Treatment and long term safety outcomes of Peptide Receptor Radionuclide Therapy for metastatic neuroendocrine tumours: an Asian experience.

Peptide-receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NET). It has been shown to be effective and well-tolerated in patients with metastatic neuroendocrine tumours in several centres in United States (US), Europe and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods One hundred and seven (107) patients with metastatic neuroendocrine tumour who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST1.1 and qualitative analysis were examined. The overall and progression free survival curves were also evaluated. Results The median progression free survival was 49 months. Response assessment after completion of treatment showed that 33(37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion Our results show that PRRT is safe and effective in the treatment of metastatic neuroendocrine tumour in the Asian population. There was a significant difference in the progression free survival curves between low-grade and high-grade NET, and in the progression free and overall survival comparing the number of cycles received.

Changing trends in the clinicopathological features, practices and outcomes in the surgical management for cystic lesions of the pancreas and impact of the international guidelines: Single institution experience with 462 cases between 1995-2018.

INTRODUCTION: The impact on clinical practice of the international guidelines including the Sendai Guidelines (SG06) and Fukuoka Guidelines (FG12) on the management of cystic lesions of the pancreas (CLP) has not been well-studied. The primary aim was to examine the changing trends and outcomes in the surgical management of CLP in our institution over time and to determine the impact of these guidelines on our institution practice. METHODS: 462 patients with surgically-treated CLP were retrospectively reviewed and classified under the 2 guidelines. The cohort was divided into 3 time periods: 1998-2006, 2007-2012 and 2013 to 2018. RESULTS: Comparison across the 3 time periods demonstrated significantly increasing frequency of older patients, asymptomatic CLP, male gender, smaller tumor size, elevated Ca 19-9, use of magnetic resonance imaging (MRI) and use of endoscopic ultrasound (EUS) prior to surgery. There was also significantly increasing frequency of adherence to the international guidelines as evidenced by the increasing proportion of HRSG06 and HRFG12 CLP with a corresponding lower proportion of LRSG06 and LRFG12 being resected. This resulted in a significantly higher proportion of resected CLP whereby the final pathology confirmed that a surgery was actually indicated. CONCLUSIONS: Over time, there was increasing adherence to the international guidelines for the selection of patients for surgical resection as evidenced by the significantly increasing proportion of HRSG06 and HRFG06 CLPs undergoing surgery. This was associated with a significantly higher proportion of patients with a definitive indication for surgery. These suggested that over time, there was a continuous improvement in our selection of appropriate CLP for surgical treatment.

Systematic review of the clinical utility and validity of the Sendai and Fukuoka Consensus Guidelines for the management of intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: This systematic review was performed to assess the clinical utility of the Sendai Consensus Guidelines (SCG) and Fukuoka Consensus Guidelines (FCG) for intraductal papillary mucinous neoplasm (IPMN). METHODS: A computerized search of PubMed was performed to identify all the studies which evaluated the SCG and FCG in surgically resected, histologically confirmed IPMNs. RESULTS: Ten studies evaluating the FCG, 8 evaluating the SCG and 4 evaluating both guidelines were included. In 14 studies evaluating the FCG, out of a total of 2498 neoplasms, 849 were malignant and 1649 were benign neoplasms. Pooled analysis showed that 751 of 1801 (42%) FCG+ve neoplasms were malignant and 599 neoplasms of 697 (86%) FCG-ve neoplasms were benign. PPV of the high risk and worrisome risk groups were 465/986 (47%) and 239/520 (46%) respectively. In 12 studies evaluating the SCG, 1234 neoplasms were analyzed of which 388 (31%) were malignant and 846 (69%) were benign. Pooled analysis demonstrated that 265 of 802 (33%) SCG+ve neoplasms were malignant and 238 of 266 SCG-ve (90%) neoplasms were benign. CONCLUSION: The FCG had a higher positive predictive value (PPV) compared to the SCG. However, the negative predictive value (NPV) of the FCG was slightly lower than that of the SCG. Malignant and even invasive IPMN may be missed according to both guidelines.

