Belgian guidelines for pathology reporting of neuroendocrine neoplasms of the pancreaticobiliary and gastrointestinal tract.

Since neuroendocrine neoplasms are rare tumors, registration of patient data in national and multinational registries is recommended. Indeed, this will facilitate multicenter studies on the epidemiology, efficacy and safety of diagnostic and therapeutic strategies for well-differentiated neuroendocrine tumors as well as for neuroendocrine carcinomas. In Belgium, data on patient and tumor characteristics of all newly diagnosed malignancies have been collected in the Belgian Cancer Registry since 2004 including anonymized full pathological reports. The Digestive Neuroendocrine Tumor (DNET) registry collects information on classification, staging, diagnostic tools and treatment in a prospective national online database. However, the terminology, classification and staging systems of neuroendocrine neoplasms have changed repeatedly over the past 20 years as a result of a better understanding of these rare tumors, by joining forces internationally. These frequent changes make it very difficult to exchange data or perform retrospective analyses. For optimal decision making, for a clear understanding and to allow reclassification according to the latest staging system, several items need to be described in the pathology report. This paper provides an overview of the essential items in reporting neuroendocrine neoplasms of the pancreaticobiliary and gastrointestinal tract.

Expert opinion on management of pancreatic exocrine insufficiency in pancreatic cancer.

Pancreatic exocrine insufficiency (PEI) is a common condition in patients with pancreatic cancer (PC). PEI can be due to the tumor, which, if located in the head, causes obstruction of the pancreatic duct with subsequent atrophy of the pancreatic parenchyma, or it can be the consequence of pancreatic surgical resection. The standard treatment of PEI is pancreatic enzyme replacement therapy (PERT). Clinical data to support the use of PERT in PC are however limited. There are very few randomized clinical trials that evaluated PERT in PC. Most data come from observational studies. Despite this limited clinical evidence, PERT treatment for PEI is an essential part of supportive therapy to ensure optimal nutritional status in PC patients who will receive surgery, neoadjuvant/adjuvant or palliative treatment. The objective of this review is to increase the awareness about PEI in PC patients and to provide expert recommendations on the use of PERT in resected, borderline resectable and unresectable patients, based on clinical experience and literature review.

High performance magnetorheological fluids: very high magnetization FeCo-Fe3O4 nanoclusters in a ferrofluid carrier.

High magnetization Fe3O4/OA-FeCo/Al2O3 nanocomposite magnetic clusters have been obtained using a modified oil-in-water miniemulsion method. These nanocomposite clusters dispersed in a ferrofluid carrier result in a magnetorheological fluid with improved characteristics. The magnetic clusters have a magnetic core consisting of a mixture of magnetite nanoparticles of about 6 nm average size, stabilized with oleic acid (Fe3O4/OA) and FeCo/Al2O3 particles of about 50 nm average size, compactly packed in the form of spherical clusters with a diameter distribution in the range 100-300 nm and a hydrophilic coating of sodium lauryl sulphate surfactant. The surface chemical composition of the Fe3O4/OA-FeCo/Al2O3 clusters investigated by XPS indicates the presence of the Co2+ and Co3+ oxidation states of cobalt and the components of Fe2+ and Fe3+ characteristic to both an enhanced oxidation state at the surface of the FeCo particles and to the presence of magnetic nanoparticles of spinel structure which are decorating the supporting FeCo. This specific decorating morphology is also indicated by TEM images. Advanced characterization of the Fe3O4/OA-FeCo/Al2O3 magnetic clusters has been performed using Mössbauer spectroscopy and magnetization measurements at various temperatures between 6 K and 200 K. The unexpected formation of Co ferrite decorating nanoparticles was supported by Mössbauer spectroscopy. The dispersion of magnetic clusters in the ferrofluid carrier highly influences the flow properties in the absence of the field (shear thinning for low and moderate shear rates) and especially in applied magnetic field, when significant magnetoviscous effect and shear thinning was observed for the whole range of shear rate values. Detailed analysis of the magnetorheological behavior of the nanocomposite magnetic clusters dispersed in a ferrofluid carrier evidence significantly higher normalized dynamic yield stress values in comparison with the magnetite nanocluster suspensions of the same mass concentration, a promising result for this new type of nanocomposite magnetorheological fluid.

Misleading clinical presentation of carcinoid syndrome.

