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Gastrointestinal Hormones Stimulate Growth of a Foregut Net Tumor by Transactivating the EGF Receptor
AGA Abstracts
to stimulate growth, using both an MTT assay and a [3H]-thymidine incorporation. Neurotensin (NT) (1μΜ), PACAP (1μM) and a Bombesin-related agonist (Bn-analogue, 1μM), in addition to EGF (16nM) and TGFα (3.2nM), stimulated the growth, while galanin (1μM) and bradykinin (1μM) did not. The EGFR tyrosine kinase inhibitor, AG1478 (1μM) strongly inhibited EGF and the GI hormones stimulated cell growth, in both growth assays. Western Blot demonstrated EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation, which is known to correlate with EGFR activation. Both NT and Bn-analogue caused a time-dependent increase in EGFR phosphorylation. With the Bn-analogue, a t1/2 =12 minutes and a maximum 3.4-fold increase at 62 minutes was followed by rapid decrease. In contrast, EGF rapidly stimulated Tyr1068 EGFR phosphorylation, reaching a peak by 3 minutes, with a rapid decrease. AG1478 (1μM) strongly inhibited EGF stimulated Tyr1068 EGFR phosphorylation, as well as inhibiting stimulation by both NT (81%) and Bn-analogue (98%). Conclusions: GI hormones, NT and Bn-analogue, stimulated proliferation of foregut NET tumor cells, is largely dependent on transactivation of the EGFR. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists, may be a novel therapeutic approach for NETs treatments, as it has been with a number of other tumors (lung cancer, head-neck tumors).
a composite gastric image formed by the sum of all acquired frames. Images were subsequently counted and “activity versus time” curves were obtained for each region and thereafter normalized, filtered and processed with spectral analysis by Fast Fourier Transform in order to obtain the dominant frequency. Curves from the three ROI were also plotted together, so as to allow the measurement with a cursor of the time lag for any individual wave to propagate from the proximal to the middle region, and from the middle to the distal antral region. Results - There were no significant differences between any antral region, for any acquisition time or test meal, concerning dominant frequency of antral contractions, which varied little (median and range from pooled data: 0.05 Hz; 0.02-0.06 Hz). There were no significant differences between liquid and solid meals concerning the lag time for antral contraction waves to progress from the proximal to the middle antral region, neither during initial (5 s; 2-8 s versus 6 s; 2-8 s) nor late (5 s; 2-6 s vs. 5 s; 2-9 s) gastric emptying. Also, there were no significant differences between meals concerning the lag time for antral contraction waves to migrate from the middle to the distal region, neither at initial (5 s; 29 s vs. 5 s; 2-8 s) nor late gastric emptying (5 s; 2-8 s vs. 5 s; 2-8 s). Conclusions Progression of post-prandial contractions throughout the human gastric antrum follows a rather regular pattern during gastric emptying and do not seem to be influenced by meal consistency nor time after meal ingestion. Financial support: Brazilian agencies CNPq and FAPESP.
Tu2018 Tu2016 Long-Term Clinical Outcome of Gastric MALT Lymphoma After Eradication of Helicobacter pylori: A Multicenter Retrospective Follow-up Study of 423 Patients in Japan Shotaro Nakamura, Katsunori Iijima, Shouko Ono, Masahiro Tajika, Akira Tari, Yasuhiko Kitadai, Hiroshi Matsumoto, Tadanobu Nagaya, Toshiro Kamoshida, Norihiko Watanabe, Toshimi Chiba, Takayuki Matsumoto, Hideki Origasa, Masahiro Asaka, Toshiro Sugiyama
The Effect of Bolus Consistency and Position Change on the Coordination of Peristaltic Contractions in Healthy Volunteers Rami Sweis, Angela Anggiansah, Terry Wong, Mark R. Fox Background and aims: Previous studies show that esophageal contractile pressure increases with workload (e.g. swallowing solids vs. liquids); however mechanistic studies show that effective esophageal clearance depends more on effective coordination between proximal and distal peristaltic contractions at the proximal transition zone (PTZ) than contractile pressure per se. This study aimed to assess the effects of bolus consistency and position change on esophageal coordination as assessed by the PTZ physiology in asymptomatic volunteers using high resolution manometry (HRM). Methods 23 healthy volunteers (11M:12F, age 20-56) underwent HRM (Manoscan 360°, SSI) with 10x5ml water and 21 with 5x1cc bread swallows in the upright seated and supine positions. Measurements of PTZ mean pressure and length defined by 30mmHg isocontour were recorded. The length of the proximal contraction (lower border of upper esophageal sphincter to start of PTZ) and distal contraction (end of PTZ to upper border of the lower esophageal sphincter) defined by 30mmHg isocontour and normalized to esophageal length(%) were calculated. Results are presented as median and inter-quartile ratio. Wilcoxon test was used for nonparametric quantitative group comparisons with Bonferroni correction to correct for multiple comparisons. Results Results are summarized in the table. PTZ mean pressure