bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of combination chemotherapy consisting of capecitabine plus fractional cisplatin for unresectable gastric cancer in an outpatient setting.
Authors: Takahashi Tsunehiro , Saikawa Yoshiro , Fukuda Kazumasa , Nakamura Rieko , Wada Norihito , Kawakubo Hirofumi , Takeuchi Hiroya , Takaishi Hiromasa , Kitagawa Yuko
Published: February 2017

173

Background: The combination chemotherapy of capecitabine and cisplatin is one of the standard regimen for unresectable gastric cancer. However, the high dose of cisplatin could cause the nephrotoxicity and require the adequate hydration to avoid the damage of renal during the administration. For that reason, the hospitalization is recommended for the patients to receive the chemotherapy including high dose of cisplatin. The present study aimed to establish the proper dose of fractional cisplatin in the combination with capecitabine in an outpatient setting. Methods: Capecitabine was administered orally every day from the evening of day 1 to the morning of 15. Cisplatin were infused on days 1, 8 and 15 for 60 minutes without hydration. The starting dose of cisplatin was 15 mg/m2 as level 1. The following cisplatin dose could be given to subsequent cohorts of patients depending on safety findings observed in the previous cohort: level 2, 20 mg/m2 and level 3, 25 mg/m2, respectively. Serum concentration of total platinum was analyzed before the administration of cisplatin on days 1, 8 and 15. Results: A total of 9 patients were recruited. The median age was 64 years and there were 8 males and one female. Histological types included intestinal (n=5) and diffuse (n=4). Eight patients had multiple metastatic sites, including lymph nodes (n=8), peritoneum (n=5), liver (n=3), lung (n=2) and bone (n=1). The major toxicities were thrombocytopenia (67%), leukopenia (56%) and neutropenia (22%). However, no dose-limiting toxicity was observed in each level. Therefore, the recommended dose of cisplatin was 25 mg/m2. Of the 9 patients, 6 patients had measurable lesions and 5 patients had partial responses, resulting in an overall response rate of 83%. The median administered course was four. In patients at level 3, the mean concentration of total platinum on days 8 and 15 were 0.25μg/ml and 0.42μg/ml, respectively. Conclusions: The recommend dose of cisplatin was confirmed with 25 mg/m2 weekly. Although its safety and feasibility should be evaluated in further clinical trial, this regimen could be expected as an outpatient treatment for unresectable gastric cancer. Clinical trial information: 000005708.
Effect of sarcopenia on prognosis of patients with gastric cancer.
Authors: Iwagami Shiro , Baba Hideo
Published: February 2017

192

Background: Recently, some studies reported the correlation between low skeletal muscle mass (sarcopenia) of patients with cancer and poor prognosis. There were no reports mentioned the relationship of sarcopenia to patients with gastric cancer. Objective: To evaluate the impact of sarcopenia on survival of patients with gastric cancer. Methods: From April 2005 to December 2010, 243 patients with gastric cancer underwent gasrectomy. Patients were divided in two groups, sarcopenia and nonsarcopenia group. Sarcopenia was defined as muscle mass below the median on preoperative CT scan. Muscle mass was assessed by psoas muscle density and total psoas area. The third lumbar vertebra (L3) was chosen as the standard landmark. We examined the relationship between sarcopenia and overall survival (OS), cancer specific survival (CSS), and disease free survival (DFS). Results: The mean age was 67.6 years old. 95 patients underwent total gastrectomy, 150 did distal gastrectomy, and 18 did proximal gastrectomy. The number of laparoscopic surgery was 62 cases. The CSS and DFS of patients in sarcopenia group were significantly shorter than nonsarcopenia group (p=0.012, p=0.023). The OS of sarcopenia tented to shorter (p=0.12). Conclusions: The presence of sarcopenia was found to significantly increase a patient’s risk of gastric cancer.
Long-term outcomes of preoperative chemotherapy with modified DCS therapy for highly advanced gastric cancer with distant metastasis.
Authors: Matsuki Atsushi , Nashimoto Atsushi , Yabusaki Hiroshi , Aizawa Masaki
Published: February 2017

193

Background: Among patients (pts) with advanced gastric cancer (AGC), the poor prognosis was exhibited and many pts died even after R0 resection. The aim of this study is to evaluate the preoperative chemotherapy with docetaxel, cisplatin and S-1 (modified DCS therapy) for treatment in highly AGC with distant metastasis. Methods: A retrospective analysis was performed in 58 pts (man/woman; 49/9, median age; 64.5-years) treated with preoperative modified DCS therapy in our hospital between 2009 and 2012. Eligibility criteria included StageIV AGC with distant metastasis (H1;14, P1;18,CY1;31, LYM;25, PUL;2, OTH;2), a Performance status of 0-2 and no prior chemotherapy. The regimen consisted of docetaxel and cisplatin infusion (35mg/m2, days 1 and 15) and oral administration of S-1 (80mg/m2, days 1-14) every 4 weeks. Surgery was planned 3 to 4 weeks after the chemotherapy. Pathological response was graded according to the JGCA criteria. Almost all pts were treated with S-1 as postoperative adjuvant chemotherapy. Results: The median cycles was 2 (1-13). The incidence of grade 3/4 toxicity was neutropenia 53.4%, anemia 8.6%, anorexia 15.5%, nausea 5.2%, and diarrhea 3.4%. All of these toxicities were well tolerable and there was no TRD. According to RECIST, The overall response rate was 79.3%. Forty-tree pts underwent gastrectomy (R0/R1/R2; 27/8/8), respectively. Postoperative morbidity rate was 20.9% and there was no mortality. Over all 5 years survival rate (5YSR) was 21.4 % and that of R0 was 44.8%, on the other hand 5YSR and MST of chemotherapy alone was 0% and 14.5 month. Pathological response rate (>=1b) was 60.5% and complete response was achieved 1 pts. 5YSR of pathological responders who underwent R0 resection was 81.4% and that of non-responders who underwent even R0 resection was 22.5% (P<0.05). Conclusions: Preoperative modified DCS therapy for AGC was tolerable, and survival benefit of pathological responders with R0 surgery was promising and warrants further investigation.
Patterns of failure following tri-modality therapy for locally advanced esophageal cancer.
Authors: Shaikh Talha , Zaki Mark A. , Dominello Michael M. , Handorf Elizabeth , Konski Andre A. , Cohen Steven J. , Scott Walter Joseph , Meyer Joshua E.
Published: February 2017