Rare cases of carcinoid syndromes can develop from either gastrointestinal neuroendocrine tumors (NETs) without liver metastasis or large retroperitoneal involvement. We report a case of a patient with isolated flushing highly suggestive of carcinoid syndrome caused by an ileal NET with adjacent lymph node metastases but with no liver metastases. The final diagnose was delayed for this patient due to a combination of misleading clinical presentation and negative usual screening tests (urinary 5-HIAA and serum chromogranine A). Given its high sensitivity and specificity, 68Ga-DOTATATE PET/CT confirmed the diagnosis of neuroendocrine tumor. Therefore, this case reminds clinicians that carcinoid syndrome may manifest as flushing only and highlights that imaging is a major aspect of the evaluation and diagnosis of patients with suspected gastrointestinal NETs.

Lessons learned about appendiceal neuroendocrine neoplasms from data analysis of the Belgian Cancer Registry 2010-2015.

BACKGROUND AND STUDY AIMS: Appendiceal neuroendocrine neo-plasms (aNENs) are a diverse group of malignant neoplasms of varying biological behavior for which information about manage-ment and outcome is sparse, with the majority of available studies being retrospective, including only a limited number of patients, and therefore not necessarily reflecting the reality in the community. In the present study clinical, epidemiological and pathological data of appendiceal neuroendocrine neoplasms in Belgium is provided and compared with current literature. METHODS: A population-based study was conducted by linking data of the Belgian Cancer Registry with medical procedures in the Belgian Health Insurance database for patients diagnosed with aNEN between 2010 and 2015. RESULTS: We found an aNEN incidence of 0.97/100.000 person years in Belgium. Neuroendocrine carcinoma of the appendix are rare. Most appendiceal neuroendocrine tumors (aNETs) are small G1 tumors. Positive lymph nodes are often found in tumors larger than 2cm, especially aNET G2. CONCLUSION: A rapid uptake of changing classifications was seen in the community. However, systematic reporting of risk factors for small aNEN can still be improved and should be stimulated. In 9% of cases, reclassifications had to be made, pointing out that in a retrospective analysis, original pathological reports should be checked for specific parameters, before reliable conclusions can be drawn.

Safety of systemic anti-cancer treatment in oncology patients with non-severe COVID-19: a cohort study.

BACKGROUND: The viral pandemic coronavirus disease 2019 (COVID-19) has disrupted cancer patient management around the world. Most reported data relate to incidence, risk factors, and outcome of severe COVID-19. The safety of systemic anti-cancer therapy in oncology patients with non-severe COVID-19 is an important matter in daily practice. METHODS: ONCOSARS-1 was a single-center, academic observational study. Adult patients with solid tumors treated in the oncology day unit with systemic anti-cancer therapy during the initial phase of the COVID-19 pandemic in Belgium were prospectively included. All patients (n = 363) underwent severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) serological testing after the first peak of the pandemic in Belgium. Additionally, 141 of these patients also had a SARS-CoV-2 RT-PCR test during the pandemic. The main objective was to retrospectively determine the safety of systemic cancer treatment, measured by the rate of adverse events according to the Common Terminology Criteria for Adverse Events, in SARS-CoV-2-positive patients compared with SARS-CoV-2-negative patients. RESULTS: Twenty-two (6%) of the 363 eligible patients were positive for SARS-CoV-2 by RT-PCR and/or serology. Of these, three required transient oxygen supplementation, but none required admission to the intensive care unit. Hematotoxicity was the only adverse event more frequently observed in SARS-CoV-2 -positive patients than in SARS-CoV-2-negative patients: 73% vs 35% (P < 0.001). This association remained significant (odds ratio (OR) 4.1, P = 0.009) even after adjusting for performance status and type of systemic treatment. Hematological adverse events led to more treatment delays for the SARS-CoV-2-positive group: 55% vs 20% (P < 0.001). Median duration of treatment interruption was similar between the two groups: 14 and 11 days, respectively. Febrile neutropenia, infections unrelated to COVID-19, and bleeding events occurred at a low rate in the SARS-CoV-2-positive patients. CONCLUSION: Systemic anti-cancer therapy appeared safe in ambulatory oncology patients treated during the COVID-19 pandemic. There were, however, more treatment delays in the SARS-CoV-2-positive population, mainly due to a higher rate of hematological adverse events.

The "Fonds Georges Brohée": a longstanding Belgian national initiative to stimulate research in hepatogastroenterology.