increased from liquid to solid in the upright (12.3(8.3,17.8) vs. 20.3(12.9,29.5)mmHg; p<0.001) and supine (15.1(10.9,25.1) vs. 34.0 (19.1,51.3)mmHg; p<0.001) positions. PTZ length decreased from liquid to solid in the upright (3.2(1.9,7.4) vs. 0.5(0,2.5)cm; p<0.001) and supine (2.9(1.1,4.5) vs. (0.0(0.0,2.3)cm; p=0.002) positions. These effects remained significant when corrected for esophageal length. Proximal contraction length was not affected by changes in viscosity (p=NS) or position (p=NS); however distal peristaltic contraction length increased with bolus consistency in the upright (p=0.004) and supine (p=0.016) positions, and on moving from upright to supine position for liquid (p<0.001) and solid (p=0.013) respectively) Conclusion: Increased bolus consistency and body position change both increase the coordination of peristaltic contraction in healthy volunteers. This effect is achieved by promoting contractility in the distal segment. The presence of an effective esophageal response to ‘physiologic challenge’ may increase specificity of manometric studies and provide a useful test of the esophagus' ability to adapt to increased workload (e.g. after fundoplication). PTZ parameters with change in bolus viscosity and position
Background: While eradication of Helicobacter pylori has been recognized as the first-line treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the long-term outcomes of the disease after the H. pylori eradication remain obscure. We conducted a multicenter retrospective study of a large number of patients with gastric MALT lymphoma treated by H. pylori eradication. Methods: A total of 423 patients with gastric MALT lymphoma were registered from 21 participating institutes in Japan. Inclusion criteria were patients with established diagnosis of gastric low-grade MALT lymphoma without any component of diffuse large B-cell lymphoma (DLBCL), who initially underwent H. pylori eradication therapy with a proton-pump inhibitor plus antibiotics (amoxicillin, clarithromycin, and/or metronidazole) and were followed-up for at least 3 years. Responders to the therapy were defined as patients whose post-treatment biopsies showed complete histological remission (CR) or probable minimal residual disease (pMRD), as determined by GELA histological grading system (Copie-Bergman, Gut 2003). Treatment failure was defined as the status of progressive disease (PD) or recurrence after CR/pMRD. Results: After eradication therapy, CR/pMRD was achieved in 325 patients (77%). A logistic regression analysis revealed that absence of H. pylori, deep submucosal invasion as determined by EUS, and t(11;18)/ API2-MALT1 were independent predictors for resistance to H. pylori eradication. During the follow-up periods from 3 to 14.6 years (median 6.1 years), the disease recurred in 11 of 325 patients (3.4%) with CR/pMRD, while PD was found in 26 of 98 patients (27%) not responding to H. pylori eradication. Thus, 37 of 423 patients (8.7%) were regarded as treatment failure. Among those 37 patients, transformation into DLBCL was found in 9 patients (2 patients with CR/pMRD, and 7 without CR/pMRD). The treatment failure-free probabilities after 5 and 10 years were 92% and 90%, respectively. Second-line treatment was performed in 90 patients. The treatments applied were radiotherapy for 50 patients, chemotherapy with or without rituximab for 28, chemoradiotherapy for 4, surgical resection for 5 and endoscopic resection for 1. Fourteen patients died (2 died of lymphoma), while 409 patients were alive. The probabilities of overall and event-free survivals after 10 years were 95% and 86%, respectively. Cox multivariate analysis revealed induction of CR/pMRD by H. pylori eradication to be an independent prognostic factor for overall and event-free survivals. Conclusions: H. pylori eradication is an optimal first-line therapy for early-stage gastric MALT lymphoma, and the excellent long-term clinical outcome was confirmed by the follow-up study ranging from 3 to 14.6 years (median 6.1 years). Tu2019 Utility of Progression-Free Survival (PFS) as a Primary Endpoint in Clinical Studies of Advanced Neuroendocrine Tumors (NET) Simron Singh, Calvin H. Law Introduction: Overall survival (OS) is an established endpoint in oncology clinical studies, but can be challenging to assess. OS evaluation requires a long follow-up time and large patient population to detect treatment differences, which can be confounded by crossover design or subsequent therapies. Dependence on OS may delay development and availability of new agents for rare malignancies, such as neuroendocrine tumors (NET). We examined progression-free survival (PFS) or time to progression (TTP), OS, and RR as endpoints in NET clinical trials and compared with disease progression definitions used in clinical practice. Methods: A 20-year literature review of published clinical data was done to assess efficacy endpoints in NET trials. Practicing physicians were also surveyed on their definitions of disease progression. Results: Three large NET clinical trials with encouraging PFS results have been recently published. In PROMID, TTP