203

Background: Although tri-modality therapy is an acceptable standard of care in patients with locally advanced esophageal cancer, data regarding patterns of failure is lacking. We report bi-institutional patterns of failure experience treating patients using tri-modality therapy. Methods: Following IRB approval, we retrospectively reviewed all pts who underwent chemoradiation followed by esophagectomy at two NCI-designated cancer centers from 2000-2013. Patient and treatment factors were analyzed for failure patterns. First failure sites were categorized as local, regional nodal, or distant. Statistical analysis was performed using Fisher’s exact test and non-parametric Wilcoxon rank-sum test. Results: A total of 132 patients met the inclusion criteria with a median age of 62 (range 36-80) and median follow-up of 28 months (range 4-128). The majority of patients had T3 (82%), N1 (64%), or M0/M1a (92%) disease. At the time of last follow-up there were a total of 6 (4.5%) local, 13 (10%) regional nodal, and 32 (23.5%) distant failures. Local failure was correlated with fewer lymph nodes assessed (p=0.01) and close or positive margins (p<0.01). Regional nodal failure was correlated with fewer lymph nodes assessed (p<0.01) and smaller pre-treatment tumor size (p=0.04). Distant recurrence was correlated with post-treatment nodal stage (p<0.01), peri-neural invasion (p=0.03), negative margins (p=0.02), ulceration (p=0.02), incomplete response (p<0.01), post-treatment PET SUV (p=0.05), 3D-CRT (0.053), metastatic disease at diagnosis (p<0.01) and post-treatment metastatic disease (p<0.01). No other patient, tumor, or treatment factor was correlated with treatment failure. Conclusions: Per our bi-institutional experience, patient, tumor, and treatment factors may predict for failure in patients undergoing tri-modality therapy for locally advanced esophageal cancer. Further data is needed to identify patterns of failure in these patients.
Clinical features and the role of surgery in stage IV gastric cancer: A single center experience.
Authors: Perez-Florez Narjust , Gromko Larysa Jessica , Yoon Eric , Jennis Andrew , Bamboat Zubin M. , Gutierrez Martin
Published: February 2017

212

Background: Gastric cancer is a prevalent global disease with significant mortality. Nearly 22,220 patients are diagnosed annually in the US, with approximately 50% of them presenting with disease that extends beyond loco-regional confines, and only a small percentage undergoing curative resection. We aim to study the clinical characteristics and survival benefit of surgery in stage IV gastric cancer. Methods: We reviewed the records of all patients diagnosed with gastric cancer in our cancer center from 1999 to 2013. A total of 272 stage IV cases were identified. Demographics, tumor characteristics, treatment modalities (surgical vs. non-surgical) and survival rate were analyzed. Kaplan-Meier was used for survival analysis and Cox regression for univariate and multivariate analysis. Results: Within the cohort 70 (26%) patients received surgery and 202 (74%) were treated with chemotherapy ± radiation. Mean age at diagnosis was 64 years in the surgical (S) patients and 66 years in the non-surgical (NS). Non-Hispanics whites were more likely to receive surgery vs. all other ethnic groups combined, representing 77% vs. 23% of the S subgroup (p<0.0001). Patients with proximal tumors were more likely to receive surgery when compared with distal tumors (37 (53%) vs. 14 (20%), p<0.0001). Total gastrectomy was the most common surgical procedure 33 (47%). There was a significant difference in disease specific survival between the two groups, being 17.3 months for S (95%CI: 11.1-23.4) and 5.3 months for NS (95%CI: 3.8-6.7) (p<0.0001). Age > 70 years (OR: 1.74, p<0.02), proximal tumor location (OR: 0.75, p<0.04), surgery (OR: 0.37, p<0.0001) and extended lymphadenectomy (D2) (OR: 0.26, p<0.02) were independent and significant predictors of survival by multivariate analysis. Conclusions: In our cohort, non-Hispanic whites and patients with proximal tumors were more likely to undergo surgery. A major survival benefit was observed for the surgical subgroup when compared to non-surgical treatment for stage IV gastric cancer. Future research should aim to further elucidate the specific role of surgery, as this could potentially impact management and transform the standard of care in stage IV gastric cancer.
Loss of lean body mass within one week as a major determinant for total weight loss at one month after gastrectomy for gastric cancer.
Authors: Aoyama Toru , Yoshikawa Takaki , Kawabe Taiichi , Fujikawa Hirohito , Hayashi Tsutomu , Yamada Takanobu , Sato Tsutomu , Oshima Takashi , Rino Yasushi , Ogata Takashi , Cho Haruhiko , Masuda Munetaka
Published: February 2017

