Prospective assessment of resection margin status following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma after standardisation of margin definitions.

BACKGROUND: Surgical resection remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). The prognostic value of resection margin status following pancreatoduodenectomy (PD) remains controversial. Standardised pathological assessment increases positive margins but limited data is available on the significance of involved margins. We investigated the impact of resection margin status in PDAC on patient outcome. METHOD: We identified all patients with PD for PDAC at one pancreatic cancer centre between August 2008 and December 2014. Demographic, operative, adjuvant therapeutic and survival data was obtained. Pathology data including resection margin status of specific anatomic margins was collected and analysed. RESULTS: 107 patients were included, all pathologically staged as T3 with 102 N1. 87.9% of patients were R1 of which 53.3% showed direct extension to the resection margin. Median survival for R0 patients versus R1<1 mm and R1 = 0 mm was 28.4 versus 15.4 and 25.1 versus 13.4 months. R1 = 0 mm status remained a predictor of poor outcome on multivariate analysis. Evaluation of individual margins (R1<1 mm) showed the SMV and SMA margins were associated with poorer overall survival. Multiple involved margins impacted negatively on outcome. SMA margin patient outcome with R1 = 1-1.9 mm was similar to R1=>2 mm. CONCLUSION: Using an R1 definition of <1 mm and standardised pathology we demonstrate that R1 rates in PDAC can approach 90%. R1 = 0 mm remained an independent prognostic factor for overall survival. Using R1<1 mm we have shown that involvement of medial margins and multiple margins has significant negative impact on overall survival. We conclude that not all margin positivity has the same prognostic significance.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Ninety day mortality following pancreatoduodenectomy in England: has the optimum centre volume been identified?

BACKGROUND: Mortality following pancreatoduodenectomy is related to centre volume although the optimal volume is not defined. METHODS: Patients undergoing PD between 2001 and 2016 were identified from UK national databases. The effects of patient variables, centre volume and time period upon 90 day mortality were studied. RESULTS: 90 day mortality (970/14,935, 6.5%) was related to advanced age, comorbidity, diagnosis, ethnicity, deprivation, centre volume and time period. Mortality rates fell markedly from 10.0% in 2001-4 to 4.1% in 2013-16. There was no difference in 90 day mortality between high (36 -60 PD per year) and very high volume (>60) centres. However, patients operated upon at very high volume centres were more elderly (66, 58 -73 vs 65, 56 -72; median, IQR; p = 0.006), deprived (38.7 vs 34.6%; p < 0.001) and co morbid (48.9 vs 46.1%; p = 0.027). CONCLUSION: Although a plateau in the centre volume and mortality relationship appears to have been demonstrated those patients treated at the highest volume centres were at higher risk of mortality. This data suggests therefore that to further understand outcomes from specialist centres characteristics of the patient population should be defined, not just centre volume.

EUS and EUS-FNA diagnosis of suspected pancreatic cystic neoplasms: Is the sum of the parts greater than the CEA?

BACKGROUND: Carcinoembryonic antigen (CEA) is suggested as the single most useful EUS/EUS-FNA derived test for the diagnosis of mucinous pancreatic cysts. STUDY AIMS: To investigate the yield and diagnostic performance of EUS/EUS-FNA on an intention to diagnose basis and to determine the utility of the recommended CEA and amylase cut-off values. PATIENTS AND METHODS: A retrospective study of a prospectively maintained database of 433 procedures performed in a 10 year period. Diagnostic performance of EUS-FNA was determined in 133 procedures with a definite diagnosis. RESULTS: CEA value was determined in significantly fewer procedures (58.6%) than EUS diagnosis was stated (83.4%; p < 0.0001), cyst fluid appearance recorded (89.4%) or adequate sample for cytology obtained (76.7%; p < 0.005). Median CEA was significantly higher in mucinous cysts than non-mucinous (175 ng/ml vs 3 ng/ml, p < 0.0001) and in malignant cysts compared to benign (8945 ng/ml vs 93 ng/ml, p < 0.001). On an intention-to-diagnose analysis, a CEA cut-off of 110 ng/ml was significantly less accurate (42.8%) than EUS diagnosis (67.7%), cytology (58.6%) or aspirate appearance (66.9%; p < 0.05 for all comparisons). However, the combination of EUS diagnosis, cytology and CEA provided higher sensitivity (91%), specificity (75%) and accuracy (85.7%) than each component test alone (p < 0.05 for all comparisons). Median amylase was significantly higher in benign compared to high-risk mucinous cysts ((11,429IU/L vs. 113IU/L; p < 0.05. CONCLUSION: The combination of EUS, cytology and CEA performed well. Malignant cysts had a higher CEA value than benign cysts. On an intention to diagnose basis a CEA cut-off of 110 ng/ml performed poorly.

