Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects

Buparlisib; Combination therapy; Primary human tumoroidsBuparlisib; Terapia de combinación; Tumoroides humanos primariosBuparlisib; Teràpia combinada; Tumoroides humans primarisPancreatic neuroendocrine neoplasms (PanNENs) are the second most common malignancy of the pancreas. Surgery remains the only curative treatment for localized disease. For patients with inoperable advanced or metastatic disease, few targeted therapies are available, but their efficacy is unpredictable and variable. Exploiting prior knowledge on pathogenetic processes involved in PanNEN tumorigenesis, we tested buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor), as single agents or in combination, in different preclinical models. First, we used cell lines representative of well-differentiated (INS-1E, NT-3) and poorly differentiated (BON-1) PanNENs. The combination of buparlisib with ribociclib reduced the proliferation of 2D and 3D spheroid cultures more potently than the individual drugs. Buparlisib, but not ribociclib, induced apoptosis. The anti-proliferative activity of the drugs correlated with downstream target inhibition at mRNA and protein levels. We then tested the drugs on primary islet microtissues from a genetic PanNET animal model (Men1-defective mice) and from wild-type mice: the drug combination was effective against the former without altering islet cell physiology. Finally, we treated PanNET patient-derived islet-like 3D tumoroids: the combination of buparlisib with ribociclib was effective in three out of four samples. Combined targeting of PI3K and CDK4/6 is a promising strategy for PanNENs spanning various molecular and histo-pathological features.This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft-DFG) within the CRC/Transregio 205/2, project number 314061271-TRR 205 (to NSP); and by the Deutsche Krebshilfe (# 70113629 to NSP). Ilaria Marinoni was supported by Wilhelm Sander Stiftung (# 2017.073.2). Aurel Perren was supported by the Swiss Cancer Research Foundation (KFS-4227-08-2017)

Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects

Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common malignancy of the pancreas. Surgery remains the only curative treatment for localized disease. For patients with inoperable advanced or metastatic disease, few targeted therapies are available, but their efficacy is unpredictable and variable. Exploiting prior knowledge on pathogenetic processes involved in PanNEN tumorigenesis, we tested buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor), as single agents or in combination, in different preclinical models. First, we used cell lines representative of well-differentiated (INS-1E, NT-3) and poorly differentiated (BON-1) PanNENs. The combination of buparlisib with ribociclib reduced the proliferation of 2D and 3D spheroid cultures more potently than the individual drugs. Buparlisib, but not ribociclib, induced apoptosis. The anti-proliferative activity of the drugs correlated with downstream target inhibition at mRNA and protein levels. We then tested the drugs on primary islet microtissues from a genetic PanNET animal model (Men1-defective mice) and from wild-type mice: the drug combination was effective against the former without altering islet cell physiology. Finally, we treated PanNET patient-derived islet-like 3D tumoroids: the combination of buparlisib with ribociclib was effective in three out of four samples. Combined targeting of PI3K and CDK4/6 is a promising strategy for PanNENs spanning various molecular and histo-pathological features

Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects.

Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common malignancy of the pancreas. Surgery remains the only curative treatment for localized disease. For patients with inoperable advanced or metastatic disease, few targeted therapies are available, but their efficacy is unpredictable and variable. Exploiting prior knowledge on pathogenetic processes involved in PanNEN tumorigenesis, we tested buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor), as single agents or in combination, in different preclinical models. First, we used cell lines representative of well-differentiated (INS-1E, NT-3) and poorly differentiated (BON-1) PanNENs. The combination of buparlisib with ribociclib reduced the proliferation of 2D and 3D spheroid cultures more potently than the individual drugs. Buparlisib, but not ribociclib, induced apoptosis. The anti-proliferative activity of the drugs correlated with downstream target inhibition at mRNA and protein levels. We then tested the drugs on primary islet microtissues from a genetic PanNET animal model (Men1-defective mice) and from wild-type mice: the drug combination was effective against the former without altering islet cell physiology. Finally, we treated PanNET patient-derived islet-like 3D tumoroids: the combination of buparlisib with ribociclib was effective in three out of four samples. Combined targeting of PI3K and CDK4/6 is a promising strategy for PanNENs spanning various molecular and histo-pathological features

High-resolution manometry is superior to endoscopy and radiology in assessing and grading sliding hiatal hernia: A comparison with surgical in\ua0vivo evaluation

Background: Hiatal hernia is diagnosed by barium-swallow esophagogram or esophagogastroduodenoscopy, with possible suboptimal results. High-resolution manometry clearly identifies crural diaphragm and lower esophageal sphincter. Objectives: To assess the diagnostic accuracy of high-resolution manometry in detecting hiatal hernia compared to esophagogram and esophagogastroduodenoscopy, using as reference the surgical in vivo measurement. Methods: Patients were studied with esophagogram, esophagogastroduodenoscopy, high-resolution manometry and in vivo evaluation of the esophago-gastric junction. Esophago-gastric junction was classified as type I (no separation between crural diaphragm and lower esophageal sphincter); type II ( 651, 64 2 cm separation); type III (>2 cm). During in vivo measurement, distance between the esophago-gastric junction and crural diaphragm proximal border was recorded. Results: Surgery identified 53 hiatal hernias in 100 patients. Forty-seven percent were classified as type I esophago-gastric junction, 35% type II and 18% type III. Referenced to in vivo evaluation, high-resolution manometry showed superior diagnostic sensitivity and specificity (94.3% and 91.5%, respectively) to esophagogram and esophagogastroduodenoscopy, with 92.6% predictive value of a positive test and 93.5% predictive value of a negative test. The kappa value for high-resolution manometry and in vivo evaluation was 0.85. High-resolution manometry showed optimal sensitivity and specificity in detecting types I, II and III esophago-gastric junction. Conclusions: High-resolution manometry enables an accurate diagnosis of hiatal hernia and a better classification than endoscopy and radiology, reaching optimal agreement with in vivo assessment

Barrett's esophagus: surgical treatments.

The following on surgical treatments for Barrett's esophagus includes commentaries on the indications for antireflux surgery after medical treatment; the effects of the various procedures on the lower esophageal sphincter; the role of impaired esophageal motility and delayed gastric emptying in the choice of the surgical procedure; indications for associated highly selective vagotomy, duodenal switch, and gastric electrical stimulation; therapeutic strategies for detection and treatment of shortened esophagus; the role of antireflux surgery on the regression of metaplastic mucosa and the risk of malignant progression; the detection of asymptomatic reflux brfore bariatric surgery; the role of non-GERD symptoms on the results of surgery; and the indications of Collis gastroplasty and choice of the type of fundoplicatio