Preoperative platelet-to-lymphocyte ratio improves the performance of the international consensus guidelines in predicting malignant pancreatic cystic neoplasms.

INTRODUCTION: To determine if neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were predictive of malignancy in pancreatic cystic neoplasms (PCN) and if these improved the performance of the international consensus guidelines (ICG) in the initial triage of these patients. METHODS: 318 patients with surgically-treated suspected PCN were retrospectively reviewed. Malignant neoplasms were defined as neoplasms harbouring invasive carcinoma. The optimal cut-off for NLR and PLR were determined by plotting the receiver operating characteristics (ROC) curves of NLR/PLR in predicting malignant PCN and utilizing the Youden index. RESULTS: The optimal NLR and PLR cut-offs were determined to be 3.33 and 205, respectively. Univariate analyses demonstrated that symptomatic PCNs, age, obstructive jaundice, presence of solid component, dilatation of main pancreatic duct ≥10 mm, high NLR and high PLR were predictive of a malignant PCN. Multivariate analyses demonstrated that obstructive jaundice, presence of solid component, MPD ≥10 mm and high PLR but not NLR were independent predictors of a malignant PCN. A high PLR significantly predicted invasive carcinoma in patients classified within the ICG(HR) group. Comparison between the ROC curves of the ICG versus ICG plus high PLR in predicting malignant PCN demonstrated a significant improvement in the accuracy of the ICG when PLR was included [AUC 0.784 (95% CI: 0.740-0.829) vs AUC 0.822 (95% CI: 0.772-0.872) (p = 0.0032)]. CONCLUSIONS: High PLR is an independent predictor of malignancy in PCN. The addition of PLR as a criterion to the ICG improved the accuracy of these guidelines in detecting invasive neoplasms.

Are preoperative blood neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios useful in predicting malignancy in surgically-treated mucin-producing pancreatic cystic neoplasms?

INTRODUCTION: The aim of this study was to determine if neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were predictive of malignancy in mucin-producing pancreatic cystic neoplasms (MpPCN). METHODS: One hundred and twenty patients with MpPCN were retrospectively reviewed. Malignant neoplasms were defined as neoplasms harbouring invasive carcinoma or high grade dysplasia. A high NLR and PLR were defined as ≥2.551 and ≥208.1, respectively. RESULTS: High NLR was significantly associated with symptomatic tumors, larger tumors, solid component, main-duct IPMN, and Sendai high risk category. High PLR was significantly associated with jaundice and Sendai high risk category. On univariate analyses, symptomatic tumors, jaundice, solid component, dilated pancreatic duct, and both a high NLR and PLR were significant predictors of malignant and invasive MpPCN. On multivariate analyses, solid component and dilated pancreatic duct were independent predictors of malignant and invasive MpPCN. PLR was an independent predictor for invasive MpPCN. When MpPCN were stratified by the Fukuoka and Sendai Guidelines, both a high NLR and PLR were significantly associated with malignant neoplasms within the high risk categories. CONCLUSIONS: PLR is an independent predictor of invasive carcinoma. The addition of PLR as a criterion to the FCG and SCG significantly improved the predictive value of these guidelines in detecting invasive neoplasms.

Are the Sendai and Fukuoka consensus guidelines for cystic mucinous neoplasms of the pancreas useful in the initial triage of all suspected pancreatic cystic neoplasms? A single-institution experience with 317 surgically-treated patients.

BACKGROUND: The Sendai Consensus Guidelines (SCG) were formulated in 2006 and updated in Fukuoka in 2012 (FCG) to guide management of cystic mucinous neoplasms of the pancreas. This study aims to evaluate the clinical utility of the SCG and FCG in the initial triage of all suspected pancreatic cystic neoplasms. STUDY DESIGN: Overall, 317 surgically-treated patients with a suspected pancreatic cystic neoplasm were classified according to the SCG as high risk (HR(SCG)) and low risk (LR(SCG)), and according to the FCG as high risk (HR(FCG)), worrisome (W(FCG)), and low risk (LR(FCG)). Cystic lesions of the pancreas (CLP) were classified as potentially malignant/malignant or benign according to the final pathology. RESULTS: The presence of symptoms, proximal lesions with obstructive jaundice, elevated serum carcinoembryonic antigen/carbohydrate antigen 19-9 (CEA/CA 19-9), size ≥3 cm, presence of solid component, main pancreatic duct dilatation, thickened enhancing walls, and change in ductal caliber with distal atrophy were predictive of a potentially malignant/malignant CLP on univariate analyses. The positive predictive value (PPV) and negative predictive value (NPV) of HR(SCG) and HR(ICG2012) for a potentially malignant/malignant lesion was 67 and 88 %, and 88 and 92.5 %, respectively. There were no malignant lesions in both LR groups but some potentially malignant lesions such as cystic pancreatic neuroendocrine neoplasms with uncertain behavior were classified as LR. CONCLUSION: The updated FCG was superior to the SCG for the initial triage of all suspected pancreatic cystic neoplasms. CLP in the LR(FCG) group can be safely managed conservatively, and those in the HR(FCG) group should undergo resection.

Clip-and-line traction method for difficult ERCP cannulation due to choledochocoele.

Video 1Clip-and-line traction method for difficult ERCP cannulation due to choledochocoele.

Successful preoperative diagnosis of heterotopic pancreas in the duodenum.

INTRODUCTION: Heterotopic pancreas (HP) is a relatively rare entity occurring in approximately 5% of the general population. It most commonly presents as an asymptomatic mass incidentally picked up on unrelated scans. HP most commonly occurs intra-abdominally, but has been known to occur in extra-abdominal sites such as the lung and brain. It is widely considered to bear little to no malignant potential. Difficulty and ambiguity in the diagnosis of HP commonly results in interventional dilemma and delay. PRESENTATION OF CASE: We present a case of uncomplicated HP that was ultimately treated conservatively. DISCUSSION: A literature review is made of the typical workup in a patient with suspected HP, and the characteristic radiological and endoscopic findings commonly used for diagnosis of this rare condition. A succinct summary of management guidelines for HP is reviewed. CONCLUSION: HP is most commonly an incidental finding. Ambiguity surrounding its diagnosis commonly gives rise to interventional dilemma and delay. The gold standard for diagnosis remains that of EUS and FNA with histological confirmation. This report has been written in concordance with the SCARE criteria Agha et al. [1].

Systematic review of current prognostication systems for pancreatic neuroendocrine neoplasms.

BACKGROUND: Pancreatic neuroendocrine neoplasms are a heterogenous group of rare tumors whose natural history remains poorly defined. Accurate prognostication of pancreatic neuroendocrine neoplasms is essential for guiding clinical decisions. This paper aims to summarize all the commonly utilized and recently proposed prognostication systems for pancreatic neuroendocrine neoplasms published in the literature to date. METHODS: A systematic review of Pubmed, Scopus, and Embase databases, of the period from January 1, 2000-November 29, 2016, was conducted to identify all published articles reporting on prognostication systems of pancreatic neuroendocrine neoplasms. RESULTS: A total of 23 articles were included in our review, and a total of 25 classification systems were identified. There were 2 modifications of the World Health Organization 2004 criteria, 4 modifications of the World Health Organization 2010 criteria, 2 modifications of the American Joint Committee on Cancer 2010 staging system, 3 modifications of the European Neuroendocrine Tumor Society 2006 tumor, node, metastasis staging system, 7 novel categorial classification systems, and 2 novel proposed continuous classifications. The most commonly included variables included age, size of tumor, presence of distant and lymph node metastases, Ki-67 index, and mitotic count. CONCLUSION: Numerous prognostication systems have been proposed for pancreatic neuroendocrine neoplasms, of which the most commonly used systems presently include the World Health Organization 2010 criteria and the two tumor, node, metastasis staging systems by the European Neuroendocrine Tumor Society and the American Joint Commission on Cancer. However, prognostication systems for pancreatic neuroendocrine neoplasms continue to evolve with time as more prognostication factors are identified. More validation and comparative studies are needed to identify the most effective prognostication system.

Outcomes of an international multicenter registry on EUS-guided gallbladder drainage in patients at high risk for cholecystectomy.

Background and study aims The aim of the current study was to review the outcomes of a large-scale international registry on endoscopic ultrasound-guided gallbladder drainage (EGBD) that encompasses different stent systems in patients who are at high-risk for cholecystectomy. Patients and methods This was a retrospective international multicenter registry on EGBD created by 13 institutions around the world. Consecutive patients who received EGBD for several indications were included. Outcomes include technical and clinical success, unplanned procedural events (UPE), adverse events (AEs), mortality, recurrent cholecystitis and learning curve of the procedure. Results Between June 2011 and November 2017, 379 patients were recruited to the study. Technical and clinical success were achieved in 95.3 % and 90.8 % of the patients, respectively. The 30-day AE rate was 15.3 % and 30-day mortality was 9.2 %. UPEs were significantly more common in patients with EGBD performed for conversion of cholecystostomy and symptomatic gallstones ( P  < 0.001); and by endoscopists with experience of fewer than 25 procedures ( P  = 0.033). Both presence of clinical failure ( P  = 0.014; RR 8.69 95 %CI [1.56 - 48.47]) and endoscopist experience with fewer than 25 procedures ( P  = 0.002; RR 4.68 95 %CI [1.79 - 12.26]) were significant predictors of 30-day AEs. Presence of 30-day AEs was a significant predictor of mortality ( P  < 0.001; RR 103 95 %CI [11.24 - 944.04]). Conclusion EGBD was associated with high success rates in this large-scale study. EGBD performed for indications other than acute cholecystitis was associated with higher UPEs. The number of cases required to gain competency with the technique by experienced interventional endosonographers was 25 procedures.

Validation and comparison between current prognostication systems for pancreatic neuroendocrine neoplasms: A single-institution experience with 176 patients.

BACKGROUND: This article aims to validate and compare the performance of 6 prognostication systems-the World Health Organization 2010 grading criteria, the European Neuroendocrine Tumour Society and the American Joint Committee for Cancer staging systems, the Memorial Sloan Kettering Cancer Center staging and grading systems, as well as the Bilimoria criteria in a cohort of patients with pancreatic neuroendocrine neoplasms at a single institution. METHODS: A retrospective review of 176 patients with histologically proven pancreatic neuroendocrine neoplasm was performed. The prognostic ability of the various prognostication systems for pancreatic neuroendocrine neoplasm was assessed by analyzing the homogeneity, discriminatory ability, monotonicity of gradient, and Akaike information criteria. RESULTS: The 5-year overall survival for the 176 patients was 69% and 5-year recurrence-free survival in 119 patients who underwent curative resection was 78%. Comparison between the 6 prognostication systems demonstrated that the World Health Organization 2010 system had the lowest Akaike information criteria score and was hence the best prognostication system in predicting overall survival and recurrence-free survival rates in our cohort of patients. The European Neuroendocrine Tumour Society was superior to the American Joint Committee for Cancer in prognosticating overall survival rates for pancreatic neuroendocrine neoplasms, as there was a statistically significant difference in overall survival across the different stages when stratified by the European Neuroendocrine Tumour Society, while the use of the American Joint Committee for Cancer was limited to distinguishing between patients in stages I and II versus stages III and IV only. CONCLUSION: All 6 prognostication systems were useful in the prognostication of pancreatic neuroendocrine neoplasm. The World Health Organization 2010 grading system was the best prognostication system in predicting both overall survival in our entire cohort of patients and recurrence-free survival in the subset of patients who underwent curative resection.