219

Background: Postoperative changes in body weight and composition during first 1 month after gastrectomy remained unclear. Methods: The patients who underwent gastrectomy for gastric cancer between May 2010 and October 2013 were examined. Body weight and composition were evaluated by bioelectrical impedance analyzer within 1 week before surgery (first measurement), at 1 week after surgery (second measurement), and at 1 month after surgery (third measurement). The changes of the early period were defined as the differences until the second measurement, while those of the late period as the differences from the second to the third measurement. Results: Two-hundred forty four patients were selected for this study. Total body weight loss (BWL) within 1 month was -3.4 kg and the rate of body weight at 1 month to the preoperative body weight was 94.1%. BWL was significantly greater in the early period rather than that of the late period (-2.1 kg vs -1.2 kg, p<0.001). In the early period, loss of lean body mass was significantly greater than loss of fat mass (-1.5 kg vs -0.6 kg, p<0.001). The same trend was observed regardless of type of gastrectomy and surgical approach. Conclusions: Loss of lean body mass within 1 week was a major determinant for total body weight loss at 1 month. To maintain lean body mass within 1 week and total body weight at 1 month, future trial should be focused on not the surgical approach but nutritional intervention within 1 week.
Interim analysis of hepatocellular carcinoma (HCC) screening and survival in 4,087 veterans diagnosed with HCC from 2008 to 2010.
Authors: Kaplan David Edward , Taddei Tamar H. , Aytaman Ayse , Hunt Kristel , Knott Astrid , Dieperink Eric , Baytarian Michelle , Fox Rena , Pedrosa Marcos , D'Addeo Kathryn , Dai Feng , Mehta Rajni , Duggal Mona , Pocha Christine , Skanderson Melissa , Valderrama Adriana ,   Veterans Outcomes and Cost Associated with Liver Disease (VOCAL) Study Group
Published: February 2017

243

Background: The Veterans Health Administration (VHA) is the largest provider of liver disease care in the US. From 2000-2007, there was a 5-fold increase in the incidence of hepatocellular carcinoma (HCC) among Veterans. The aim of the VOCAL group is to study outcomes and cost of Veterans diagnosed with cirrhosis and HCC from 2008-2010. Methods: The VA Corporate Data Warehouse was queried to identify all patients with ICD9 codes for HCC (155.0, 155.2) and cirrhosis (571.2, 571.5, 571.6). Chart abstraction was performed for each HCC patient to determine tumor characteristics, BCLC stage, and eligibility for transplantation. Results: This is an interim analysis of the first 4087 of 7,111 patients with HCC. HCC was confirmed in 3,207/4,087 (78%). Of these 3,207 patients, 778 (24%) were managed outside the VHA and 156 (6%) were diagnosed prior to 2008. Thus, 2,323 patients were analyzed. Median age was 60y (38-91). Males comprised 99% of the cohort; 61% were white, 24% were black, and 0.5% were Asian. Etiologies of cirrhosis were hepatitis C (HCV) (27%), alcohol-related (11%), HCV+alcohol (49%), hepatitis B (HBV) (9%), and other (metabolic, NASH) (2%). 63 (3%) were HIV-infected. Cirrhosis was coded in 83% (1918) prior to HCC diagnosis. Of cirrhotics, 11% (248) were optimally screened and 14% (335) were near-optimally screened; 75% of HCC were diagnosed incidentally or due to symptoms. AJCC stage was I/II/IIIA/IIIB/IIIC/IVA/IVB in 42/23/10/13/1/4/7%, respectively. 963 (41%) of patients were within Milan Criteria. BCLC staging was 0/A/B/C/D in 8/39/27/13/13%, respectively. Median OS was 400d and 1214/857/404/163/107d in BCLC 0/A/B/C/D, respectively. In multivariate survival model, age, the presence of ascites, serum albumin, serum bilirubin, serum sodium, CirCom score, Charlson-Deyo index, number of tumors, largest tumor size, and total tumor size were all statistically significantly predictive of survival. Conclusions: ICD9 codes for HCC have a PPV of ~80% for identifying true HCC cases in the CDW. Approximately 1/4 of patients received screening within AASLD 2010 guidelines. The majority of Veterans diagnosed with HCC present with intermediate to advanced disease with median survival 4.5-9.2 months.
Is proliferative index (Ki-67) useful to stratify patients (pts) with G2 gastroenteropancreatic neuroendocrine tumors (GEP-NETs)? Clinicopathologic correlation.
Authors: Angel Martin , O Connor Juan , Pesce Veronica , Mendez Guillermo Ariel , Bestani Claudia , Marmissolle Fabiana , Giacomi Nora , Belli Susana , Domenichini Enzo , Chacon Matias , Zamora Victor , Cabanne Ana Maria , Parma Patricia , Roca Enrique Luis ,   ARGENTUM Group
Published: February 2017

255

Background: Grade 2 (G2) Neuroendocrine tumors (NETs), of the digestive tract is a heterogeneous group of tumors. Several treatment options including chemotherapy and target therapy are available, but there is a lack of prospective trials assessing the role of pronostic factors in this population. Aim(s): to analyze prognostic factors and clinical characteristics in a population of patients with G2 GEP-NETs. To determine the role of ki 67 in the stratification of G2 population. Methods: Study population was obtained from our prospective database (Argentum Group). Survival was estimated using the Kaplan-Meier method and compared between Ki-67 quartiles using the log-rank test. Value of Ki-67 to discriminate mortality was assesed with a ROC curve analysis Results: 144 pts were evaluated. Mean age 54.9, 46.7% male. 102 (70.8%) with metastatic disease, mainly hepatic in 97 pts. (67.4%). 67.9 % underwent surgery. 34% received chemotherapy, and 10.9% target therapy. Median Ki-67 value was 6 (IQR 4-10), ROC curve=0.62 (95% CI 0.53 a 0.72 p=0.021. cut-off: 6.5 (sensitivity 62.2%, specificity 57.7%). Median survival was 97, 67, 51 and 27 months according stratification by quartile (p.001), 45 events (31.7%). Conclusions: Our results suggest that in the heterogenous G2 GEP-NETs there are significant differences in survival. This study was underpowered to detect differences between Ki-67 quartiles, we detected that chemotherapy was mostly used in the higher quartiles.
Prognostic value of gender in hospitalized pancreatic patients.
Authors: Zhang Shuang Yin , Zhang Shuang Qin , Jiang Jimmy Jing , El-Rayes Bassel F.
Published: February 2017

