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Inhibition of Sonic Hedgehog Signaling Pathway: A Novel Preventive Approach for Esophageal Adenocarcinoma
Vol. 223, No. 4S2, October 2016
Scientific Forum: 2016 Clinical Congress
e45
survival differences based on receipt of MMT. Predictors of receipt of multimodality therapy for stage II and III were then analyzed.
patients but does not appear to be influenced by pre-diagnosis comorbidities or stage of cancer at presentation.
RESULTS: There were 212,634 patients in the Gastric PUF File with 112,789 included in the study cohort (75.8% white, 16.1% black, 6.7% Asian, 1.5% other). MMT was shown to improve survival regardless of race (white, black, Asian, other; all p<0.001) and in stages II-IV (p<0.0001). On multivariable analysis for stage II/III patients, factors significant for increased likelihood of receipt of MMT include male, younger age, white, non-Hispanic, private insurance, more educated, Charlson-Deyo score of 0, and moderate/poorly differentiated grade (all p<0.001).
Incidence and Risk Factors of Symptomatic Hiatal Hernia after Resection for Gastric and Esophageal Cancer Andreas Andreou, MD, Benjamin Struecker, MD, Igor M Sauer, MD, Marcus Bahra, MD, Christian Denecke, MD, Sascha S Chopra, MD, Johann Pratschke, MD, PhD, FACS, Matthias Biebl, MD ChariteeUniversitatsmedizin, Berlin, Germany
CONCLUSIONS: MMT improves survival for all races in stage II-IV GA. When controlling for stage at presentation, there are significant race and socioeconomic differences that predict whether patients receive MMT. Additional research could target these populationa to improve more equitable benefit from MMT.
Gain of Disability after Cancer Surgery among Elderly Americans: A Population-Based Matched Case-Control Study Clancy J Clark, MD, Harveshp D Mogal, MD, Rebecca Dodson, MD, Perry Shen, MD, FACS Wake Forest Baptist Health, Winston-Salem, NC INTRODUCTION: Disability among cancer survivors is well recognized; however, onset of impairments in activities of daily living (ADLs) is not clear. The aim of the current study was to investigate the acquisition of disability among elderly cancer patients treated with surgery compared with matched patients with no history of cancer. METHODS: Using the 1998-2011 SEER-Health Outcomes Survey linked database, patients older than 65 years with breast, colorectal, lung, and prostate cancer who underwent curative resection were identified and matched (1:4) to similar patients without history of cancer. Baseline and two-year follow-up surveys were performed and self-reported impairments in ADLs collected. Initial survey for cancer patients was obtained before diagnosis and treatment. Univariate and multivariate analysis were performed to compare cancer patients to controls. RESULTS: A total of 1,101 patients with breast, colorectal, lung, and prostate cancer treated with surgery were identified and matched to 4,404 patients with no history of cancer. Over a 2 year period spanning their diagnosis of cancer, 15.1% of patients reported a gain of impairment in ADLs compared with 12.0% in matched non-cancer patients, p<0.001. Type of cancer was a significant factor in predicting gain of disability, 11.1% breast cancer vs 21.7% lung cancer, p<0.001. Development of disability was not associated with stage of cancer (p¼0.727). Multiple comorbidities were associated with development of disability in non-cancer patients (p¼0.048), but not cancer patients (p¼0.732). CONCLUSIONS: For elderly Americans, development of disability is common among cancer survivors compared with non-cancer
INTRODUCTION: Symptomatic hiatal hernia (HH) after resection for gastric or esophageal cancer is a potentially life-threatening event that may lead to emergent surgery. However, the incidence and risk factors of this complication remain unclear. METHODS: Data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed and the incidence of symptomatic HH was evaluated. Factors associated with an increased risk for HH were investigated. RESULTS: Resection for gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in stomach, cardia and esophagus in 36%, 24%, and 40% of patients, respectively. The incidence of symptomatic HH was 2.8% (n¼13). All patients underwent surgical hernia repair, 8 patients (61.5%) required emergent procedure, and 3 patients (23%) underwent bowel resection. Morbidity and mortality after HH repair was 38.5% and 7.7%, respectively. Factors associated with increased risk for symptomatic HH included BMI (median BMI with HH 27 [23-35] vs BMI without HH 25 [15-51], p¼.043), diabetes (HH rate:with diabetes, 6.3% vs without diabetes, 2%, p¼.034), tumor location (HH rate:stomach, 1.2% vs. esophagus, 1.1% vs cardia, 7.9%, P¼.001), and resection type (HH rate:total/subtotal gastrectomy, 0.7% vs. transthoracic esophagectomy, 2.7% vs extended gastrectomy, 6.1%, p¼.038). CONCLUSIONS: HH is a major adverse event after resection for gastric or esophageal cancer especially among patients undergoing extended gastrectomy for cardia cancer requiring a high rate of repeat surgery. Therefore, intensive follow-up examinations for high-risk patients and early diagnosis of asymptomatic patients are essential for selecting patients for elective surgery to avoid unpredictable emergent events with high morbidity and mortality. Inhibition of Sonic Hedgehog Signaling Pathway: A Novel Preventive Approach for Esophageal Adenocarcinoma Amir M Ansari, MD, Tomoharu Miyashita, Frank E Lay, A Karim Ahmed, Christopher Ng, Calver Pang, MBChB, Ken-ichi Mukaisho, Elizabeth Montgomery, MD, Ronan J Kelly, MBA, MBBCh, MD, John W Harmon, MD, FACS Johns Hopkins University, Baltimore, MD
e46
Scientific Forum: 2016 Clinical Congress
INTRODUCTION: Esophageal metaplasia proceeds to Barrett’s esophagus and then cancer. The Sonic Hedgehog (SHH) cascade is implicated in the development of esophageal metaplasia and cancer. Inhibitors of the SHH cascade could potentially play a useful role in preventing this devastating disease. METHODS: A surgical model of Barrett’s metaplasia and esophageal cancer was utilized to investigate the potential of Itraconazole, a SHH inhibitor, to prevent adenocarcinoma. The jejunum was anastomosed to the esophagus using a previously published, reflux model. A pharmacokinetic experiment showed that 200 mg/kg of Itraconazole intraperitoneally weekly, produced a mean esophageal tissue concentration of 0.7 uM. Weekly intraperitoneal injections of saline (control group) or Itraconazole were performed starting at 24 weeks after surgery when Barrett’s metaplasia first appears. Esophageal tissues was harvested 40 weeks after the surgery. H&E stained sections were evaluated according to the presence or absence of adenocarcinoma. RESULTS: Barrett’s metaplasia was present in almost all the rats: Control Saline 29/31, (93%), versus Itraconazole, 22/24, (91%). The incidence of adenocarcinoma was lower in the Itraconazole group: Control Saline 20/31 (32%) versus Itraconazole 2/34 (8%). Chi Squared p value <0.05. CONCLUSIONS: The weekly dosage, of 200 mg/kg Itraconazole was selected as it produced tissue levels that were in the potentially effective range at a dosage that could be tolerated in humans. The incidence of esophageal adenocarcinoma was reduced in the Itraconazole group compared to the non-treatment group. Itraconazole, a known Hedgehog pathway inhibitor, deserves consideration as an agent to impede the progression of Barrett’s metaplasia to esophageal adenocarcinoma. Initial Report of Phase II Study of Adjuvant Chemotherapy of Gemcitabine with Nafamostat Mesilate for Pancreatic Cancer Tadashi Uwagawa, MD, PhD, Taro Sakamoto, Yuichi Nakaseko, Yuki Takano, Kenei Furukawa, MD, PhD, Masaru Kanehira, Shinji Onda, Takeshi Gocho, MD, Hiroaki Shiba, MD, PhD, Katsuhiko Yanaga, MD, PhD, FACS Jikei University School of Medicine, Tokyo, Japan INTRODUCTION: It has been reported that GEM-induced nuclear factor kappa b (NF-kB) activation induces chemoresistance. We previously reported combination chemotherapy of GEM with nafamostat mesilate (NAM), which is NF-kB inhibitor, for unresectable pancreatic cancer. The median overall survival and the 1-year survival rates were 10 months and 40%, respectively. Phase II study of adjuvant chemotherapy with NAM/GEM combination for pancreatic cancer was conducted (UMIN000006163). METHODS: This study is a single-arm, single center, institutional review board-approved phase II trial, and is in progress. Overall survival (OS), disease-free survival (DFS), 2-year survival rate, and adverse events were evaluated. Patients whose curative resection was more than 6 months ago were evaluated in this initial report.
