Defining the Role of Lymphadenectomy for Pancreatic Neuroendocrine Tumors: An Eight-Institution Study of 695 Patients from the US Neuroendocrine Tumor Study Group.

BACKGROUND: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. METHODS: Patients who underwent curative-intent resection of non-functional PanNETs at eight institutions from 2000 to 2016 were analyzed. Preoperative factors associated with LN metastases were identified. A procedure-specific target for LN retrieval to accurately stage patients was determined. RESULTS: Of 695 patients who underwent resection, 33% of tumors were proximal (head/uncinate) and 67% were distal (neck/body/tail). Twenty-six percent of patients (n = 158) had LN-positive disease, which was associated with a worse 5-year recurrence-free survival (RFS; 60% vs. 86%; p < 0.001). The increasing number of positive LNs was not associated with worse RFS. Preoperative factors associated with positive LNs included tumor size ≥ 2 cm (odds ratio [OR] 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate versus well-differentiation (OR 2.1; p = 0.006), and Ki-67 ≥ 3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2 cm (9%), distal location (19%), well-differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage patients was not identified. However, for DP, removal of less than seven LNs failed to discriminate 5-year RFS between LN-positive and LN-negative patients (less than seven LNs: 72% vs. 83%, p = 0.198; seven or more LNs: 67% vs. 86%; p = 0.002). CONCLUSIONS: Tumor size ≥ 2 cm, proximal location, moderate differentiation, and Ki-67 ≥ 3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. PD inherently includes sufficient LN retrieval, while DP should aim to remove seven or more LNs for accurate staging.

Premalignant Lesions of the Biliary Tract.

Although the most common presentation of biliary disorder in North America is secondary to gallstone disease, an awareness of benign biliary cystic neoplasms is important because of the risk of malignant transformation. The incidence of premalignant cystic neoplasms of the bile duct is not well characterized and they often are detected incidentally for suspicion of other abdominal disorders. This article describes the 4 most common premalignant biliary cystic neoplasms: biliary mucinous cystic neoplasms, intraductal papillary mucinous neoplasms of the bile duct, intraductal tubular papillary neoplasms of the bile duct, and choledochal cysts.

Predictive Value of Chromogranin A and a Pre-Operative Risk Score to Predict Recurrence After Resection of Pancreatic Neuroendocrine Tumors.

INTRO: Chromogranin A (CgA) may be prognostic for patients with neuroendocrine tumors; however, the clinical utility of this test is unclear. METHODS: Patients undergoing resection for pancreatic neuroendocrine tumors (pNET) were selected from the eight institutions of the US Neuroendocrine Tumor Study Group database. Cox regression was used to identify pre-operative variables that predicted recurrence-free survival (RFS), and those with p < 0.1 were included in a risk score. The risk score was tested in a unique subset of the overall cohort. RESULTS: In the entire cohort of 287 patients, median follow-up time was 37 months, and 5-year RFS was 73%. Cox regression analysis identified four variables for inclusion in the risk score: CgA > 5x ULN (HR 4.3, p = 0.01), tumor grade 2/3 (HR 3.7, p = 0.01), resection for recurrent disease (HR 6.2, p < 0.01), and tumor size > 4 cm (HR 4.5, p = 0.1). Each variable was assigned 1 point. Risk-score testing in the unique validation cohort of 63 patients revealed a 95% negative predictive value for recurrence in patients with zero points. DISCUSSION: This simple pre-operative risk scoring system resulted in a high degree of specificity for identifying patients at low-risk for tumor recurrence. This test can be utilized pre-operatively to aid informed decision-making.

The microbiology of infected pancreatic necrosis in the era of minimally invasive therapy.

We aimed to determine the microbiology of infected walled-off pancreatic necrosis (WON) in an era of minimally invasive treatment, since current knowledge is based on surgical specimens performed over two decades ago. We retrospectively analyzed a prospectively maintained database of patients who were treated for symptomatic WON using combined endoscopic and percutaneous drainage between 2008 and 2017. Aspirates from WON at initial treatment were evaluated. One hundred eighty-two patients were included with a mean age of 56 of whom 67% were male. Culture results were obtained at a median of 45 days from onset of acute pancreatitis of which 41% were infected. Candida spp. accounted for 27%; yet, multidrug-resistant organisms were found in only five patients. Approximately 64% were transferred to our institution for continuation of care. Of those, 55% were infected, most frequently with Candida spp., Enterococcus spp., and coagulase-negative Staphylococcus. Patients seen and admitted initially at our institution had milder forms of pancreatitis, fewer comorbidities, and 85% had symptomatic sterile WON. Empiric antibiotic use successfully predicted infection 70% of the time. Multivariate analysis demonstrated that elderly age, severity of pancreatitis, and prior use of antibiotics were indicators of infection. Necrotic pancreatic tissue remains sterile in the majority of cases treated with minimally invasive therapy, enabling judicious selection of antibiotics. Candida and Enterococcus spp. were common. Patients at highest risk for infection were previously treated with antibiotics and those transferred from outside institutions.

Duration of antibiotic treatment after endoscopic ultrasound-guided drainage of walled-off pancreatic necrosis not affecting outcomes.