The Fonds Brohée/Brohée fund was created in 1964 at the initiative of 16 Belgian physicians, in the memory of Georges Brohée, the founder of the Belgian Society of Gastroenterology in 1928 and of its Journal in 1933, first published under the name "Le Journal Belge de Gastro-entérologie", then until today as "Acta Gastro-Enterologica Belgica". The goal of the Fonds is to stimulate research in the field of gastroenterology in Belgium, by awarding a young researcher (< 40 years) for an outstanding work in the clinical, translational or fundamental setting. Since 1966, 26 remarkable works have been awarded in various areas of interest in gastrointestinal diseases, whether in IBD, functional disorders, digestive oncology and, last but not least, hepatology. Since the recognition of their work, many of the awardees have become recognized for their expertise well beyond Belgium. Hopefully, the Foundation will continue to thrive and flourish after 55 years, as the members of its board and its healthy finances will allow to continue to promote and encourage high-quality research by young hepato-gastroenterologists in Belgium.

Current practice in approaching controversial diagnostic and therapeutic topics in gastroenteropancreatic neuroendocrine neoplasm management. Belgian multidisciplinary expert discussion based on a modified Delphi method.

BACKGROUND AND STUDY AIMS: Neuroendocrine neoplasms (NENs) are relatively rare, with marked clinical and biological heterogeneity. Consequently, many controversial areas remain in diagnosis and optimal treatment stratification for NEN patients. We wanted to describe current clinical practice regarding controversial NEN topics and stimulate critical thinking and mutual learning among a Belgian multidisciplinary expert panel. PATIENTS AND METHODS: A 3-round, Delphi method based project, coordinated by a steering committee (SC), was applied to a predefined multidisciplinary NEN expert panel studying the following controversial topics : factors guiding therapeutic decision making, the use of somatostatin analogues (SSA) in adjuvant setting, the interference between non-radioactive and radioactive SSAs, challenging small intestine neuroendocrine tumor (NET) cases, the approach of the carcinoid syndrome, the role of chemotherapy in well differentiated NET, the relevance of NET G3 and neuroendocrine carcinoma subclassification and the role of imaging techniques in NEN management. RESULTS: A high level of consensus exists regarding the necessary diagnostic work-up, use of imaging techniques and interference between non-radioactive and radioactive SSAs. However, the prognostic impact of tumor functionality might be overrated and adequate diarrhea differential diagnostic work-up in these patients is underused. Significant differences are seen between individual experts and centers regarding treatment preferences both on the treatment modality level, as well as the choice of specific drugs (e.g. chemotherapy regimen). CONCLUSIONS: A Delphi-like multi-round expert discussion proves useful to boost critical thinking and discussion among experts of different background, as well as to describe current clinical practice and stimulate mutual learning in the absence of high-level scientific guidance.

Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial.

BACKGROUND: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).

A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial.

Background: Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors (NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET. Patients and methods: Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis. Results: Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64-1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively. Conclusions: The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.

Outcome of hepatitis B and C virus-associated hepatocellular carcinoma occurring after renal transplantation.

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case-control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6 ± 6.5 years (53.5 ± 5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7 ± 2.7 years. Six HCCs were related to HBV, six to HCV and two to co-infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha-fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2 years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.

Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study.

BACKGROUND: In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib. PATIENTS AND METHODS: In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses. RESULTS: Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib. CONCLUSIONS: BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib. TRIAL REGISTRATION NUMBER: NCT00428597.

Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms.

Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC)) are limited. We retrospectively study patients with NET G3 and NEC from eight European centers. Data examined included clinical and pathological characteristics at diagnosis, therapies and outcomes. Two hundred and four patients were analyzed (37 NET G3 and 167 NEC). Median age was 64 (21-89) years. Tumor origin included pancreas (32%) and colon-rectum (27%). The primary tumor was resected in 82 (40%) patients. Metastatic disease was evident at diagnosis in 88% (liver metastases: 67%). Median Ki-67 index was 70% (30% in NET G3 and 80% in NEC; P<0.001). Median overall survival (OS) for all patients was 23 (95% CI: 18-28) months and significantly higher in NET G3 (99 vs 17 months in NEC; HR=8.3; P<0.001). Platinum-etoposide first line chemotherapy was administered in 113 (68%) NEC and 12 (32%) NET G3 patients. Disease control rate and progression free survival (PFS) were significantly higher in NEC compared to NET G3 (P<0.05), whereas OS was significantly longer in NET G3 (P=0.003). Second- and third-line therapies (mainly FOLFIRI and FOLFOX) were given in 79 and 39 of NEC patients; median PFS and OS were 3.0 and 7.6 months respectively after second-line and 2.5 and 6.2 months after third-line chemotherapy. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.