Influence of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma: a systematic review.

BACKGROUND/OBJECTIVES: Cachexia affects ∼ 80% of pancreatic cancer patients. An international consensus defines cachexia as an ongoing loss of skeletal muscle mass (sarcopenia) with or without loss of fat, which impairs body functioning and cannot be reversed by conventional nutritional measures. Weight loss percentage and elevated inflammation markers have been employed to define this condition earlier. This review aimed to assess the prevalence and consequences of cachexia and sarcopenia on survival in patients with pancreatic ductal adenocarcinoma. METHODS: The systematic review was performed by searching the articles with preset terms published in PubMed and Cochrane Database until December 2013. After identifying relevant titles, abstracts were read and eligible articles data retrieved on preformatted sheets. The prevalence and impact of sarcopenia/cachexia on survival was evaluated. RESULTS: In total 1145 articles were retrieved, only 10 were eligible. Definitions of cachexia and sarcopenia were heterogeneous. In patients with normal weight (BMI 18.5-24.9 kg/m(2)) the prevalence of sarcopenia ranged from 29.7 to 65%. In overweight or obese patients (BMI >25 kg/m(2)) were 16.2%-67%. Sarcopenia alone was not demonstrated to be an independent factor of decreased survival, although obese sarcopenic patients were shown to have significantly worse survival in two studies. CONCLUSIONS: Impact of cachexia and sarcopenia on survival in pancreatic ductal adenocarcinoma is currently understudied in the available literature. Definitive association between cachexia and survival cannot be drawn from available studies, although weight loss and sarcopenic obesity might be considered as poor prognostic factors. Further prospective trials utilizing the consensus definition of cachexia and including other confounding factors are needed to investigate the impact of cachexia and sarcopenia on survival in pancreatic adenocarcinoma.

Oncological feasibility of laparoscopic distal pancreatectomy for adenocarcinoma: a single-institution comparative study.

BACKGROUND: Laparoscopic distal pancreatectomy (LDP) is performed increasingly for pancreatic pathology in the body and tail of the pancreas. However, only few reports have compared its oncological efficacy with open distal pancreatectomy (ODP). We compared these two techniques in patients with pancreatic ductal adenocarcinoma. METHODS: From a prospectively maintained database, all patients who underwent either LDP or ODP for adenocarcinoma in the body and tail of the pancreas between January 2008 and December 2011 were compared. Data were analysed using SPSS(®) v19 utilising standard tests. A p value <0.05 was considered significant. RESULTS: Of 101 patients who underwent distal pancreatectomy, 22 had histologically confirmed adenocarcinoma (LDP n = 8, ODP n = 14). Both groups were well matched for age and the size of tumour (22 vs. 32 mm, p = 0.22). Intraoperative blood loss was 306 ml compared with 650 ml for ODP (p = 0.152). A longer operative time was noted for LDP (376 vs. 274 min, p < 0.05). Total length of stay was shorter for LDP compared with ODP (8 vs. 12 days, p = 0.05). The number of postoperative pancreatic fistulas were similar (LDP n = 2 vs. ODP n = 3, p = 0.5). Complete resection (R0) was achieved in 88 % of LDP (n = 7) compared with 86 % of ODP (n = 12). The median number of lymph nodes harvested was 16 for LDP versus 14 for ODP. Overall 3-year survival also was similar: LDP = 82 %, ODP = 74 % (p = 0.89). CONCLUSIONS: From an oncological perspective, LDP is a viable procedure and its results are comparable to ODP for ductal adenocarcinomas arising in the body and tail of the pancreas.

Prognostic factors and survival after resection of colorectal liver metastasis in the era of preoperative chemotherapy: an 11-year single-centre study.

INTRODUCTION: A variety of factors have been identified in the literature which influence survival following resection of colorectal liver metastases (CRLM). Much of this literature is historical, and its relevance to contemporary practice is not known. The aim of this study was to identify those factors which influence survival during the era of preoperative chemotherapy in patients undergoing resection of CRLM in a UK centre. METHODS: All patients having liver resection for CRLM during an 11-year period up to 2011 were identified from a prospectively maintained database. Prognostic factors analysed included tumour size (≥5 or <5 cm), lymph node status of the primary tumour, margin positivity (R1; <1 mm), neo-adjuvant chemotherapy (for liver), tumour differentiation, number of liver metastases (≥4), preoperative carcinoembryonic antigen (CEA; ≥200 ng/ml) and whether metastases were synchronous (i.e. diagnosed within 12 months of colorectal resection) or metachronous to the primary tumour. Overall survival (OS) was compared using Kaplan-Meier plots and a log rank test for significance. Multivariate analysis was performed using a Cox regression model. Statistical analysis was performed in SPSS v19, and p < 0.05 was considered to be significant. RESULTS: 432 patients underwent resection of CRLM during this period (67% male; mean age 64.5 years), and of these, 54 (13.5%) had re-resections. The overall 5-year survival in this series was 43% with an actuarial 10-year survival of 40%. A preoperative CEA ≥200 ng/ml was present in 10% of patients and was associated with a poorer 5-year OS (24 vs. 45%; p < 0.001). A positive resection margin <1 mm was present in 16% of patients, and this had a negative impact on 5-year OS (15 vs. 47%; p < 0.001). Tumour differentiation, number, biliary or vascular invasion, size, relationship to primary disease, nodal status of the primary disease or the use of neo-adjuvant chemotherapy had no impact on OS. Multivariate analysis identified only the presence of a positive resection margin (OR 1.75; p < 0.05) and a preoperative CEA ≥200 ng/ml (OR 1.88; p < 0.01) as independent predictors of poor OS. CONCLUSION: Despite the wide variety of prognostic factors reported in the literature, this study was only able to identify a preoperative CEA ≥200 ng/ml and the presence of tumour within 1 mm of the resection margin as being of value in predicting survival. These variables are likely to identify patients who may benefit from intensive follow-up to enable early aggressive treatment of recurrent disease.

Effects of low cardiopulmonary reserve on pancreatic leak following pancreaticoduodenectomy.

BACKGROUND: Postoperative complications are increased in patients with reduced cardiopulmonary reserve undergoing major surgery. Pancreatic leak is an important contributor to postoperative complications and death following pancreaticoduodenectomy. The aim of this study was to determine whether reduced cardiopulmonary reserve was a risk factor for pancreatic leak. METHODS: All patients who underwent pancreaticoduodenectomy between January 2006 and July 2010 were identified from a prospectively held database. Data analysis was restricted to those who underwent cardiopulmonary exercise testing during preoperative assessment. Pancreatic leak was defined as grade A, B or C according to the International Study Group on Pancreatic Fistula definition. An anaerobic threshold (AT) cut-off value of 10·1 ml per kg per min was used to identify patients with reduced cardiopulmonary reserve. Univariable and multivariable analyses were performed to identify other risk factors for pancreatic leak. RESULTS: Some 67 men and 57 women with a median age of 66 (range 37-82) years were identified. Low AT was significantly associated with pancreatic leak (45 versus 19·2 per cent in patients with greater cardiopulmonary reserve; P = 0·020), postoperative complications (70 versus 38·5 per cent; P = 0·013) and prolonged hospital stay (29·4 versus 17·5 days; P = 0·001). On multivariable analysis, an AT of 10·1 ml per kg per min or less was the only independent factor associated with pancreatic leak. CONCLUSION: Low cardiopulmonary reserve was associated with pancreatic leak following pancreaticoduodenectomy. AT seems a useful tool for stratifying the risk of postoperative complications.