was significantly longer with octreotide LAR treatment (14.3 mo vs 6.0 mo) in patients (pts) with advanced NET; median OS was not reached and RR was 2% in both arms. In the RADIANT-1 trial of everolimus ± octreotide LAR in patients with advanced pNET who had previously progressed on or after chemotherapy, median PFS was 9.7-16.7 months and RRs were 4-10%; median OS was reached in only one stratum. In a phase 2 sunitinib trial, PFS was 7.7 and 10.2 months and RR was 2% and 17% in patients with GI/lung NET and pNET, respectively. These results support the use of PFS as a relevant endpoint for treatment success in patients with NET. Likewise, a survey of 502 US and EU practicing physicians reported that PFS had the most influence on their treatment decisions and that symptomatic change was also a major consideration in defining disease progression in their practices. Conclusions: PFS appears to be a viable, promising endpoint in NET studies when OS is difficult to obtain. Preliminary survey of
*break in contractile pressure front at 30mmHg isocontour Tu2017 Gastrointestinal Hormones Stimulate Growth of a Foregut Net Tumor by Transactivating the EGF Receptor Alessia Di Florio, Veronica Sancho, Gianfranco Delle Fave, Robert T. Jensen Background: Foregut Neuroendocrine Tumors [NETs] (carcinoids, pancreatic endocrine tumors [PETs]) usually pursuit a benign course but, a subset shows aggressive behavior. At present, the treatment of patients with advanced NETs is marginally effective and new approaches are needed. Recent studies show in other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate cell growth, which has led to new treatments. Such a mechanism may be important for NET growth because studies show a direct correlation between NET malignancy and EGFR expression and GI hormones can act as autocrine growth factors, for some NETs. Aim: To determine if GI hormones can stimulate foregut NET growth by inducing transactivation of EGFR. Methods and Results: BON cells [derived from a pancreatic NET], which are known to express EGFR, were examined for the ability of EGF, TGFα and various GI hormones
AGA Abstracts
S-872
to stimulate growth, using both an MTT assay and a [3H]-thymidine incorporation. Neurotensin (NT) (1μΜ), PACAP (1μM) and a Bombesin-related agonist (Bn-analogue, 1μM), in addition to EGF (16nM) and TGFα (3.2nM), stimulated the growth, while galanin (1μM) and bradykinin (1μM) did not. The EGFR tyrosine kinase inhibitor, AG1478 (1μM) strongly inhibited EGF and the GI hormones stimulated cell growth, in both growth assays. Western Blot demonstrated EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation, which is known to correlate with EGFR activation. Both NT and Bn-analogue caused a time-dependent increase in EGFR phosphorylation. With the Bn-analogue, a t1/2 =12 minutes and a maximum 3.4-fold increase at 62 minutes was followed by rapid decrease. In contrast, EGF rapidly stimulated Tyr1068 EGFR phosphorylation, reaching a peak by 3 minutes, with a rapid decrease. AG1478 (1μM) strongly inhibited EGF stimulated Tyr1068 EGFR phosphorylation, as well as inhibiting stimulation by both NT (81%) and Bn-analogue (98%). Conclusions: GI hormones, NT and Bn-analogue, stimulated proliferation of foregut NET tumor cells, is largely dependent on transactivation of the EGFR. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists, may be a novel therapeutic approach for NETs treatments, as it has been with a number of other tumors (lung cancer, head-neck tumors).
a composite gastric image formed by the sum of all acquired frames. Images were subsequently counted and “activity versus time” curves were obtained for each region and thereafter normalized, filtered and processed with spectral analysis by Fast Fourier Transform in order to obtain the dominant frequency. Curves from the three ROI were also plotted together, so as to allow the measurement with a cursor of the time lag for any individual wave to propagate from the proximal to the middle region, and from the middle to the distal antral region. Results - There were no significant differences between any antral region, for any acquisition time or test meal, concerning dominant frequency of antral contractions, which varied little (median and range from pooled data: 0.05 Hz; 0.02-0.06 Hz). There were no significant differences between liquid and solid meals concerning the lag time for antral contraction waves to progress from the proximal to the middle antral region, neither during initial (5 s; 2-8 s versus 6 s; 2-8 s) nor late (5 s; 2-6 s vs. 5 s; 2-9 s) gastric emptying. Also, there were no significant differences between meals concerning the lag time for antral contraction waves to migrate from the middle to the distal region, neither at initial (5 s; 29 s vs. 5 s; 2-8 s) nor late gastric emptying (5 s; 2-8 s vs. 5 s; 2-8 s). Conclusions Progression of post-prandial contractions throughout the human gastric antrum follows a rather regular pattern during gastric emptying and do not seem to be influenced by meal consistency nor time after meal ingestion. Financial support: Brazilian agencies CNPq and FAPESP.