256

Background: Women with pancreatic cancer (PC) are known to have a longer overall survival compared with men. However, no data address the association of gender with acute medical complications in the inpatient setting. We hypothesize that women with PC have fewer inpatient medical complications than men. Methods: The Nationwide Inpatient Sample (NIS) database was queried to identify all non-surgical hospital admissions for patients with a diagnosis of pancreatic cancer for 2011. We compared inpatient complications and mortality between females and males with PC using univariate and multivariate logistic regression model. Two sample independent t-tests were used to compare all linear variables, and Chi-squared tests were used to compare categorical data. Results: Of the 16,616 PC patients analyzed, there were 8,324 females (F) and 8,292 males (M). Mean age was 69 (F) and 67 (M). Length of stay for both averaged 6 days. After adjusting for gender, age, race, inpatient chemotherapy, and comorbidities (depression, alcoholism, arthritis, coagulopathies, drug use, diabetes, hypertension, hypothyroidism, liver disease [dz], metastatic dz, obesity, perivascular dz, renal failure), multivariate analysis showed that male gender in PC patients is independently associated with increased incidence of pneumonia (p<0.001, RR 0.77), pulmonary embolism (p=0.006, RR 0.80), ileus (p=0.001, RR 0.79), and acute renal failure (p<0.001, RR 0.76). Female patients experienced higher incidence of urinary tract infection (p<0.001, RR 1.9). Although incidence of mortality for male patients with PC was higher by univariate analysis (p= 0.005), it was not significantly higher by multivariate analysis (p= 0.087). Conclusions: In this study, men admitted with PC suffer higher incidences of inpatient complications compared to women. These findings may partly explain the higher overall survival rate of women compared to men with PC. It also implicates gender as prognostic tool in the management of hospitalized PC patients.
Exploration of rural disparities in pancreatic cancer staging and mortality to incidence ratio in Illinois.
Authors: Kistner Bridget , Zahnd Whitney , Ali Aman , Mellinger John D. , Ganai Sabha
Published: February 2017

260

Background: Despite recent impetus towards regionalization of pancreatectomy to high-volume centers, rural disparities have not been explored for pancreas cancer outcomes. Analysis of the National Cancer Database showed less than one third of patients with resectable disease actually undergo surgery, suggesting opportunities for improvement in global systems related to pancreas cancer care, including appropriate referral for surgical resection. We intended to explore the impact of rurality and gastroenterologist (GI) density on staging and mortality for pancreas cancer. Methods: Age-adjusted pancreas cancer incidence and staging proportion were calculated for each county using 1991-2010 data from the Illinois State Cancer Registry. Age-adjusted mortality rates were calculated using SEER*STAT. Choropleth maps were created to illustrate Mortality-Incidence Ratios (MIRs) by Illinois county using ArcGIS. Mean GI density for each county was calculated from the US Area Health Resource File. USDA Economic Research Service rural-urban continuum codes (RUCC) and US census percent rurality data were used to designate county rurality and adjacency to metro counties. Chi-square, ANOVA, and Spearman’s rho calculations were performed. Results: A greater proportion of counties with high MIR were in Southern, more rural, Illinois. No GIs were located in 65 out of 102 Illinois counties (64%) during the time interval analyzed, with a mean density of 1.0 per 100,000. Counties without GIs were significantly more rural, poorer, and less educated than counties with GIs. Unstaged pancreas cancers were inversely correlated with GI density (Spearman’s rho=-0.20; p=0.04). MIR was positively correlated with percent rurality (Spearman’s rho=0.23; p=0.02). MIR was also predicted by RUCC category, and was significantly greater in rural regions not adjacent to metro counties (p=0.02). Conclusions: Higher rates of unstaged pancreas cancer and higher MIR were noted in rural regions, which may be influenced by the availability of gastroenterologists or other specialty services. Further exploration of the impact of distance from high-volume cancer centers on rural cancer outcomes is warranted.
T-cell redirected killing and cure of pancreatic and gastric cancer xenografts by targeting Trop-2.
Authors: Goldenberg David M. , Rossi Edmund A. , Rossi Diane L , Cardillo Thomas M. , Chang Chien-Hsing
Published: February 2017

262

Background: Trop-2 [also called tumor-associated calcium signal transducer 2 (TACSTD2), EGP-1 (epithelial glycoprotein-1), GA733-1, or M1S1]is a 35 kDa transmembrane glycoprotein that is overexpressed relative to normal tissues in a variety of human cancers, including pancreatic and gastric carcinomas, where increased expression correlates with poor prognosis. Trop-2 appears to be more tumor-specific than the related molecule, EpCAM (Trop-1). MT110, the EpCAM antibody x CD3 bispecific T-cell engager (BiTE), is currently undergoing a Phase I study in various solid tumors, including lung, gastric, colorectal, breast, prostate, and ovarian cancers. We produced a similar T-cell redirecting bispecific tandem scFv, E1-3, using the variable domains of hRS7 (humanized anti-Trop-2 mAb) and Okt-3 (anti-CD3 mAb). Methods: T-cell activation, cytokine induction and cytotoxicity were evaluated ex vivo using PBMCs or purified T cells with human pancreatic (Capan-1 and BxPC3) and gastric (NCI-N87) cancer cell lines as target cells. In vivo activity was assayed with NCI-N87 xenografts that were inoculated s.c. in a mixture with twice the number of human PBMCs and matrigel. Results: In the presence of target cells and PBMCs, E1-3 potently induced T-cell activation, proliferation, and dose-dependent cytokine production of IL-2 (>2 ng/mL), IL-6 (>1 ng/mL), IL-10 (>7 ng/mL), TNF-α (>1 ng/mL) and IFN-γ (>50 ng/mL). In vitro, E1-3 mediated a highly potent T-cell lysis of BxPC3 [IC50=0.09(±0.04) pM], Capan-1 [IC50=1.2(±1.1) pM] and NCI-N87 [IC50=1.2(±1.2) pM] target cells. In vivo, two 50-µg doses of E1-3 given three days apart cured all of the mice (N=8) bearing NCI-N87 xenografts (P=0.0005; Log-Rank). Tumors in the control group (PBMCs only) reached the endpoint (TV>1 cm3) with a median of 39.5 days. All mice remained tumor-free in the E1-3 group at 78 days. Conclusions: Trop-2 is an attractive target for T-cell-mediated killing of pancreatic, gastric and other epithelial cancers.
S100P tumor-marker response to chemotherapy in patients with advanced pancreatic cancer.
Authors: Mitsunaga Shuichi , Umemoto Kumiko , Watanabe Kazuo , Okuyama Hiroyuki , Hashimoto Yusuke , Takahashi Hideaki , Ohno Izumi , Shimizu Satoshi , Ochiai Atsushi , Ikeda Masafumi
Published: February 2017