Acute pancreatitis and the influence of socioeconomic deprivation.

BACKGROUND: A comprehensive epidemiological study of acute pancreatitis (AP) using reliable objective methods of patient identification with the inclusion of socioeconomic factors has not been reported previously. METHODS: The study included all patients with AP identified by raised serum amylase or lipase levels admitted to 18 hospitals over 6 months. Clinical records were reviewed to confirm the diagnosis, aetiology and outcome. Patients were stratified into quintiles of socioeconomic deprivation. Age-standardized incidence (ASI) and mortality were calculated. RESULTS: Clinical data were reviewed for all 963 identified patients. The ASI was 56.5 per 10(5) per annum, double the highest figure reported previously in the UK. Univariable logistic regression analysis showed a high ASI among older age groups (odds ratio (OR) 1.06 per year; P < 0.001) and in areas of high deprivation (OR 2.40 between least and most deprived; P < 0.001); the latter was predominantly related to alcoholic aetiology (OR 6.50 (95 per cent confidence interval 3.90 to 10.84)). CONCLUSION: The incidence of AP based on a highly sensitive method of case identification was higher than previously reported. A clear relationship was found between socioeconomic deprivation and incidence of AP, which was largely explained by a higher incidence of alcoholic aetiology.

Management strategies in isolated pancreatic trauma.

AIM: In the absence of damage to other organs, pancreatic injury is rare. We have reviewed our experience with isolated pancreatic injury. METHODS: Patients treated for isolated pancreatic trauma at our unit were identified prospectively and then retrospectively entered onto a database. The mode of presentation, mechanism of injury and management strategies were reviewed. RESULTS: Seven male and four female patients, median age 30 years (range 13-51 years) were treated. All suffered blunt abdominal trauma with different mechanisms of injury, each being characterised by a direct blow to the central abdomen. In two patients, somatostatin analogue treatment used as primary treatment resulted in early resolution of symptoms and signs. Six patients underwent surgery at various stages post-injury. At a median follow-up of 58 months (range 22-106 months), eight patients are asymptomatic, two patients have chronic pain following distal pancreatectomy and one patient has occasional discomfort. CONCLUSION: Confirmation of the mechanism of trauma and suspicion of pancreatic injury are essential for early diagnosis and appropriate management. Early contrast computed tomography examination is vital in the recognition of these injuries. Somatostatin analogue therapy may have an important role in the treatment regimen, especially when patients present early after sustaining a pancreatic injury. Only selected patients require open surgery.

Genetic susceptibility in pancreatic ductal adenocarcinoma.

BACKGROUND: The strongest risk factors for pancreatic adenocarcinoma are tobacco smoking and increasing age. However, only a few smokers or elderly individuals develop the disease and genetic factors are also likely to be important. METHODS: The literature on genetic factors modifying susceptibility to cancer was reviewed, with particular regard to the interindividual variation that exists in the development of pancreatic adenocarcinoma. RESULTS: Tobacco-derived carcinogen-metabolizing enzyme gene variants have been the main area of study in stratifying the risk of sporadic pancreatic cancer. Inconsistent results have emerged from the few molecular epidemiological studies performed. CONCLUSION: There is great scope for further investigation of critical pathways and unidentified genetic influences may be revealed. This may eventually allow the identification of individuals at high risk who might be targeted for screening.

Comparison of multislice computed tomography and endoscopic ultrasonography with operative and histological findings in suspected pancreatic and periampullary malignancy.