Systematic review and meta-analysis of the spectrum and outcomes of different histologic subtypes of noninvasive and invasive intraductal papillary mucinous neoplasms.

BACKGROUND: Our aim was to review the available evidence to determine the clinical importance of the histologic subtypes of noninvasive and invasive intraductal papillary mucinous neoplasms (IPMNs) on disease characteristics and overall survival. METHODS: We reviewed systematically 14 comparative studies that reported clinicopathologic characteristics and survival of 1,617 patients with IPMN (900 noninvasive and 717 invasive). RESULTS: The pancreatobiliary subtype was associated with the greatest likelihood of tumor invasion (67.9%; odds ratio [OR], 2.87; 95% CI, 1.90-4.35), harboring an associated mural nodule (56.6%; OR, 2.92; 95% CI, 1.21-7.04), demonstrating tumor recurrence (46.3%; OR, 3.28; 95% CI, 1.41-7.66) and transformation to tubular adenocarcinoma (81.8%; OR, 92.96; 95% CI, 20.76-416.28) among all subtypes. The gastric subtype was associated with the least likelihood of tumor invasion (10.2%; OR, 0.18; 95% CI, 0.13-0.26), association with main duct IPMN (19.2%; OR, 0.12; 95% CI, 0.06-0.26), and tumor recurrence (9.4%; OR, 0.47; 95% CI, 0.26-0.83) among all subtypes. The intestinal subtype had the greatest likelihood of progressing to colloid carcinoma among all subtypes. Tubular adenocarcinoma was associated with an increased risk of vascular invasion (32.9%; OR, 4.86; 95% CI, 1.96-12.01), perineural invasion (54.5%; OR, 2.30; 95% CI, 1.22-4.34), nodal metastasis (52.4%; OR, 3.31; 95% CI, 1.79-6.14), and a positive margin status (17.3%; OR, 8.45; 95% CI, 1.52-46.83). Tubular adenocarcinoma (hazard ratio [HR], 1.90; 95% CI, 1.36-2.67) had a poorer 5-year overall survival compared with colloid carcinoma and was similar to the survival observed in pancreatic ductal adenocarcinoma (HR, 2.00; 95% CI, 1.59-2.52). CONCLUSION: The prognosis of IPMN depends on its pathologic subtype. Subtype identification should be considered an essential component in future guidelines for the management of IPMN.

Evaluation of the Fukuoka Consensus Guidelines for intraductal papillary mucinous neoplasms of the pancreas: Results from a systematic review of 1,382 surgically resected patients.

BACKGROUND: International consensus guidelines to guide management of intraductal papillary mucinous neoplasms (IPMN) were revised in Fukuoka and published in 2012. However, despite widespread acceptance of the Fukuoka Consensus Guidelines (FCG), the utility of these guidelines have not been well-validated. This systematic review was performed to evaluate the clinical utility of the FCG. DESIGN: A computerized search of the PubMed and Scopus databases was performed to identify all studies evaluating the utility of the FCG in surgically resected IPMN. IPMN were stratified according to the FCG as high risk (HR), worrisome risk (WR), and low risk (LR). HR and WR IPMN were termed FCG+ve and LR IPMN were termed FCG-ve. RESULTS: Seven studies analyzing 1,382 patients were included. There were 402 malignant neoplasms (29%), including 242 invasive IPMNs. There were 1,000 IPMN classified as FCG+ve. The FCG+ve group had a positive predictive value (PPV) ranging from 27 to 62% and the FCG-ve group had negative predictive value ranging from 82 to 100%. Pooled analysis demonstrated that there was 362 of 1,000 (36%) malignant FCG+ve IPMN and 342 of 382 (90%) benign FCG-ve IPMN. PPV of the HR group and the WR groups alone were 104 of 158 (66%) and 75 of 261 (29%), respectively. Forty of 382 (11%), including 22 (6%) invasive FCG-ve IPMN, were malignant. Twenty-six malignant including 18 invasive FCG-ve IPMN were reported from a single study. When the results from this study were excluded, there were only 14 of 241 malignant neoplasms (6%), including 4 of 241 (2%) invasive FCG-ve IPMN in the remaining 6 studies. CONCLUSION: The FCG+ve criteria had a similarly low PPV compared with the 2006 consensus criteria. Stratification of IPMN into HR and WR groups resulted in a higher PPV in the HR group. Some malignant and even invasive IPMN may be missed by the FCG criteria.

Utility of the sendai consensus guidelines for branch-duct intraductal papillary mucinous neoplasms: a systematic review.

INTRODUCTION: The Sendai Consensus Guidelines (SCG) was formulated in 2006 to guide the management of intraductal papillary mucinous neoplasms (IPMN). The main area of controversy is the criteria for selection of branch duct (BD)-IPMN for resection. Although these guidelines have gained widespread acceptance, there is limited data to date supporting its use. This systematic review is performed to evaluate the utility of the Sendai Consensus Guidelines (SCG) for BD-IPMN. METHODS: Studies evaluating the clinical utility of the SCG in surgically resected neoplasms were identified. The SCG were retrospectively applied to all resected neoplasms in these studies. BD-IPMNs which met the criteria for resection were termed SCG+ve and those for surveillance were termed SCG-ve. RESULTS: Twelve studies were included, of which, 9 were suitable for pooled analysis. There were 690 surgically resected BD-IPMNs, of which, 24% were malignant. Five hundred one BD-IPMNs were classified as SCG+ve and 189 were SCG-ve. The positive predictive value (PPV) of SCG+ve neoplasms ranged from 11 to 52% and the NPV of SCG-ve neoplasms ranged from 90 to 100%. Overall, there were 150/501 (29.9%) of malignant BD-IPMNs in the SCG+ve group and 171/189 (90%) of benign BD-IPMNs in the SCG-ve group. Of the 18 reported malignant (11 invasive) BD-IPMNs in the SCG-ve group, 17 (including all 11 invasive) were from a single study. When the results from this single study were excluded, 170/171 (99%) of SCG-ve BD-IPMNs were benign. CONCLUSION: The results of this review confirm the limitations of the SCG for BD-IPMN. The PPV of the SCG in predicting a malignant BD-IPMN was low and some malignant lesions may be missed based on these guidelines.

Evaluation of the Sendai and 2012 International Consensus Guidelines based on cross-sectional imaging findings performed for the initial triage of mucinous cystic lesions of the pancreas: a single institution experience with 114 surgically treated patients.

BACKGROUND: The Sendai Consensus Guidelines (SCG) were formulated in 2006 to guide the management of mucinous cystic lesions of the pancreas (CLPs) and were updated in 2012 (International Consensus Guidelines, ICG 2012). This study aims to evaluate the clinical utility of the ICG 2012 with the SCG based on initial cross-sectional imaging findings. METHODS: One hundred fourteen patients with mucinous CLPs were reviewed and classified according to the ICG 2012 as high risk (HR(ICG2012)), worrisome (W(ICG2012)), and low risk (LR(ICG2012)), and according to the SCG as high risk (HR(SCG)) and low risk (LR(SCG)). RESULTS: On univariate analysis, the presence of symptoms, obstructive jaundice, elevated serum carcinoembryonic antigen (CEA)/carbohydrate antigen (CA)19-9, solid component, main pancreatic duct ≥ 10 mm, and main pancreatic duct ≥ 5 mm was associated with high grade dysplasia/invasive carcinoma in all mucinous CLPs. Increasing number of HR(SCG) or HR(ICG2012) features was associated with a significantly increased likelihood of malignancy. The positive predictive value of HR(SCG) and HR(ICG2012) for high grade dysplasia/invasive carcinoma was 46% and 62.5% respectively. The negative predictive value of both LR(SCG) and LR(ICG2012) was 100%. CONCLUSION: Both the guidelines were useful in the initial cross-sectional imaging evaluation of mucinous CLPs. The ICG 2012 guidelines were superior to the SCG guidelines.