265

Background: The serum tumor-marker in monitoring response to chemotherapy is not valid in advanced pancreatic cancer (PC). S100 calcium-binding protein P (S100P) has been reported as a predictive diagnostic index for PC and may serve as an early marker to activity of chemotherapy. The aim of this study was to analyze the correlation between the efficacies of chemotherapy and the kinetics of tumor-markers including serum S100P, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in prospective cohort of advanced PC. Methods: Patients who were treatment naïve for advanced PC with liver mets were eligible. Serum levels of S100P, CEA, and CA19-9 were measured at baseline and at one month later. The patients without monitoring of tumor-markers were excluded. A response of tumor-marker was defined as a decrease of at least 25%. Clinical data including radiological response according to the Response Evaluation Criteria In Solid Tumors ver. 1.1 were prospectively collected. S100P, CEA, and CA19-9 responses were tested in association with progression free survival (PFS) and overall survival (OS). Results: Fifty patients were analyzed in this study (male: 64%, median age: 67 years, Eastern Cooperative Oncology Group performance status [PS] 0: 60%). All of 50 patients received chemotherapy (gemcitabine [GEM]: 13 pts, GEM doublets: 34 pts, 5FU-based regimen: 3 pts). PFS and OS were 2.8 and 6.1 months. Responses of S100P, CEA, and CA19-9 were founded in 50%, 16%, and 32% of all, respectively. Multivariate analysis for PFS in Cox regression hazard model was performed using age, gender, PS, CEA, CA19-9, and S100P, and revealed that the independent predictors to longer PFS were responses of S100P (HR to progression: 0.47, P=0.02) and CEA (HR: 0.29, P=0.01). S100P or CEA responders showed better OS in univariate analysis using log-rank test, compared to non-responders of S100P (responder vs. non-responder: 8.4 vs. 3.7 months, P=0.04) or CEA (12.0 vs. 5.9 months, P=0.02), but not in multivariate analysis. Conclusions: Biochemical response of S100P might be useful for monitoring response to chemotherapy in advanced PC, which warranted further study in relationship between serum S100P response and treatment efficacies.
Cytology from endoscopic retrograde cholangiopancreatography in the evaluation of invasive pancreatic head intraductal papillary mucinous neoplasm: A necessity?
Authors: Roch Alexandra M , House Michael Garrett , Sharma Neil R , Cioffi Jessica L , DeWitt John M , Easler Jeffrey J , Ceppa Eugene P , Zyromski Nicholas J , Nakeeb Attila , Schmidt C. Max
Published: February 2017

266

Background: Endoscopic retrograde cholangiopancreatography (ERCP) with brushing/fluid sampling has historically been the standard to establish invasive transformation of pancreatic head intraductal papillary mucinous neoplasm (IPMN). More recently, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) has been employed for this purpose. We hypothesized that for patients with invasive IPMN, in the era of EUS FNA, there is no additional benefit of ERCP brushing/fluid sampling. Methods: A retrospective review of a prospectively maintained database of patients who underwent surgical resection for IPMN at a single academic center (1992-2014) was performed. Patients with invasive pancreatic head IPMN on surgical pathology were included. Cytopathology was considered positive if it showed adenocarcinoma or markedly atypical cells. Results: Of the 74 patients with invasive IPMN, 55 had a pancreatic head neoplasm. Preoperatively, 4 patients had neither EUS nor ERCP, 27 had only 1 endoscopic study (ERCP n=16, EUS n=11), and 24 had both EUS and ERCP. In 11 patients with EUS, 8 had positive FNA (73% sensitivity for cancer detection). In 16 patients with ERCP (brushing n=7, fluid n=9), 5 had positive cytology resulting in 31% sensitivity. Further analysis revealed 29% and 33% sensitivity for brushing and fluid sampling, respectively. When both procedures were performed (n=24; EUS+ERCP fluid n=10, EUS+ERCP brushing n=14), the sensitivity was 75%, but ERCP cytology changed the diagnosis in only 2 patients. EUS FNA was performed regardless of ERCP cytology results in 18 patients (after brushing n=6, after fluid sampling n=4, same day n=8; median interval=4 days). 6 patients had negative cytology from both EUS and ERCP. Conclusions: In patients with invasive pancreatic head IPMN, sensitivity of ERCP cytology for cancer detection was poor (31%), making an impact on diagnosis in only 2/55 patients. EUS FNA was performed in 75% patients regardless of ERCP cytology results. Aside from the therapeutic impact of ERCP (biliary endoprosthesis in jaundiced patients), its cytological role is limited, resulting in unnecessary and potentially avoidable cost.
Effect of light irradiation by light emitting diode on colon cancer cells and cancer stem cells.
Authors: Nishi Masaaki , Shimada Mitsuo , Yoshikawa Kozo , Higashijima Jun , Nakao Toshihiro , Takasu Chie , Eto Shohei , Teraoku Hiroki
Published: February 2017

