Ulrich-frank Pape - Academia.edu (original) (raw)

Papers by Ulrich-frank Pape

Research paper thumbnail of PP158-MON Systematic Nutritional Status Assessment, Prevalence of Malnutrition and Clinical Outcome in Patients with Short Bowel Syndrome

Research paper thumbnail of Randomized phase II trial of the carboxylesterase (CES)-converted novel drug EDO-S7.1 in patients (pts) with advanced biliary tract cancers (BTC)

Journal of Clinical Oncology

264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing... more 264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing administration of higher doses, reducing resistance, and permitting treatment of advanced tumors. Methods: The primary objective was to compare disease control rate (DCR) in 22 pts with unresectable BTC randomized 1:1 to 3-week cycles of EDO-S7.1 (200 or 150mg/m2; iv) given on days (d) 1–5, or best supportive care (BSC) until progression (assessed every 4 weeks). Secondary objectives were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. BSC pts could crossover to EDO-S7.1 upon progression. Results: DCR favored EDO-S7.1 (55.6% [CI 21.2, 86.3] vs BSC (20.0% [2.5, 55.6]; treatment difference –12.80, 72.39). More EDO-S7.1 treated pts achieved sustainable stable disease (SD) or partial response (PR) vs BSC. Progressive disease occurred in 40% EDO-S7.1 vs 70% BSC pts. Three pts (30%) who progressed on BSC achieved SD following crossover to ED...

Research paper thumbnail of Efficacy and Safety of CAP7.1 as Second-Line Treatment for Advanced Biliary Tract Cancers: Data from a Randomised Phase II Study

Cancers

CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase ... more CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m2; iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI −18.44, 69.22, full analysis set [FAS]), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio [HR] 0.31; 95%CI 0.11, 0.86; p = 0...

Research paper thumbnail of A review of systemic therapy in biliary tract carcinoma

Journal of Gastrointestinal Oncology

Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surge... more Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surgery, chemotherapy and other treatment modalities have improved, surgery remains the only potential curative treatment and is appropriate for only those few patients who present with localized, resectable disease. However, for the majority of patients, unresectable disease is evident at diagnosis and about 95% of patients die within 10 years, despite the majority receiving chemotherapy. Long-term survival is significantly greater for patients with resected BTC compared to those with unresectable disease. In unresected disease, life expectancy is limited, with first-line gemcitabine/cisplatin (GEM/CIS) accepted as standard of care. Currently no standard second-line regimen which provides significant improvement of clinical outcomes exists for those who present with refractory disease or who relapse after first-line treatment. Of particular importance is establishing the impact of best supportive care (BSC) as a benchmark for survival outcomes to which the impact of treatment modalities can be compared. Survival outcome often differs significantly for patients with different prognostic factor profiles even when receiving the same therapy so that it can be difficult to predict which patient subgroup might benefit most from which therapy. Therefore, the influence of prognostic factors on survival under different therapies as well as under BSC needs to be further assessed in order to arrive at truly evidence-based, best therapeutic decisions for individual patients. Encouraging new research into the genomic landscape of BTC may help to further subdivide the BTC population into molecular-genetic clusters likely to be sensitive to different targeted therapy approaches leading to further improvements in survival. Consequently, an unmet need exists not only to develop new and more effective therapies for this devastating disease, but also to integrate original research findings into a more complex, dynamic, individualized therapeutic decision model to aid clinicians in making evidence-based, best therapeutic decisions for individual patients.

Research paper thumbnail of De Novo Development of Distal Jejunal and Duodenal Adenomas After 41 Months of Teduglutide Treatment in a Patient With Short‐Bowel Syndrome: A Case Report

Journal of Parenteral and Enteral Nutrition

Research paper thumbnail of Oral intake and plasma citrulline predict quality of life in patients with intestinal failure

Research paper thumbnail of Efficacy and Toxicity of 5-Fluorouracil–Oxaliplatin in Gastroenteropancreatic Neuroendocrine Neoplasms

Research paper thumbnail of Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry

Langenbeck's Archives of Surgery

Research paper thumbnail of Assessing Non-Invasive Liver Function in Patients with Intestinal Failure Receiving Total Parenteral Nutrition—Results from the Prospective PNLiver Trial

Nutrients

Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can p... more Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB–4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group...