BACKGROUND AND AIM: Although society guidelines recommend a short course of antibiotics after drainage of walled-off necrosis (WON), the exact duration is unclear. METHODS: This is a retrospective review of patients with no prior antibiotic exposure who underwent dual-modality drainage (DMD) for sterile WON from 2008 to 2017. Patients were grouped into short duration (SD, ≤5 days) versus long duration (LD, >5 days). The main outcome was the frequency of recurrent infections. RESULTS: Sixty-one patients (25 in the SD group and 36 in the LD group) were included. Patients in the two groups had comparable age, comorbidities, and severity of disease (P = 0.89). Patients in the SD group were treated with antibiotics for a median of 3 days compared with 8.5 days in the LD group. There were no differences in recurrent febrile episodes within 30 days of procedure-44% of SD group versus 39% of LD (P = 0.69). There was also no difference in time to resolution of WON (64 days for both groups, P = 0.72) or duration of hospitalization post-DMD (SD 7.7 days versus LD 7.5 days, P = 0.42). Three cases of Clostridium difficile colitis were observed in the LD group. CONCLUSIONS: Longer course of antibiotics seems to have similar outcomes compared with shorter courses in patients with WON treated with DMD. Prolonged-course therapy may predispose to secondary infections like C. difficile colitis. A randomized controlled trial is needed to evaluate the role and duration of peri-procedural antibiotics after drainage of sterile WON.

Gemcitabine and Taxane Adjuvant Therapy with Chemoradiation in Resected Pancreatic Cancer: A Novel Strategy for Improved Survival?

BACKGROUND: Gemcitabine-taxane combination chemotherapy has demonstrated a survival benefit clinically in metastatic pancreatic cancer (PC). The authors present their experience with gemcitabine and docetaxel (gem/tax)-based adjuvant treatment (Rx) after surgery with curative intent. METHODS: Patients with de novo resectable PC from January 2010 to December 2015 were identified from the authors' institutional database and registry. The study included only patients who received gem/tax as their initial Rx administered exclusively at the authors' institution with or without chemoradiation (CRTx). Survival analysis was performed using Kaplan-Meier methods, and prognostic factors were investigated by Cox proportional hazard modeling. RESULTS: Of 102 patients identified, 58 met the study criteria. The median age at diagnosis was 65 years, with 55% of the patients undergoing an R1 resection (margin ≤ 1 mm). Tumor characteristics included a median tumor size of 28 mm, a poor differentiation rate of 54%, and a lymph node positivity of 67%. Most of the patients (90%, 52/58) completed 80% or more of the 24 week Rx. Of these patients, 71% received post-gem/tax CRTx Rx. Grade 3 or 4 toxicity was observed in 52% of the patients. The median follow-up period was 51.2 months, and the observed median overall survival (OS) was 52 months [95% confidence interval (CI) 27.4-not reached]. The actuarial 5-year OS was 49% (95% CI 33.7-63.4%). In the multivariate analysis, an R1 resection and American Joint Committee on Cancer (AJCC) stage 2 versus stage 1 disease were negatively associated with OS, whereas administration of CRTx was positively associated with OS. CONCLUSIONS: Adjuvant gem/tax with or without CRTx is feasible, with a favorable OS. Future prospective studies of gem/taxane-based adjuvant Rx for PC are warranted.

New guidelines for use of endoscopic ultrasound for evaluation and risk stratification of pancreatic cystic lesions may be too conservative.

BACKGROUND: The role of EUS in managing asymptomatic pancreatic cystic lesions (PCLs) remains unresolved. We retrospectively evaluated EUS in risk stratification of PCLs when adhering to the most recent AGA guidelines. METHODS: Asymptomatic PCLs that were evaluated by EUS from January 2014 to December 2014 were retrospectively reviewed including associated cytology, fluid analysis, and relevant surgical pathology. Cross-sectional imaging reports were reviewed blindly by an expert radiologist using AGA risk stratification terminology. Accepted imaging high-risk features (HRF) included cyst diameter > 3 cm, dilated upstream pancreatic ducts, and a solid component in the cyst. RESULTS: We reviewed 125 patients who underwent EUS. Expert review of cross-sectional imaging resulted in a different interpretation 25% of the time including 1 malignant cyst. Ninety-three patients (75%) had no HRFs on cross-sectional imaging; 28 patients (22%) were diagnosed with 1 HRF and 4 patients (3%) had 2 HRFs. Adhering to AGA guidelines using 2 HRF as threshold for use of EUS, the diagnosis of malignant and high-risk premalignant lesions (including pancreatic adenocarcinoma, mucinous cystadenoma, neuroendocrine tumors, and IPMN with dysplasia) had a 40% sensitivity and 100% specificity. Had EUS been utilized based on a threshold of 1 HRF on imaging, malignant and high-risk premalignant lesions would have been identified with 80% sensitivity and 95% specificity. By adding EUS to radiographic imaging, the specificity for detecting carcinomas (p = 0.0009) and detection of all premalignant lesions (p = 0.003) statistically improved. Furthermore, EUS allowed 14 patients (11%) to avoid further surveillance by lowering their risk stratification. CONCLUSION: EUS remains an essential risk stratification modality for incidental PCLs. Current guideline suggestions of its utility may be too stringent. Our study justifies expert radiology review when managing PCLs. Further studies are required to identify the optimal approach to PCL management.