Pancreatic neuroendocrine tumour grading on endoscopic ultrasound-guided fine needle aspiration: high reproducibility and inter-observer agreement of the Ki-67 labelling index.

OBJECTIVES: Assessment of proliferation by the Ki-67 labelling index (Ki67-LI) is an important parameter of pancreatic neuroendocrine tumour (pNET) prognosis on resection specimens. Ki67-LI values for grading are not fully established on endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). The aim of the study was to determine the accuracy of Ki67-LI on EUS-FNA to predict a final grade of pNET and to analyse the relationship between cytological grading and progression-free survival (PFS). METHODS: Between 1996 and 2010, 46 pNETs (33 were resected) from 45 patients were diagnosed by EUS-FNA. Ki67-LI was evaluated on cytological and histological material for each tumour and classified according to the 2010 WHO grading system. RESULTS: A very good inter-observer agreement for Ki67-LI on EUS-FNA and surgical specimens, respectively, were obtained. Discrepancies were observed between histology and cytology, especially in grade 2 (G2) tumours, where cytology underestimated grading owing to tumour heterogeneity. Still, EUS-FNA was able to distinguish a poor prognostic group, as the actuarial PFS of cytological (c) G3 tumours was 10 ± 4 months versus 29 ± 7 and 68 ± 10 for cG2 and cG1 tumours, respectively (P < 0.0001). CONCLUSION: This study attests the reproducibility of Ki67-LI of pNETs whether counted on cytology or histology with a very good inter-observer correlation. Determination of Ki67-LI on EUS-FNA of pNETs should be included systematically in their prognostic work-up.

Severe symptomatic hypomagnesaemia induced by the chronic use of proton pump inhibitors: a case report of a patient with Zollinger-Ellison syndrome.

The association between proton pump inhibitor (PPI) therapy and hypomagnesaemia has been recognized since 2006. We report the case of a 51-year-old woman who developed severe symptomatic hypomagnesaemia after a long-term PPI therapy given for recurrent peptic ulcer disease. Hypomagnesaemia could only partially be resolved during substitution therapy, but was corrected after withdrawal of the PPI. Recurrence of hypomagnesaemia occurred after retreatment with PPIs, supporting the causal relationship. An underlying gastric acid hypersecretion (Zollinger-Ellison syndrome) was highly suspected and eventually controlled by a combination of a histamine 2-receptor antagonist and octreotide, without the need for further PPI therapy after 2 years of follow-up.

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology.

BACKGROUND: Cholangiocarcinomas are uncommon tumours with a poor prognosis, that frequently present epidermal growth factor receptor overexpression. METHODS: In a multi-centre phase II trial, patients with unresectable cholangiocarcinoma, naïve to chemotherapy, received Cetuximab (400 mg/m(2) at week 1, then 250 mg/m(2)/week) and Gemcitabine (1 g/m(2) on day 1, 8 and 15 every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months, using a Simon 2-stage design. Moreover, we assessed the impact of KRAS status and skin toxic effect on efficacy. RESULTS: Forty-four patients (41% locally advanced/59% metastatic) were enrolled. Median age was 61.5 years; ECOG PS was 0 (68%) or 1. Six months PFS reached 47%. Median OS was 13.5 months [95% confidence interval (CI) 9.8-31.8 months]. Nine patients (20.4%) had PR and disease-control rate was 79.5%. Grade 3/4-related toxic effects were haematological (52.2%), skin rash (13.6%) and fatigue (11.4%). KRAS mutations were found in 7 of 27 patients and had no influence on PFS. Skin toxic effect ≥grade 2 was associated with increased PFS (P = 0.05). CONCLUSION(S): Our study met its primary end point, suggesting that Gemcitabine-Cetuximab has activity in cholangiocarcinoma. KRAS status was not associated with PFS, unlike skin toxic effect, which could be used as a surrogate marker for efficacy. ClinicalTrials.gov Identifier: NCT00747097.