Research paper thumbnail of Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials

Therapeutic Advances in Gastroenterology

Background: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a cons... more Background: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome–associated intestinal failure (SBS–IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. Methods: Safety data from four prospective clinical trials of teduglutide in patients with SBS–IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. Results: Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were repor...

Research paper thumbnail of Prognostic relevance of circulating PIGF levels in patients with neuroendocrine tumors

Journal of Clinical Oncology

4128 Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis ... more 4128 Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. As antiangiogenic treatments are introduced in the management of neuroendocrine tumors (NETs), we addressed the expression and function of PlGF in NETs. Methods: Serum levels of PlGF were determined in two independent cohorts of NET patients collected retrospectively and prospectively (n=87 and n=84) using Roche Elecsys and correlated with clinical data. Expression of PlGF in tumors was evaluated by immunohistochemistry. PlGF effects on proliferation and migration were examined in vitro using NET cell lines. Results: Circulating and tumoral PlGF were found elevated in NET patients as compared to control sera and pancreatic tissues in a retrospective analysis restricted to patients with pancreatic NETs (pNETs). De novo expression of PlGF occurred primarily in the tumor stroma, suggesting paracrine s...

Research paper thumbnail of A meta-analysis of the accuracy of a neuroendocrine tumor mRNA biomarker (NETest) in the blood

Journal of Clinical Oncology

606 Background: There is no accurate blood biomarker of neuroendocrine tumor (NET) disease. The i... more 606 Background: There is no accurate blood biomarker of neuroendocrine tumor (NET) disease. The inability to effectively assess disease in real-time has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy – liquid biopsy – to facilitate management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD) to assess clinical utility. Methods: A systematic review of the literature using PRISMA guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified 10 original scientific papers, which met inclusion criteria. These were assessed by qualitative analysis, and thereafter meta-analysis. Data were pooled and median (95% CI) diagnostic odds ratio (DOR), positive likelihood ratio (+LR) and negative likelihood ratio (–LR) calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and AUC d...

Research paper thumbnail of Assessing prognosis of neuroendocrine neoplasms: Results of a collaborative multinational effort including over 10.000 european patients—The ENETS registry

Journal of Clinical Oncology

Research paper thumbnail of Peritoneal carcinomatosis in gastro-entero-pancreatic neuroendocrine neoplasms: clinical impact and effectiveness of the available therapeutic options

Neuroendocrinology

Background: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro... more Background: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Peritoneal disease control by medical therapies in these patients has been poorly investigated Objectives: To describe, in a consecutive series of GEP-NENs, the clinical impact of PC and to report the effectiveness of available treatments in PC control. Methods: A retrospective, monocenter analysis was performed of 135 GEP-NENs (1993–2016) with at least a 12-month follow-up. Peritoneal disease progression was defined as detection of a significant increase in size or appearance of new implants by imaging. Results: A total of 62.9% of cases had diffuse PC (involving at least 2 abdominal quadrants). According to WHO 2017 classification, cases were 42.3% neuroendocrine tumors NET-G1, 45.5% NET-G2, 6.5% NET-G3, 4.9% neuroendocrine carcinomas NEC-G3, and 0.8% mixed neuroendocrine-nonneuroendocrine neoplasms. Bowel obstruction occurred in ...

Research paper thumbnail of Intestinale Rehabilitation bei Kurzdarmsyndrom und chronischem Darmversagen