BACKGROUND: This study compared multislice computed tomography (MSCT) with endoscopic ultrasonography (EUS) in the diagnosis and staging of pancreatic and periampullary malignancy. METHODS: Data were collected prospectively on patients having MSCT and EUS for suspected pancreatic and periampullary malignancy. RESULTS: Eighty-four patients had MSCT and EUS, of whom 35 underwent operative assessment (29 resections). In assessing malignancy, there was no significant difference between MSCT and EUS, and agreement was good (82 per cent, kappa = 0.49); the sensitivity and specificity of MSCT were 97 and 87 per cent, compared with 95 and 52 per cent respectively for EUS (P = 0.264). For portal vein/superior mesenteric vein invasion, MSCT was superior (P = 0.017) and agreement was moderate (72 per cent, kappa = 0.42); the sensitivity and specificity were 88 and 92 per cent for MSCT, and 50 and 83 per cent for EUS. For resectability, there was no significant difference and agreement was good (78 per cent, kappa = 0.51). EUS had an impact on the management of 14 patients in whom MSCT suggested benign disease or equivocal resectability. CONCLUSION: MSCT is the imaging method of choice for pancreatic and periampullary tumours. Routine EUS should be reserved for those with borderline resectability on MSCT.

Management of hilar cholangiocarcinoma in the North of England: pathology, treatment, and outcome.

AIM: To assess the management and outcome of hilar cholangiocarcinoma (Klatskin tumor) in a single tertiary referral center. METHODS: The notes of all patients with a diagnosis of hilar cholangiocarcinoma referred to our unit for over an 8-year period were identified and retrospectively reviewed. Presentation, management and outcome were assessed. RESULTS: Seventy-five patients were identified. The median age was 64 years (range 34-84 years). Male to female ratio was 1:1. Eighty-nine percent of patients presented with jaundice. Most patients referred were under Bismuth classification 3a, 3b or 4. Seventy patients required biliary drainage, 65 patients required 152 percutaneous drainage procedures, and 25 had other complications. Forty-one patients had 51 endoscopic drainage procedures performed (15 failed). Of these, 36 subsequently required percutaneous drainage. The median number of drainage procedures for all patients was three, 18 patients underwent resection (24%), nine had major complications and three died post-operatively. The 5-year survival rate was 4.2% for all patients, 21% for resected patients and 0% for those who did not undergo resection (P = 0.0021). The median number of admissions after diagnosis in resected patients was two and three in non-resected patients (P<0.05). Twelve patients had external-beam radiotherapy, seven brachytherapy, and eight chemotherapy. There was no significant benefit in terms of survival (P = 0.46) or hospital admissions. CONCLUSION: Resection increases survival but carries the risk of significant morbidity and mortality. Percutaneous biliary drainage is almost always necessary and endoscopic drainage should be avoided if possible.

Implications of the index cholecystectomy and timing of referral for radical resection of advanced incidental gallbladder cancer.

INTRODUCTION: Advanced (pT2/T3) incidental gallbladder cancer is often deemed unresectable after restaging. This study assesses the impact of the primary operation, tumour characteristics and timing of management on re-resection. METHODS: The records of 60 consecutive referrals for incidental gallbladder cancer in a single tertiary centre from 2003 to 2011 were reviewed retrospectively. Decision on re-resection of incidental gallbladder cancer was based on delayed interval restaging at three months following cholecystectomy. Demographics, index cholecystectomy data, primary pathology, CA19-9 tumour marker levels at referral and time from cholecystectomy to referral as well as from referral to restaging were analysed. RESULTS: Thirty-seven patients with pT2 and twelve patients with pT3 incidental gallbladder cancer were candidates for radical re-resection. Following interval restaging, 24 patients (49%) underwent radical resection and 25 (51%) were deemed inoperable. The inoperable group had significantly more patients with positive resection margins at cholecystectomy (p=0.002), significantly higher median CA19-9 levels at referral (p=0.018) and were referred significantly earlier (p=0.004) than the patients who had resectable tumours. On multivariate analysis, urgent referral (p=0.036) and incomplete cholecystectomy (p=0.048) were associated significantly with inoperable disease following restaging. CONCLUSIONS: In patients with incidental, potentially resectable, pT2/T3 gallbladder cancer, inappropriate index cholecystectomy may have a significant impact on tumour dissemination. Early referral of breached tumours is not associated with resectability.

Inhalation of a minitracheotomy tube.

Inhalation of a minitracheotomy tube during sputum aspiration in a patient with sputum retention is reported. Precautionary measures in the insertion and management of a minitracheotomy tube are discussed.