271

Background: Recent studies demonstrate the efficacy of irradiation from light emitting diodes (LED) for wound healing and anti-inflammation and anti-cancertherapies. However, little is known about the effects of LED in colon cancer cells. Furthermore, most solid cancers are believed to be initiated from and maintained by cancer stem cells (CSCs). The purpose of this study was to evaluate the biological response of human colon cancer cells and CSCs to LED irradiation. Methods:  Human colon cancer cells (HT29 or HCT116) were seeded onto laboratory dishes that were put on LED irradiation equipment with a 465 nm-, 525 nm-, or 635 nm-LED. Irradiation at 15 or 30 mW was performed 10 min/day, each day for 5 days. Cell counting kit8 was then used to measure cell viability. Apoptosis and expression of several mRNAs (caspase, MAPK and autophagy pathway) in HT29 cultures irradiated with 465 nm LED were evaluated via AnnexinV/PI and RT-PCR, respectively.  HCT-116 cell line was cultured with fetal bovine serum in RPMI-1640 medium and its sphere was grown in serum-free non-adherent culture. Cancer sphere were seeded onto laboratory dishes that were then put on LED irradiation equipment with a 465 nm-LED. Stemness gene and cell surface markers of CSCs expressions (Oct4, CD44, Nanog, EPCAM) were analyzed by RT-PCR. Results:  Viability of HT29 and HCT116 cells was lower in 465 nm-LED irradiated cultures than in control cultures, but viability of HT29 cells did not differ between control cultures and 525 nm-LED or 635 nm-LED irradiated cultures. Moreover, the expression of FAS, caspase3, capase8, and JUK were significantly higher in 465 nm-LED irradiated cultures than in control cultures, and expression of ERK1/2 and LC3 was lower in blue-irradiated cells.  Cell viability of cancer sphere were significantly decreased by LED irradiation(p<0.05). And, stemness gene and cell surface markers of CSCs expressions (Oct4, CD44, Nanog, EPCAM) were significantly decreased by LED irradiation (p<0.05) Conclusions: LED irradiation at 465 nm inhibited the proliferation of both normal colon cancer cell lines and CSCs.
The Yale Gastrointestinal Cancer Biorepository: A comprehensive biospecimen and data resource for studying determinants of pancreatic ductal adenocarcinoma prognosis following curative-intent pancreaticoduodenectomy.
Authors: Gould Rothberg Bonnie Elyssa , Deminie Carol , Lazowski Heather , Gibson Joanna A , Cha Charles , Lacy Jill , Hochster Howard S. , Salem Ronald R
Published: February 2017

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Background: Although surgical resection can be curative for pancreatic ductal adenocarcinoma (PDAC), only 20% of patients qualify and, of these, only 20% survive for 5 or more years. Because tumor biology, germline genetics, environmental exposures and lifestyle factors all contribute, we designed the Yale Gastrointestinal (GI) Cancer Biorepository to partner biospecimen science best practices with comprehensive clinico-epidemiologic annotations evaluate determinants of outcome for PDAC and other GI cancers. Methods: Adult patients presenting to Yale GI Oncology Clinics with incident cancers who consent are interviewed using a validated instrument to capture demographics, medical comorbidities, family history of cancer, employment history and lifestyle choices including tobacco, alcohol, diet and physical activity. Buffy coat and 20 mL of plasma are collected pre-operatively. Surgical Pathology provides three 3 mm tissue cores to be stored in RNALater at -190°C in addition to formalin-fixed tissue blocks with time to fixation at ≤30 minutes. Confirmatory touch-preparations are required for all RNALater-preserved specimens. Periodic medical record abstraction documents recurrence, progression, treatment and vital status. Quality-of-life and lifestyle reassessments occur at 6 and 12 months post-diagnosis then annually thereafter. Results: Since our March 2012 launch, we consented 388 individuals including 57 PDAC patients undergoing pancreaticoduodenectomy with 16 (28%) having received FOLFIRINOX-based neoadjuvant therapy prior to surgery. Median follow-up is 7.9 months with 11 PDAC recurrences and 7 PDAC-related deaths confirmed. Receipt of neoadjuvant therapy trended towards downstaged cancers upon resection (p=0.08). Women (n=20) were more likely to be older (p=0.02) and trended towards less advanced cancers (p=0.06) but smoked, used aspirin similarly and have BMIs comparable with men (n=37). Exome and transcriptome analysis of tumor and germline are ongoing. Conclusions: Determinants of early-stage PDAC prognosis will emerge as this cohort matures.
Characterization of a novel mutation in fibrolamellar hepatocellular carcinoma.
Authors: Riggle Kevin M , Kenerson Heidi , Kazami Machiko , Bauer Renay , Yeung Raymond Sze , Riehle Kimberly J
Published: February 2017

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Background: Fibrolamellar hepatocellular carcinoma (FL-HCC) is a subtype of HCC occurring in children and young adults in the absence of underlying liver disease. Currently, there is no effective therapy for unresectable or metastatic FL-HCC. Recent genomic analysis identified a consistent mutation in FL-HCC involving a deletion on chromosome 19 resulting in a chimeric transcript containing the 5’-region of a heat shock protein (DNAJB1) fused to the catalytic subunit of protein kinase A (PRKACA). We sought to characterize the resultant protein and its effects on PKA activity in human FL-HCC. Methods: We prepared tissue lysates from four snap-frozen FL-HCC samples with paired, non-tumor liver as well as adult HCCs. PKA activity was determined via a radioactive kinase assay in the presence and absence of cAMP, a PKA activator. RNA was extracted using TRIZOL, and used for qRT-PCR. Triple immuno-fluorescent labeling was performed using antibodies to PRKACA, PKA RIIα, and a nuclear marker, DRAQ5. Results: We found that expression of the chimeric transcript was increased 40-fold in FL-HCC compared to normal liver, and was significantly higher than that of wild-type DNAJB1 and PRKACA in FL-HCC. The corresponding mutant protein was highly expressed in the tumors and was unique to FL-HCC. Basal PKA activities from freshly lysed tumors and paired livers were not significantly different, but cAMP-stimulated PKA activity was significantly higher in FL-HCC tumors when compared to normal liver. Using multi-color immuno-fluorescence we detected mutant DNAJB1-PRKACA within the nucleus, while wild-type PRKACA localizes to the cytoplasm. Conclusions: The expression of DNAJB1-PRKACA is unique to FL-HCC and not found in classic forms of HCC. Markedly elevated expression of the mutant transcript is indicative of dysregulated DNAJB1 promoter activity. PKA activity in FL-HCCs remains cAMP-dependent, but is greatly enhanced in the presence of cAMP; this could reflect an altered intrinsic activity of the mutant protein and/or elevated expression. Further, the mutant protein showed aberrant localization to the nucleus. These findings suggest that DNAJB1-PRKACA in FL-HCC leads to over-activation of PKA, which may contribute to tumor development.
Effect of MM-141 on gemcitabine and nab-paclitaxel potentiation in preclinical models of pancreatic cancer through induction of IGF-1R and ErbB3 degradation.
Authors: Pace Emily , Adams Sharlene , Camblin Adam , Curley Michael , Rimkunas Victoria , Nie Lin , Iadevaia Sergio , Tan Gege , Baum Jason , Czibere Akos Gabor , Lugovskoy Alexey
Published: February 2017

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Background: Gemcitabine, the first-line treatment for pancreatic cancer, has been improved by addition of nab-paclitaxel. However, patient response to this regimen is limited. Oncogenic insulin-like growth factor 1 (IGF-1) and heregulin (HRG) signaling are associated with increased cancer risk and decreased response to anti-metabolites and taxanes. Therefore, we explored MM-141, a novel bispecific antibody that blocks ErbB3 and IGF-1 receptor (IGF-1R) signaling, in combination with nab-paclitaxel and gemcitabine in preclinical models of pancreatic cancer. Methods: Combinations with MM-141, gemcitabine, and nab-paclitaxel were investigated in pancreatic cancer cell lines, in vitro and in vivo. The effects of MM-141, gemcitabine, and nab-paclitaxel on tumor growth and signaling were measured by 3D spheroid growth, ELISA, Western, and mouse xenograft experiments. Results: In vitro studies show that IGF-1 and HRG are potent activators of AKT signaling, leading to increased pancreatic tumor cell proliferation and decreased sensitivity to gemcitabine and nab-paclitaxel. MM-141 inhibits ligand-induced AKT activation, induces IGF-1R and ErbB3 degradation better than a mixture of IGF-1R and ErbB3 antibodies, and sensitizes cells to gemcitabine and nab-paclitaxel, in vitro. In vivo, MM-141 combines favorably with a nab-paclitaxel/gemcitabine regimen, leading to curative outcomes in a subset of treated mice. Conclusions: ErbB3 and IGF-1R co-inhibition is required to inhibit AKT signaling in pancreatic adenocarcinoma cell lines. These receptors are associated with chemoresistance to gemcitabine and nab-paclitaxel, which is abrogated by co-administration with MM-141. MM-141-induced degradation of oncogenic receptor complexes is likely essential to reverse chemoresistance and enhance effects of the nab-paclitaxel/gemcitabine regimen. These data, taken together with wide-spread expression of IGF-1R and ErbB3 in Stage IV pancreatic adenocarcinoma tissue, support clinical exploration of a MM-141/nab-paclitaxel/gemcitabine regimen in frontline metastatic pancreatic cancer. Preparations for a randomized Phase 2 study are underway.
HER3 as a potential prognostic biomarker in pancreatic cancer.
Authors: Wang-Gillam Andrea , Rimkunas Victoria , Abu-Yousif Adnan , Nywening Timothy M. , Gao Feng , DeNardo David G , Linehan David , Czibere Akos Gabor , Lugovskoy Alexey
Published: February 2017

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Background: HER 3 is revealing itself to be increasingly important in HER family signaling. Understanding the role of HER 3 in pancreatic cancer may shed light on targeted therapy development. Methods: A large human pancreatic cancer tumor tissue microarray (TMA) was established at our institution from 165 patients with pancreatic cancer who underwent surgical resection. The TMA contains two cores from each patient. Clinical information of these patients has been prospectively maintained in a clinical database. Immunohistochemistry (IHC) was performed on the TMA using a monoclonal antibody against HER 3. An independent pathologist blinded to the patient data applied the H score to grade the expression level of HER 3. The association between expression levels of HER 3 and survival were evaluated by the Kaplan-Meyer product limit method and log-rank test, while the optimal cut-off for each marker was determined using the Martingale residuals from Cox proportional hazard models. Results: Out of 165 patients, 136 patients’ tumors were identified to have adequate tumor content for IHC analysis. The group with higher HER 3 levels at the cell membrane (n=50)(H score ≥150) had a superior overall survival compared to the low HER 3 membrane expression group (n=86) (22.5 months vs. 17 months; p=0.036). Interestingly, the group with higher expression levels at both the cell membrane and in the cytosol (n=37) (H score ≥190) had a more striking survival difference compared to the lower group (n=99) (26 months vs. 15 months; p= 0.035). Conclusions: Patients with high HER 3 expression either at the cell membrane only or at both the membrane and in the cytosol have longer survival, perhaps indicating a lower heregulin and inactive HER 3 signaling. Additional biomarker analyses are ongoing. The functional role of HER 3 in pancreatic cancer is being further explored to assist clinical evaluation of HER 3 targeting in pancreatic cancer.
Clinical characteristics and outcomes for gastric cancer patients over age 80: A retrospective case-control study.
Authors: Park Hee-Jung , Ahn Ji Yong , JUNG Hwoon-Yong , Lee Jeong Hoon , Choi Kwi-Sook , Jung Kee Wook , Kim Do Hoon , Choi Kee Don , Song Ho June , Lee Gin Hyug , Kim Jin-Ho , Han Seungbong
Published: February 2017