DMW - Deutsche Medizinische Wochenschrift

Was ist neu? Anatomische und funktionelle Klassifikation Das chronische Darmversagen (CVD) bei Ku... more Was ist neu? Anatomische und funktionelle Klassifikation Das chronische Darmversagen (CVD) bei Kurzdarmsyndrom (KDS) wird sowohl durch die postoperative Anatomie als auch funktionell anhand des parenteralen Kalorien- und Volumenbedarfs klassifiziert. Spontane intestinale Adaptation Die postoperative Anpassungsreaktion nach Darmresektion verläuft in 3 Phasen, die jeweils eines interdisziplinären Managements bedürfen. Therapie des chronischen Darmversagens bei Kurzdarmsyndrom Ziel der Therapie ist eine ausreichende Kalorien- und Nährstoffversorgung unter Vermeidung einer Hyperalimentation bzw. die Linderung/Beherrschung der Diarrhöen. Chirurgische Maßnahmen einschließlich Transplantation Die chirurgische Wiederherstellung der Kontinuität ausgeschalteter Darmabschnitte ist unverzichtbar. Es bestehen prinzipiell verschiedene Optionen der Transplantation, der Nachweis für eine Verbesserung der Gesamtprognose steht allerdings noch aus. Funktionelle intestinale Rehabilitation durch GLP-2-A...

Research paper thumbnail of Gastric neuroendocrine neoplasias: manifestations and comparative outcomes

Endocrine-Related Cancer

Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is risin... more Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analyzed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification were: gNEN-1 (n=86/60.6%), gNEN-2 (n=7/4.9%) gNEN-3 (n= 24/16.9%) and gNEN-4 (n=25/17.6%); while hypergastrinemia-associated gNEN-1 and -2 were all low grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system....

Research paper thumbnail of Determinants of Quality of Life in Patients With Intestinal Failure Receiving Long-Term Parenteral Nutrition Using the SF-36 Questionnaire: A German Single-Center Prospective Observational Study

Journal of Parenteral and Enteral Nutrition

Research paper thumbnail of Unmet Needs in Appendiceal Neuroendocrine Neoplasms

Neuroendocrinology, Jan 20, 2018

Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendice... more Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course, thus appendicectomy alone is considered as curative. However in some cases a malignant potential is suspected and therefore additional operations, such as completion right hemicolectomy, are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide quite useful data about epidemiology and prognosis, as well as, practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, those guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, and identified risk factors, which would indicate a more aggressive surgical approach at the beginn...

Research paper thumbnail of Competitive Testing the Who 2010 vs the Who 2017 Grading of Pancreas Neuroendocrine Neoplasia: Data from a Large International Cohort Study

Neuroendocrinology, Jan 9, 2018

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) mo... more Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a threetier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

Research paper thumbnail of A score derived from routine biochemical parameters increases the diagnostic accuracy of chromogranin A in detecting patients with neuroendocrine neoplasms

Endocrine, 2018

Chromogranin A (CgA) is a valuable biomarker for detection and follow-up of patients with neuroen... more Chromogranin A (CgA) is a valuable biomarker for detection and follow-up of patients with neuroendocrine neoplasms (NENs). However, various comorbidities may influence serum CgA, which decreases its diagnostic accuracy. We aimed to investigate which laboratory parameters are independently associated with increased CgA in real-life setting and to develop a scoring system, which could improve the diagnostic accuracy of CgA in detecting patients with NENs. This retrospective study included 55 treatment naïve patients with NENs and160 patients with various comorbidities but without NEN (nonNENs). Scoring system (CgA-score) was developed based on z-scores obtained from receiver operating curve analysis for each parameter that was associated with elevated serum CgA in nonNENs. CgA correlated positively with serum BUN, creatinine, α2-globulin, red-cell distribution width, erythrocyte sedimentation rate, plasma glucose and correlated inversely with hemoglobin, thrombocytes and serum albumin...

Research paper thumbnail of PP158-MON Systematic Nutritional Status Assessment, Prevalence of Malnutrition and Clinical Outcome in Patients with Short Bowel Syndrome

Research paper thumbnail of Randomized phase II trial of the carboxylesterase (CES)-converted novel drug EDO-S7.1 in patients (pts) with advanced biliary tract cancers (BTC)

Journal of Clinical Oncology

264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing... more 264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing administration of higher doses, reducing resistance, and permitting treatment of advanced tumors. Methods: The primary objective was to compare disease control rate (DCR) in 22 pts with unresectable BTC randomized 1:1 to 3-week cycles of EDO-S7.1 (200 or 150mg/m2; iv) given on days (d) 1–5, or best supportive care (BSC) until progression (assessed every 4 weeks). Secondary objectives were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. BSC pts could crossover to EDO-S7.1 upon progression. Results: DCR favored EDO-S7.1 (55.6% [CI 21.2, 86.3] vs BSC (20.0% [2.5, 55.6]; treatment difference –12.80, 72.39). More EDO-S7.1 treated pts achieved sustainable stable disease (SD) or partial response (PR) vs BSC. Progressive disease occurred in 40% EDO-S7.1 vs 70% BSC pts. Three pts (30%) who progressed on BSC achieved SD following crossover to ED...