J Am Coll Surg
Patients received 6 cycles of NAM (4.8 mg/kg continuous regional arterial infusion for 24 hours) with GEM (1,000 mg/m2 intravenously for 30 minutes) on days 1, 8, 15. This treatment was repeated at 28-day intervals. RESULTS: Twenty-three patients (male/female: 14/9, age (median): 65 (range 48-76) years, pathological stage IA/IB/IIA/ IIB/III 2/2/5/10/4) were candidates in this report. Median OS and DFS were 26.0 (95% CI, 21.6 -31.5 months) and 16.4 months (95% CI, 13.0-20.4 months), respectively. Two-year survival rate was 60.9%. Concerning adverse events, Grade 4 treatment-related hematological toxicities were seen in 3 patients (neutropenia: 3). So far, no febrile neutropenia has been observed. No patients developed Grade 3/4 non-hematological toxicities. Twenty patients excluding 3 disease-free patients received secondary or more treatments. CONCLUSIONS: Adjuvant chemotherapy with NAM/GEM is safe, and has potential as a new option for resectable pancreatic cancer. Laparoscopic Surgery Increases Return to Intended Oncologic Treatment after Resection for Gastric and Esophageal Cancer and Improves Outcomes Andreas Andreou, MD, Matthias Biebl, MD, Benjamin Struecker, MD, Sascha S Chopra, MD, Christian Denecke, MD, Peter C Thuss-Patience, MD, Prisca Sturm, MD, Igor M Sauer, MD, Marcus Bahra, MD, Johann Pratschke, MD, PhD, FACS ChariteeUniversitatsmedizin, Berlin, Germany INTRODUCTION: Minimal invasive resection for upper gastrointestinal tumors has been increasingly performed with most promising results. However, the role of laparoscopic surgery (LS) in the multimodal treatment of patients with advanced gastric and esophageal cancer needs further investigation. METHODS: Clinicopathological data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2015 were assessed. Outcomes of patients undergoing LS were compared with those of patients treated with a conventional open resection (OR). RESULTS: Curative resection for gastric or esophageal cancer was performed in 727 patients. The primary tumor was located in the stomach and esophagus in 54% and 46% of patients, respectively. Beginning in June 2014, the majority of patients underwent LS (n¼66) including 37 resections for gastric cancer and 29 resections for esophageal cancer. The 90-day postoperative mortality rate was significantly lower following LS compared to OR (1.5% vs 8%, p¼0.048). Among patients with advanced disease requiring perioperative systemic therapy, LS was associated with a higher rate of postoperative return to intended oncologic treatment compared to OR (98% vs 80% p¼0.005). Disease-free survival (DFS) after LS was significantly higher than after OR (1-year DFS: 96% vs 81%, p¼0.012); however, longer follow-up time (current median:
Scientific Forum: 2016 Clinical Congress
e45
survival differences based on receipt of MMT. Predictors of receipt of multimodality therapy for stage II and III were then analyzed.
patients but does not appear to be influenced by pre-diagnosis comorbidities or stage of cancer at presentation.
RESULTS: There were 212,634 patients in the Gastric PUF File with 112,789 included in the study cohort (75.8% white, 16.1% black, 6.7% Asian, 1.5% other). MMT was shown to improve survival regardless of race (white, black, Asian, other; all p<0.001) and in stages II-IV (p<0.0001). On multivariable analysis for stage II/III patients, factors significant for increased likelihood of receipt of MMT include male, younger age, white, non-Hispanic, private insurance, more educated, Charlson-Deyo score of 0, and moderate/poorly differentiated grade (all p<0.001).
Incidence and Risk Factors of Symptomatic Hiatal Hernia after Resection for Gastric and Esophageal Cancer Andreas Andreou, MD, Benjamin Struecker, MD, Igor M Sauer, MD, Marcus Bahra, MD, Christian Denecke, MD, Sascha S Chopra, MD, Johann Pratschke, MD, PhD, FACS, Matthias Biebl, MD ChariteeUniversitatsmedizin, Berlin, Germany
CONCLUSIONS: MMT improves survival for all races in stage II-IV GA. When controlling for stage at presentation, there are significant race and socioeconomic differences that predict whether patients receive MMT. Additional research could target these populationa to improve more equitable benefit from MMT.
