistent or recurrent pseudocyst beyond 2 months. CONCLUSION: Combined radiological and endoscopic drainage is safe, cost-effective and highly efficient in preventing recurrent pseudocyst formation.

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

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

Oesophageal metastasis from colorectal cancer.

Metastasis to the oesophagus is most frequently described in association with lung or breast cancer. Diagnosis is frequently complicated as often only normal tissue is present in endoscopic biopsy specimens. Although oesophagectomy for metastasis has been described, few patients are suitable for curative resection. We report the case of a 62-year-old man who developed an oesophageal metastasis from colorectal cancer and review the available literature.

Ten-year experience in the management of gallbladder cancer from a single hepatobiliary and pancreatic centre with review of the literature.

BACKGROUND: There is no consensus regarding the optimum surgical approach to gallbladder cancer. This study reviews the management of gallbladder cancer in a single unit. METHODS: Retrospective study of 73 consecutive patients diagnosed with gallbladder cancer. Twenty-three patients underwent surgery with curative intent (surgical group), 28 patients underwent exploratory surgery but had inoperable disease (surgically inoperable group) and 22 patients had inoperable disease radiologically (radiologically inoperable group). Within the surgical group, nine patients (cholecystectomy group) were diagnosed with gallbladder cancer after routine cholecystectomy. RESULTS: The inoperable groups had significantly higher bilirubin and alkaline phosphatase (ALP) than the surgical group (p=0.02 and p<0.01, respectively). Age>68, white cell count (WCC)>7.6 x 109/L, platelet>345 x 109/L, bilirubin>16 mol/L, ALP >124 iu/L and sodium < or = 137 mmol/L were markers of inoperability. Age, haemoglobin and neutrophil:lymphocyte ratio (NLR) were predictors for survival following surgery (p=0.04, p=0.01 and p<0.01, respectively). The surgical and cholecystectomy groups had significantly higher median survivals than the surgically and radiologically inoperable groups (18.97 and 26.17 months versus 5.03 and 12.20 months, p=0.04). CONCLUSION: Curative surgical resection of gallbladder cancer improved survival. Exploratory laparotomy which revealed inoperable disease reduced survival. Preoperative WCC, platelet, bilirubin and ALP may be used as additional discriminators during the investigation and work up prior to surgery.

Dietary polyphenolic phytochemicals--promising cancer chemopreventive agents in humans? A review of their clinical properties.

Epidemiological and preclinical evidence suggests that polyphenolic phytochemicals exemplified by epigallocatechin gallate from tea, curcumin from curry and soya isoflavones possess cancer chemopreventive properties. Whilst such naturally occurring polyphenols have been the subject of numerous mechanistic studies in cells, information on their clinical properties, which might help assess their promise as human cancer chemopreventive agents, is scarce. Therefore, we present a review of pilot studies and trials with a cancer chemoprevention-related rationale, in which either healthy individuals or patients with premalignant conditions or cancer received polyphenolic phytochemicals. The review identifies trial design elements specifically applicable to polyphenolic phytochemicals. The available evidence for tea polyphenols tentatively supports their advancement into phase III clinical intervention trials aimed at the prevention of progression of prostate intraepithelial neoplasia, leukoplakia or premalignant cervical disease. In the case of curcumin and soya isoflavones more studies in premalignacies seem appropriate to optimise the nature and design of suitable phase III trials. The abundance of flavonoids and related polyphenols in the plant kingdom makes it possible that several hitherto uncharacterised agents with chemopreventive efficacy are still to be identified, which may constitute attractive alternatives to currently used chemopreventive drugs.

Post-coronary artery bypass graft liver failure: a possible association with leflunomide.

We report the case of a 75-year-old woman who died of liver failure following coronary artery bypass grafting. The possibility of an association with leflunomide is discussed.