Research paper thumbnail of Efficacy and Safety of CAP7.1 as Second-Line Treatment for Advanced Biliary Tract Cancers: Data from a Randomised Phase II Study

Cancers

CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase ... more CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m2; iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI −18.44, 69.22, full analysis set [FAS]), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio [HR] 0.31; 95%CI 0.11, 0.86; p = 0...

Research paper thumbnail of A review of systemic therapy in biliary tract carcinoma

Journal of Gastrointestinal Oncology

Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surge... more Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surgery, chemotherapy and other treatment modalities have improved, surgery remains the only potential curative treatment and is appropriate for only those few patients who present with localized, resectable disease. However, for the majority of patients, unresectable disease is evident at diagnosis and about 95% of patients die within 10 years, despite the majority receiving chemotherapy. Long-term survival is significantly greater for patients with resected BTC compared to those with unresectable disease. In unresected disease, life expectancy is limited, with first-line gemcitabine/cisplatin (GEM/CIS) accepted as standard of care. Currently no standard second-line regimen which provides significant improvement of clinical outcomes exists for those who present with refractory disease or who relapse after first-line treatment. Of particular importance is establishing the impact of best supportive care (BSC) as a benchmark for survival outcomes to which the impact of treatment modalities can be compared. Survival outcome often differs significantly for patients with different prognostic factor profiles even when receiving the same therapy so that it can be difficult to predict which patient subgroup might benefit most from which therapy. Therefore, the influence of prognostic factors on survival under different therapies as well as under BSC needs to be further assessed in order to arrive at truly evidence-based, best therapeutic decisions for individual patients. Encouraging new research into the genomic landscape of BTC may help to further subdivide the BTC population into molecular-genetic clusters likely to be sensitive to different targeted therapy approaches leading to further improvements in survival. Consequently, an unmet need exists not only to develop new and more effective therapies for this devastating disease, but also to integrate original research findings into a more complex, dynamic, individualized therapeutic decision model to aid clinicians in making evidence-based, best therapeutic decisions for individual patients.

Research paper thumbnail of De Novo Development of Distal Jejunal and Duodenal Adenomas After 41 Months of Teduglutide Treatment in a Patient With Short‐Bowel Syndrome: A Case Report

Journal of Parenteral and Enteral Nutrition

Research paper thumbnail of Oral intake and plasma citrulline predict quality of life in patients with intestinal failure

Research paper thumbnail of Efficacy and Toxicity of 5-Fluorouracil–Oxaliplatin in Gastroenteropancreatic Neuroendocrine Neoplasms

Research paper thumbnail of Long-term outcome of surgical resection in patients with gastroenteropancreatic neuroendocrine neoplasia: results from a German nation-wide multi-centric registry

Langenbeck's Archives of Surgery

Research paper thumbnail of Assessing Non-Invasive Liver Function in Patients with Intestinal Failure Receiving Total Parenteral Nutrition—Results from the Prospective PNLiver Trial

Nutrients

Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can p... more Liver abnormalities in intestinal failure (IF) patients receiving parenteral nutrition (PN) can progress undetected by standard laboratory tests to intestinal failure associated liver disease (IFALD). The aim of this longitudinal study is to evaluate the ability of non-invasive liver function tests to assess liver function following the initiation of PN. Twenty adult patients with IF were prospectively included at PN initiation and received scheduled follow-up assessments after 6, 12, and 24 months between 2014 and 2019. Each visit included liver assessment (LiMAx [Liver Maximum Capacity] test, ICG [indocyanine green] test, FibroScan), laboratory tests (standard laboratory test, NAFLD [non-alcoholic fatty liver disease] score, FIB–4 [fibrosis-4] score), nutritional status (bioelectrical impedance analysis, indirect calorimetry), and quality of life assessment. The patients were categorized post-hoc based on their continuous need for PN into a reduced parenteral nutrition (RPN) group...