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Background: The average human life expectancy is increasing worldwide, thus proportion of elderly gastric cancer patients are also increasing. In this study, we investigated the clinical and oncologic outcomes of gastric cancer in patients over 80 years old through a case-control study. Methods: From January 2004 to December 2010, 291 patients aged over 81 years old (case group) were diagnosed and treated with gastric cancer at the Asan Medical Center. During the same period, 291 patients aged 18 to 80 years old were selected as control group. The clinical findings, histopathological parameters, and clinical outcomes of gastric cancer were reviewed retrospectively and compared between the two groups. Results: There were significant differences in overall 5-year survival rate between the two groups (30.9% vs 73.8%, P< 0.001). When analysis was confined to resectable elderly patients with favorable performance of American Society of Anesthesiologists (ASA) score 1 or 2, curative resection group showed significantly better overall 3- and 5-year survival rate than the conservative treatment group (73.7% and 58.8% vs 29.8% and 0%, respectively). In multivariate analysis, lower BMI and advanced TNM stage were found to be independent prognostic predictors for poorer survival. ASA score showed borderline significance for predictors for poorer survival (P=0.087). Conclusions: Although elderly patients showed advanced stage at diagnosis and poor prognosis compared to non-elderly patients, elderly patients with good performance could benefit from curative resection of gastric cancer, thus the clinical decision whether to undergo curative resection or conservative management should be made on individualized approach.
Exceptional responses in patients with upper gastrointestinal malignancies enrolled in first-in-man studies: 2002-2012.
Authors: Reese Zachary L , Tometich Danielle , Patel Shiven B. , Sharma Sunil , Garrido-Laguna Ignacio
Published: February 2017

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Background: First-in-man (FIM) studies test the efficacy and safety of novel therapeutic agents with proven in vitro activity when used for the first time in humans. Patients with advanced upper gastrointestinal malignancies (UGIM) have limited systemic treatment options. We established a database of FIM studies published from 2002-2012 to identify exceptional responders in patients with UGIM. Methods: Using a Scopus search, we compiled a database of published FIM studies enrolling patients with UGIM between 2002 and 2012. We identified exceptional responders to therapy among these patients as a complete response or a partial response lasting at least 6 months. Results: We identified 84 FIM studies enrolling at least one patient with UGIM. In total 554 patients with UGIM were enrolled including 290 pancreatic adenocarcinomas (52.3%), 110 gastric adenocarcinomas (19.9%), 83 esophageal carcinomas (15.0%), 41 hepatocellular carcinomas (7.4%), and 30 cholangiocarcinomas/gallbladder carcinomas (5.4%). One patient with pancreatic cancer treated with bosutinib, a src kinase inhibitor, had a complete response with a progression-free survival (PFS) of 42 months. Four partial responses were reported including one pancreatic cancer patient treated with CHR-3996, a histone deacetylase inhibitor (PFS 12 mo); two pancreatic cancer patients treated with trametinib, a MEK inhibitor (10 and 11.75 mo); and one cholangiocarcinoma patient treated with SB-743921, a kinesin inhibitor (11 mo). Two additional partial responses were noted without available PFS data including one pancreatic cancer patient treated with KOS-1584, a second generation epothilone, and one gastric cancer patient treated with apatinib, a VEGFR-2 inhibitor. Conclusions: Exceptional responses are seen in patients with UGIM enrolled in FIM studies. Actionable genetic aberrations may be driving disease in these patients. Further studies are needed to understand these responses at the molecular level. These molecular studies could open new treatment opportunities for patients with advanced UGIM.
LDH serum levels as prognostic and predictive factor in advanced biliary tract cancer patients treated with first-line chemotherapy.
Authors: Faloppi Luca , Del Prete Michela , Scartozzi Mario , Santini Daniele , Bianconi Maristella , Giampieri Riccardo , Cascinu Stefano
Published: February 2017

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Background: Previous data suggested that LDH serum levels may be associated with tumour hypoxia and VEGFA and VEGFR-1 over-expression. LDH may then represent an indirect marker of activated tumour neo-angiogenesis and worse prognosis in many tumour types. In our analysis, we analyzed the role of LDH serum levels in predicting clinical outcome for biliary tract cancer patients treated with first-line cisplatin and gemcitabine chemotherapy, to individuate a potentially reliable and easy to use marker for patients stratification. Methods: 71 advanced biliary tract cancer patients treated with cisplatin and gemcitabine in first-line chemotherapy were available for our analysis. For all patients, LDH values were collected within one month before treatment beginning. We chose the laboratory cut-off (Upper Normal Rate, UNR) as LDH cut-off value (450 U/l) and then we divided the patients into two groups (A and B, below and above the UNR respectively). Survival distribution was estimated by the Kaplan-Meier method. Disease control rate (DCR) was assessed with chi-square test. A significant level of 0.05 was chosen to assess the statistical significance. Results: Patients in group A (46 patients) and B (25 patients) proved homogeneous for all clinical characteristics analyzed. Median progression free survival (PFS) was 3.97 months and 1.8 months respectively in group A (patients with LDH level below the UNR) and in group B (patients with LDH level above the UNR), p=0.0064 (HR=2.07, 95%CI: 1.07-3.99). Median overall survival (OS) was 9.24 months and 2.55 months in group A and B respectively, p<0.0001 (HR=2.93; 95%CI: 1.37-6.27). DCR was 65% in group A vs. 21% in group B (p=0.004). Conclusions: Our observations seem to suggest a prognostic role of LDH in biliary tract cancer patients. Our findings showing an improved PFS and DCR in patients with low LDH serum levels also suggest a possible predictive role in patients treated with a cisplatin and gemcitabine regimen as first-line chemotherapy. After further confirmation in larger trial, these results may be relevant for a better patients stratification and selection.