Do lumen-apposing metal stents (LAMS) improve treatment outcomes of walled-off pancreatic necrosis over plastic stents using dual-modality drainage?

BACKGROUND AND STUDY AIMS: Endoscopic ultrasound-guided drainage of symptomatic walled-off pancreatic necrosis (WON) usually has been performed with double pigtail plastic stents (DPS) and more recently, with lumen-apposing metal stents (LAMS). However, LAMS are significantly more expensive and there are no comparative studies with DPS. Accordingly, we compared our experience with combined endoscopic and percutaneous drainage (dual-modality drainage [DMD]) for symptomatic WON using LAMS versus DPS. PATIENTS AND METHODS: Patients who underwent DMD of WON between July 2011 and June 2016 using LAMS were compared with a matched group treated with DPS. Technical success, clinical success, need for reintervention and adverse events (AE) were recorded. RESULTS: A total of 50 patients (31 males, 25 patients treated with LAMS and 25 patients treated with DPS) were matched for age, sex, computed tomography severity index, and disconnected pancreatic ducts. Technical success was achieved in all patients. Mean days hospitalized post-intervention (14.5 vs. 13.1, P  = 0.72), time to resolution of WON (77 days vs. 63 days, P  = 0.57) and mean follow-up (207 days vs. 258 days, P  = 0.34) were comparable in both groups. AEs were similar in both groups (6 vs. 8, P  = 0.53). Patients treated with LAMS had significantly more reinterventions per patient (1.5 vs. 0.72, P  = 0.01). CONCLUSIONS: In treatment of symptomatic WON using DMD, LAMS did not shorten time to percutaneous drain removal and was not associated with fewer AEs.

Malrotation with midgut volvulus in an adult: a case report and review of the literature.

We report a case of a 53-year-old male who presented with acute onset right upper quadrant (RUQ) abdominal pain with investigations demonstrating malrotation causing midgut volvulus and subsequent intestinal obstruction. The patient was consented for an emergent operation and underwent an exploratory laparotomy. Operative findings included the presence of adhesive bands in the RUQ (Ladd's Band), volvulus of the mid-portion of the small bowel in a clockwise fashion and multiple intra-abdominal adhesions causing internal hernias. We subsequently performed a Ladd's procedure and the patient had an uneventful recovery with eventual discharge on postoperative day 8. This case report reviews the incidence of malrotation in adults. It also highlights the difficulty in diagnosing midgut volvulus in the adult population given the nonspecific, insidious symptoms therefore prompting awareness of its existence and a high degree of clinical suspicion.

Liver resection after chemotherapy and tumour downsizing in patients with initially unresectable colorectal cancer liver metastases.

OBJECTIVES: Among patients with initially unresectable colorectal cancer liver metastases (CLM), a subset are rendered resectable following the administration of systemic chemotherapy. This study reports the results achieved in liver resections performed at a single hepatobiliary referral centre after downsizing chemotherapy in patients with initially unresectable CLM. METHODS: All liver resections for CLM performed over a 10-year period at the Toronto General Hospital were considered. Data on initially non-resectable patients who received systemic therapy and later underwent surgery were included for analysis. RESULTS: Between January 2002 and July 2012, 754 liver resections for CLM were performed. A total of 24 patients were found to meet the study inclusion criteria. Bilobar CLM were present in 23 of these 24 patients. The median number of tumours was seven (range: 2-15) and median tumour size was 7.0 cm (range: 1.0-12.8 cm) before systemic therapy. All patients received oxaliplatin- or irinotecan-based chemotherapy. Fourteen patients received combined treatment with bevacizumab. Negative margin (R0) resection was accomplished in 21 of 24 patients. There was no perioperative mortality. Ten patients suffered perioperative morbidity. Eighteen patients suffered recurrence of disease within 9 months. Rates of disease-free survival at 1, 2 and 3 years were 47.6% [95% confidence interval (CI) 30.4-74.6%], 23.8% (95% CI 11.1-51.2%) and 19.0% (95% CI 7.9-46.0%), respectively. Overall survival at 1, 2 and 3 years was 91.5% (95% CI 80.8-100%), 65.3% (95% CI 48.5-88.0%) and 55.2% (95% CI 37.7-80.7%), respectively. CONCLUSIONS: Liver resection in initially unresectable CLM can be performed with low rates of morbidity and mortality in patients who respond to systemic chemotherapy, although these patients do experience a high frequency of disease recurrence.

Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer.

We sequenced 11 germline exomes from five families with familial pancreatic cancer (FPC). One proband had a germline nonsense variant in ATM with somatic loss of the variant allele. Another proband had a nonsense variant in PALB2 with somatic loss of the variant allele. Both variants were absent in a relative with FPC. These findings question the causal mechanisms of ATM and PALB2 in these families and highlight challenges in identifying the causes of familial cancer syndromes using exome sequencing.