Research paper thumbnail of Teduglutide for the treatment of adults with intestinal failure associated with short bowel syndrome: pooled safety data from four clinical trials

Therapeutic Advances in Gastroenterology

Background: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a cons... more Background: In multiple clinical studies, teduglutide reduced parenteral support (PS) with a consistent safety profile in adults with short bowel syndrome–associated intestinal failure (SBS–IF). The objective of this study was to assess adverse events (AEs) from a pooled data set. Methods: Safety data from four prospective clinical trials of teduglutide in patients with SBS–IF were assimilated. AEs were evaluated in patient groups based on treatment received in each study and in populations stratified to create distinct subgroups based on aetiology, bowel anatomy and baseline PS volume requirements. Results: Safety data are reported for up to 2.5 years, totalling 222 person-years exposure to teduglutide. In most patients, AEs were reported as mild or moderate in severity in all patient groups and occurred at comparable rates between patients who received teduglutide or placebo. Several common gastrointestinal AEs, including abdominal pain, nausea and abdominal distension, were repor...

Research paper thumbnail of Prognostic relevance of circulating PIGF levels in patients with neuroendocrine tumors

Journal of Clinical Oncology

4128 Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis ... more 4128 Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. As antiangiogenic treatments are introduced in the management of neuroendocrine tumors (NETs), we addressed the expression and function of PlGF in NETs. Methods: Serum levels of PlGF were determined in two independent cohorts of NET patients collected retrospectively and prospectively (n=87 and n=84) using Roche Elecsys and correlated with clinical data. Expression of PlGF in tumors was evaluated by immunohistochemistry. PlGF effects on proliferation and migration were examined in vitro using NET cell lines. Results: Circulating and tumoral PlGF were found elevated in NET patients as compared to control sera and pancreatic tissues in a retrospective analysis restricted to patients with pancreatic NETs (pNETs). De novo expression of PlGF occurred primarily in the tumor stroma, suggesting paracrine s...

Research paper thumbnail of A meta-analysis of the accuracy of a neuroendocrine tumor mRNA biomarker (NETest) in the blood

Journal of Clinical Oncology

606 Background: There is no accurate blood biomarker of neuroendocrine tumor (NET) disease. The i... more 606 Background: There is no accurate blood biomarker of neuroendocrine tumor (NET) disease. The inability to effectively assess disease in real-time has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy – liquid biopsy – to facilitate management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD) to assess clinical utility. Methods: A systematic review of the literature using PRISMA guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified 10 original scientific papers, which met inclusion criteria. These were assessed by qualitative analysis, and thereafter meta-analysis. Data were pooled and median (95% CI) diagnostic odds ratio (DOR), positive likelihood ratio (+LR) and negative likelihood ratio (–LR) calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and AUC d...

Research paper thumbnail of Assessing prognosis of neuroendocrine neoplasms: Results of a collaborative multinational effort including over 10.000 european patients—The ENETS registry

Journal of Clinical Oncology

Research paper thumbnail of Peritoneal carcinomatosis in gastro-entero-pancreatic neuroendocrine neoplasms: clinical impact and effectiveness of the available therapeutic options

Neuroendocrinology

Background: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro... more Background: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Peritoneal disease control by medical therapies in these patients has been poorly investigated Objectives: To describe, in a consecutive series of GEP-NENs, the clinical impact of PC and to report the effectiveness of available treatments in PC control. Methods: A retrospective, monocenter analysis was performed of 135 GEP-NENs (1993–2016) with at least a 12-month follow-up. Peritoneal disease progression was defined as detection of a significant increase in size or appearance of new implants by imaging. Results: A total of 62.9% of cases had diffuse PC (involving at least 2 abdominal quadrants). According to WHO 2017 classification, cases were 42.3% neuroendocrine tumors NET-G1, 45.5% NET-G2, 6.5% NET-G3, 4.9% neuroendocrine carcinomas NEC-G3, and 0.8% mixed neuroendocrine-nonneuroendocrine neoplasms. Bowel obstruction occurred in ...