Tu2018 Tu2016 Long-Term Clinical Outcome of Gastric MALT Lymphoma After Eradication of Helicobacter pylori: A Multicenter Retrospective Follow-up Study of 423 Patients in Japan Shotaro Nakamura, Katsunori Iijima, Shouko Ono, Masahiro Tajika, Akira Tari, Yasuhiko Kitadai, Hiroshi Matsumoto, Tadanobu Nagaya, Toshiro Kamoshida, Norihiko Watanabe, Toshimi Chiba, Takayuki Matsumoto, Hideki Origasa, Masahiro Asaka, Toshiro Sugiyama
The Effect of Bolus Consistency and Position Change on the Coordination of Peristaltic Contractions in Healthy Volunteers Rami Sweis, Angela Anggiansah, Terry Wong, Mark R. Fox Background and aims: Previous studies show that esophageal contractile pressure increases with workload (e.g. swallowing solids vs. liquids); however mechanistic studies show that effective esophageal clearance depends more on effective coordination between proximal and distal peristaltic contractions at the proximal transition zone (PTZ) than contractile pressure per se. This study aimed to assess the effects of bolus consistency and position change on esophageal coordination as assessed by the PTZ physiology in asymptomatic volunteers using high resolution manometry (HRM). Methods 23 healthy volunteers (11M:12F, age 20-56) underwent HRM (Manoscan 360°, SSI) with 10x5ml water and 21 with 5x1cc bread swallows in the upright seated and supine positions. Measurements of PTZ mean pressure and length defined by 30mmHg isocontour were recorded. The length of the proximal contraction (lower border of upper esophageal sphincter to start of PTZ) and distal contraction (end of PTZ to upper border of the lower esophageal sphincter) defined by 30mmHg isocontour and normalized to esophageal length(%) were calculated. Results are presented as median and inter-quartile ratio. Wilcoxon test was used for nonparametric quantitative group comparisons with Bonferroni correction to correct for multiple comparisons. Results Results are summarized in the table. PTZ mean pressure increased from liquid to solid in the upright (12.3(8.3,17.8) vs. 20.3(12.9,29.5)mmHg; p<0.001) and supine (15.1(10.9,25.1) vs. 34.0 (19.1,51.3)mmHg; p<0.001) positions. PTZ length decreased from liquid to solid in the upright (3.2(1.9,7.4) vs. 0.5(0,2.5)cm; p<0.001) and supine (2.9(1.1,4.5) vs. (0.0(0.0,2.3)cm; p=0.002) positions. These effects remained significant when corrected for esophageal length. Proximal contraction length was not affected by changes in viscosity (p=NS) or position (p=NS); however distal peristaltic contraction length increased with bolus consistency in the upright (p=0.004) and supine (p=0.016) positions, and on moving from upright to supine position for liquid (p<0.001) and solid (p=0.013) respectively) Conclusion: Increased bolus consistency and body position change both increase the coordination of peristaltic contraction in healthy volunteers. This effect is achieved by promoting contractility in the distal segment. The presence of an effective esophageal response to ‘physiologic challenge’ may increase specificity of manometric studies and provide a useful test of the esophagus' ability to adapt to increased workload (e.g. after fundoplication). PTZ parameters with change in bolus viscosity and position
Background: While eradication of Helicobacter pylori has been recognized as the first-line treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma, the long-term outcomes of the disease after the H. pylori eradication remain obscure. We conducted a multicenter retrospective study of a large number of patients with gastric MALT lymphoma treated by H. pylori eradication. Methods: A total of 423 patients with gastric MALT lymphoma were registered from 21 participating institutes in Japan. Inclusion criteria were patients with established diagnosis of gastric low-grade MALT lymphoma without any component of diffuse large B-cell lymphoma (DLBCL), who initially underwent H. pylori eradication therapy with a proton-pump inhibitor plus antibiotics (amoxicillin, clarithromycin, and/or metronidazole) and were followed-up for at least 3 years. Responders to the therapy were defined as patients whose post-treatment biopsies showed complete histological remission (CR) or probable minimal residual disease (pMRD), as determined by GELA histological grading system (Copie-Bergman, Gut 2003). Treatment failure was defined as the status of progressive disease (PD) or recurrence after CR/pMRD. Results: After eradication therapy, CR/pMRD was achieved in 325 patients (77%). A logistic regression analysis revealed that absence of H. pylori, deep submucosal invasion as determined by EUS, and t(11;18)/ API2-MALT1 were independent predictors for resistance to H. pylori eradication. During the follow-up periods from 3 to 14.6 years (median 6.1 years), the disease recurred in 11 of 325 patients (3.4%) with CR/pMRD, while PD was found in 26 of 98 patients (27%) not responding to H. pylori eradication. Thus, 37 of 423 patients (8.7%) were regarded as treatment failure. Among those 37 patients, transformation into DLBCL was found in 9 patients (2 patients with CR/pMRD, and 7 without CR/pMRD). The treatment failure-free probabilities after 5 and 10 years were 92% and 90%, respectively. Second-line treatment was performed in 90 patients. The treatments applied were radiotherapy for 50 patients, chemotherapy with or without rituximab for 28, chemoradiotherapy for 4, surgical resection for 5 and endoscopic resection for 1. Fourteen patients died (2 died of lymphoma), while 409 patients were alive. The probabilities of overall and event-free survivals after 10 years were 95% and 86%, respectively. Cox multivariate analysis revealed induction of CR/pMRD by H. pylori eradication to be an independent prognostic factor for overall and event-free survivals. Conclusions: H. pylori eradication is an optimal first-line therapy for early-stage gastric MALT lymphoma, and the excellent long-term clinical outcome was confirmed by the follow-up study ranging from 3 to 14.6 years (median 6.1 years). Tu2019 Utility of Progression-Free Survival (PFS) as a Primary Endpoint in Clinical Studies of Advanced Neuroendocrine Tumors (NET) Simron Singh, Calvin H. Law Introduction: Overall survival (OS) is an established endpoint in oncology clinical studies, but can be challenging to assess. OS evaluation requires a long follow-up time and large patient population to detect treatment differences, which can be confounded by crossover design or subsequent therapies. Dependence on OS may delay development and availability of new agents for rare malignancies, such as neuroendocrine tumors (NET). We examined progression-free survival (PFS) or time to progression (TTP), OS, and RR as endpoints in NET clinical trials and compared with disease progression definitions used in clinical practice. Methods: A 20-year literature review of published clinical data was done to assess efficacy endpoints in NET trials. Practicing physicians were also surveyed on their definitions of disease progression. Results: Three large NET clinical trials with encouraging PFS results have been recently published. In PROMID, TTP was significantly longer with octreotide LAR treatment (14.3 mo vs 6.0 mo) in patients (pts) with advanced NET; median OS was not reached and RR was 2% in both arms. In the RADIANT-1 trial of everolimus ± octreotide LAR in patients with advanced pNET who had previously progressed on or after chemotherapy, median PFS was 9.7-16.7 months and RRs were 4-10%; median OS was reached in only one stratum. In a phase 2 sunitinib trial, PFS was 7.7 and 10.2 months and RR was 2% and 17% in patients with GI/lung NET and pNET, respectively. These results support the use of PFS as a relevant endpoint for treatment success in patients with NET. Likewise, a survey of 502 US and EU practicing physicians reported that PFS had the most influence on their treatment decisions and that symptomatic change was also a major consideration in defining disease progression in their practices. Conclusions: PFS appears to be a viable, promising endpoint in NET studies when OS is difficult to obtain. Preliminary survey of
*break in contractile pressure front at 30mmHg isocontour Tu2017 Gastrointestinal Hormones Stimulate Growth of a Foregut Net Tumor by Transactivating the EGF Receptor Alessia Di Florio, Veronica Sancho, Gianfranco Delle Fave, Robert T. Jensen Background: Foregut Neuroendocrine Tumors [NETs] (carcinoids, pancreatic endocrine tumors [PETs]) usually pursuit a benign course but, a subset shows aggressive behavior. At present, the treatment of patients with advanced NETs is marginally effective and new approaches are needed. Recent studies show in other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate cell growth, which has led to new treatments. Such a mechanism may be important for NET growth because studies show a direct correlation between NET malignancy and EGFR expression and GI hormones can act as autocrine growth factors, for some NETs. Aim: To determine if GI hormones can stimulate foregut NET growth by inducing transactivation of EGFR. Methods and Results: BON cells [derived from a pancreatic NET], which are known to express EGFR, were examined for the ability of EGF, TGFα and various GI hormones
AGA Abstracts
S-872