Gain of Disability after Cancer Surgery among Elderly Americans: A Population-Based Matched Case-Control Study Clancy J Clark, MD, Harveshp D Mogal, MD, Rebecca Dodson, MD, Perry Shen, MD, FACS Wake Forest Baptist Health, Winston-Salem, NC INTRODUCTION: Disability among cancer survivors is well recognized; however, onset of impairments in activities of daily living (ADLs) is not clear. The aim of the current study was to investigate the acquisition of disability among elderly cancer patients treated with surgery compared with matched patients with no history of cancer. METHODS: Using the 1998-2011 SEER-Health Outcomes Survey linked database, patients older than 65 years with breast, colorectal, lung, and prostate cancer who underwent curative resection were identified and matched (1:4) to similar patients without history of cancer. Baseline and two-year follow-up surveys were performed and self-reported impairments in ADLs collected. Initial survey for cancer patients was obtained before diagnosis and treatment. Univariate and multivariate analysis were performed to compare cancer patients to controls. RESULTS: A total of 1,101 patients with breast, colorectal, lung, and prostate cancer treated with surgery were identified and matched to 4,404 patients with no history of cancer. Over a 2 year period spanning their diagnosis of cancer, 15.1% of patients reported a gain of impairment in ADLs compared with 12.0% in matched non-cancer patients, p<0.001. Type of cancer was a significant factor in predicting gain of disability, 11.1% breast cancer vs 21.7% lung cancer, p<0.001. Development of disability was not associated with stage of cancer (p¼0.727). Multiple comorbidities were associated with development of disability in non-cancer patients (p¼0.048), but not cancer patients (p¼0.732). CONCLUSIONS: For elderly Americans, development of disability is common among cancer survivors compared with non-cancer
INTRODUCTION: Symptomatic hiatal hernia (HH) after resection for gastric or esophageal cancer is a potentially life-threatening event that may lead to emergent surgery. However, the incidence and risk factors of this complication remain unclear. METHODS: Data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2012 were assessed and the incidence of symptomatic HH was evaluated. Factors associated with an increased risk for HH were investigated. RESULTS: Resection for gastric or esophageal cancer was performed in 471 patients. The primary tumor was located in stomach, cardia and esophagus in 36%, 24%, and 40% of patients, respectively. The incidence of symptomatic HH was 2.8% (n¼13). All patients underwent surgical hernia repair, 8 patients (61.5%) required emergent procedure, and 3 patients (23%) underwent bowel resection. Morbidity and mortality after HH repair was 38.5% and 7.7%, respectively. Factors associated with increased risk for symptomatic HH included BMI (median BMI with HH 27 [23-35] vs BMI without HH 25 [15-51], p¼.043), diabetes (HH rate:with diabetes, 6.3% vs without diabetes, 2%, p¼.034), tumor location (HH rate:stomach, 1.2% vs. esophagus, 1.1% vs cardia, 7.9%, P¼.001), and resection type (HH rate:total/subtotal gastrectomy, 0.7% vs. transthoracic esophagectomy, 2.7% vs extended gastrectomy, 6.1%, p¼.038). CONCLUSIONS: HH is a major adverse event after resection for gastric or esophageal cancer especially among patients undergoing extended gastrectomy for cardia cancer requiring a high rate of repeat surgery. Therefore, intensive follow-up examinations for high-risk patients and early diagnosis of asymptomatic patients are essential for selecting patients for elective surgery to avoid unpredictable emergent events with high morbidity and mortality. Inhibition of Sonic Hedgehog Signaling Pathway: A Novel Preventive Approach for Esophageal Adenocarcinoma Amir M Ansari, MD, Tomoharu Miyashita, Frank E Lay, A Karim Ahmed, Christopher Ng, Calver Pang, MBChB, Ken-ichi Mukaisho, Elizabeth Montgomery, MD, Ronan J Kelly, MBA, MBBCh, MD, John W Harmon, MD, FACS Johns Hopkins University, Baltimore, MD
e46
Scientific Forum: 2016 Clinical Congress
INTRODUCTION: Esophageal metaplasia proceeds to Barrett’s esophagus and then cancer. The Sonic Hedgehog (SHH) cascade is implicated in the development of esophageal metaplasia and cancer. Inhibitors of the SHH cascade could potentially play a useful role in preventing this devastating disease. METHODS: A surgical model of Barrett’s metaplasia and esophageal cancer was utilized to investigate the potential of Itraconazole, a SHH inhibitor, to prevent adenocarcinoma. The jejunum was anastomosed to the esophagus using a previously published, reflux model. A pharmacokinetic experiment showed that 200 mg/kg of Itraconazole intraperitoneally weekly, produced a mean esophageal tissue concentration of 0.7 uM. Weekly intraperitoneal injections of saline (control group) or Itraconazole were performed starting at 24 weeks