Research paper thumbnail of Intestinale Rehabilitation bei Kurzdarmsyndrom und chronischem Darmversagen

DMW - Deutsche Medizinische Wochenschrift

Was ist neu? Anatomische und funktionelle Klassifikation Das chronische Darmversagen (CVD) bei Ku... more Was ist neu? Anatomische und funktionelle Klassifikation Das chronische Darmversagen (CVD) bei Kurzdarmsyndrom (KDS) wird sowohl durch die postoperative Anatomie als auch funktionell anhand des parenteralen Kalorien- und Volumenbedarfs klassifiziert. Spontane intestinale Adaptation Die postoperative Anpassungsreaktion nach Darmresektion verläuft in 3 Phasen, die jeweils eines interdisziplinären Managements bedürfen. Therapie des chronischen Darmversagens bei Kurzdarmsyndrom Ziel der Therapie ist eine ausreichende Kalorien- und Nährstoffversorgung unter Vermeidung einer Hyperalimentation bzw. die Linderung/Beherrschung der Diarrhöen. Chirurgische Maßnahmen einschließlich Transplantation Die chirurgische Wiederherstellung der Kontinuität ausgeschalteter Darmabschnitte ist unverzichtbar. Es bestehen prinzipiell verschiedene Optionen der Transplantation, der Nachweis für eine Verbesserung der Gesamtprognose steht allerdings noch aus. Funktionelle intestinale Rehabilitation durch GLP-2-A...

Research paper thumbnail of Gastric neuroendocrine neoplasias: manifestations and comparative outcomes

Endocrine-Related Cancer

Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is risin... more Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analyzed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification were: gNEN-1 (n=86/60.6%), gNEN-2 (n=7/4.9%) gNEN-3 (n= 24/16.9%) and gNEN-4 (n=25/17.6%); while hypergastrinemia-associated gNEN-1 and -2 were all low grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system....

Research paper thumbnail of Determinants of Quality of Life in Patients With Intestinal Failure Receiving Long-Term Parenteral Nutrition Using the SF-36 Questionnaire: A German Single-Center Prospective Observational Study

Journal of Parenteral and Enteral Nutrition

Research paper thumbnail of Unmet Needs in Appendiceal Neuroendocrine Neoplasms

Neuroendocrinology, Jan 20, 2018

Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendice... more Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course, thus appendicectomy alone is considered as curative. However in some cases a malignant potential is suspected and therefore additional operations, such as completion right hemicolectomy, are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide quite useful data about epidemiology and prognosis, as well as, practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, those guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, and identified risk factors, which would indicate a more aggressive surgical approach at the beginn...

Research paper thumbnail of Competitive Testing the Who 2010 vs the Who 2017 Grading of Pancreas Neuroendocrine Neoplasia: Data from a Large International Cohort Study

Neuroendocrinology, Jan 9, 2018

Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) mo... more Background: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a threetier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). Objectives: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. Method: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. Results: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. Conclusions: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

Research paper thumbnail of A score derived from routine biochemical parameters increases the diagnostic accuracy of chromogranin A in detecting patients with neuroendocrine neoplasms

Endocrine, 2018

Chromogranin A (CgA) is a valuable biomarker for detection and follow-up of patients with neuroen... more Chromogranin A (CgA) is a valuable biomarker for detection and follow-up of patients with neuroendocrine neoplasms (NENs). However, various comorbidities may influence serum CgA, which decreases its diagnostic accuracy. We aimed to investigate which laboratory parameters are independently associated with increased CgA in real-life setting and to develop a scoring system, which could improve the diagnostic accuracy of CgA in detecting patients with NENs. This retrospective study included 55 treatment naïve patients with NENs and160 patients with various comorbidities but without NEN (nonNENs). Scoring system (CgA-score) was developed based on z-scores obtained from receiver operating curve analysis for each parameter that was associated with elevated serum CgA in nonNENs. CgA correlated positively with serum BUN, creatinine, α2-globulin, red-cell distribution width, erythrocyte sedimentation rate, plasma glucose and correlated inversely with hemoglobin, thrombocytes and serum albumin...