after surgery when Barrett’s metaplasia first appears. Esophageal tissues was harvested 40 weeks after the surgery. H&E stained sections were evaluated according to the presence or absence of adenocarcinoma. RESULTS: Barrett’s metaplasia was present in almost all the rats: Control Saline 29/31, (93%), versus Itraconazole, 22/24, (91%). The incidence of adenocarcinoma was lower in the Itraconazole group: Control Saline 20/31 (32%) versus Itraconazole 2/34 (8%). Chi Squared p value <0.05. CONCLUSIONS: The weekly dosage, of 200 mg/kg Itraconazole was selected as it produced tissue levels that were in the potentially effective range at a dosage that could be tolerated in humans. The incidence of esophageal adenocarcinoma was reduced in the Itraconazole group compared to the non-treatment group. Itraconazole, a known Hedgehog pathway inhibitor, deserves consideration as an agent to impede the progression of Barrett’s metaplasia to esophageal adenocarcinoma. Initial Report of Phase II Study of Adjuvant Chemotherapy of Gemcitabine with Nafamostat Mesilate for Pancreatic Cancer Tadashi Uwagawa, MD, PhD, Taro Sakamoto, Yuichi Nakaseko, Yuki Takano, Kenei Furukawa, MD, PhD, Masaru Kanehira, Shinji Onda, Takeshi Gocho, MD, Hiroaki Shiba, MD, PhD, Katsuhiko Yanaga, MD, PhD, FACS Jikei University School of Medicine, Tokyo, Japan INTRODUCTION: It has been reported that GEM-induced nuclear factor kappa b (NF-kB) activation induces chemoresistance. We previously reported combination chemotherapy of GEM with nafamostat mesilate (NAM), which is NF-kB inhibitor, for unresectable pancreatic cancer. The median overall survival and the 1-year survival rates were 10 months and 40%, respectively. Phase II study of adjuvant chemotherapy with NAM/GEM combination for pancreatic cancer was conducted (UMIN000006163). METHODS: This study is a single-arm, single center, institutional review board-approved phase II trial, and is in progress. Overall survival (OS), disease-free survival (DFS), 2-year survival rate, and adverse events were evaluated. Patients whose curative resection was more than 6 months ago were evaluated in this initial report.
J Am Coll Surg
Patients received 6 cycles of NAM (4.8 mg/kg continuous regional arterial infusion for 24 hours) with GEM (1,000 mg/m2 intravenously for 30 minutes) on days 1, 8, 15. This treatment was repeated at 28-day intervals. RESULTS: Twenty-three patients (male/female: 14/9, age (median): 65 (range 48-76) years, pathological stage IA/IB/IIA/ IIB/III 2/2/5/10/4) were candidates in this report. Median OS and DFS were 26.0 (95% CI, 21.6 -31.5 months) and 16.4 months (95% CI, 13.0-20.4 months), respectively. Two-year survival rate was 60.9%. Concerning adverse events, Grade 4 treatment-related hematological toxicities were seen in 3 patients (neutropenia: 3). So far, no febrile neutropenia has been observed. No patients developed Grade 3/4 non-hematological toxicities. Twenty patients excluding 3 disease-free patients received secondary or more treatments. CONCLUSIONS: Adjuvant chemotherapy with NAM/GEM is safe, and has potential as a new option for resectable pancreatic cancer. Laparoscopic Surgery Increases Return to Intended Oncologic Treatment after Resection for Gastric and Esophageal Cancer and Improves Outcomes Andreas Andreou, MD, Matthias Biebl, MD, Benjamin Struecker, MD, Sascha S Chopra, MD, Christian Denecke, MD, Peter C Thuss-Patience, MD, Prisca Sturm, MD, Igor M Sauer, MD, Marcus Bahra, MD, Johann Pratschke, MD, PhD, FACS ChariteeUniversitatsmedizin, Berlin, Germany INTRODUCTION: Minimal invasive resection for upper gastrointestinal tumors has been increasingly performed with most promising results. However, the role of laparoscopic surgery (LS) in the multimodal treatment of patients with advanced gastric and esophageal cancer needs further investigation. METHODS: Clinicopathological data of patients who underwent resection for gastric or esophageal cancer between 2005 and 2015 were assessed. Outcomes of patients undergoing LS were compared with those of patients treated with a conventional open resection (OR). RESULTS: Curative resection for gastric or esophageal cancer was performed in 727 patients. The primary tumor was located in the stomach and esophagus in 54% and 46% of patients, respectively. Beginning in June 2014, the majority of patients underwent LS (n¼66) including 37 resections for gastric cancer and 29 resections for esophageal cancer. The 90-day postoperative mortality rate was significantly lower following LS compared to OR (1.5% vs 8%, p¼0.048). Among patients with advanced disease requiring perioperative systemic therapy, LS was associated with a higher rate of postoperative return to intended oncologic treatment compared to OR (98% vs 80% p¼0.005). Disease-free survival (DFS) after LS was significantly higher than after OR (1-year DFS: 96% vs 81%, p¼0.012); however, longer follow-up time (current median: