bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of tumor-infiltrating T-cell reactivity to metastatic gastrointestinal cancers.
Authors: Turcotte Simon , Gros Alena , Wunderlich John R , Hogan Katherine , Wang Qiong J. , Fetsch Patricia , Dudley Mark E. , Rosenberg Steven A. 
Published: March 2020

e14179 Background: A high density of tumor-infiltrating lymphocytes (TIL) found in gastrointestinal cancers has been associated with improved prognosis. Evidence supporting specific autologous tumor recognition by TIL remains sparse and limits the development of innovative immunotherapy approaches. Methods: Metastases from 15 GI cancer patients (13 colorectal, 1 gastric, 1 cholangiocarcinoma) processed into fragments and fresh tumor cell suspensions (FrTu) were used to grow TIL and cancer cell lines. TIL phenotype was assessed by flowcytometry and reactivity by coculture with available cryopreserved FrTu and cancer cell lines. Limiting dilution techniques were used to isolate reactive CD8+ TIL clones. T-cell receptors (TCR) were sequenced using PCR amplification. Results: TIL were expanded successfully in all 15 cases. TIL phenotype studied from 7 freshly resected colorectal cancer metastases revealed a higher percentage of immunosuppressive T cells (CD4+CD25HIFoxP3+) compared to adjacent normal tissue and blood (respectively 5.4 ± 1.0%, 1.3 ± 0.5%, and 1.0 ± 0.4% of CD3+ cells). Interferon-gamma release by TIL after their first outgrowth upon coculture with cryopreserved FrTu was significant in all 6 cases studied, with positive results ranging from 7% (3/42) to 89% (8/9) of patient’s distinct cultures. Two newly established cancer cell lines allowed extensive investigation of TIL reactivity. In a case of gastric cancer, 65% of the CD3+CD8+ TIL expanded from liver metastases expressed the same TCR. TIL clones expressing this TCR could recognize the autologous cancer cell line with a high degree of specificity, suggesting that within this tumor a productive immune response occurred. In a case of metastatic cholangiocarcinoma, two TIL clones with distinct TCR represented less than 1% of the CD3+CD8+ cells grown from an omental metastasis and the malignant ascites, but could nonetheless lyse the autologous tumor with specificity. Conclusions: Despite the immunosuppressive microenvironment of GI cancer metastases, CD8+ TIL that recognize autologous tumor with specificity can be identified and expanded in vitro. The adoptive transfer of TIL for the therapy of metastatic GI cancer patients is currently being studied.
Phase I study of ursodeoxycholic acid in combination with 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab for metastatic colorectal cancer.
Authors: Lai Lily L. , Chiu Ken , Chung Vincent M. , Lim Dean , Chao Joseph , Frankel Paul Henry , Shibata Stephen 
Published: March 2020

e14182 Background: Significant treatment advances have doubled the median survival in patients with metastatic colorectal cancer (mCRC). An emerging body of literature links cancer with aberrant metabolism. These findings suggest that treatment directed against CRC metabolism may add to improved survival outcomes. The bile acid, ursodeoxycholic acid (UDCA), lowers cholesterol and improves insulin sensitivity when used clinically. Moreover, UDCA protects against intestinal polyp development in animal and human studies. UDCA effects may be mediated through activation of FXR, since bile acids are the endogenous ligands for this nuclear receptor. FXR is a tumor suppressor in mouse models of colon cancer and a prognostic biomarker in patients with CRC. Activation of FXR with bile acids in mouse models suppresses intestinal tumorigenesis. We propose to determine the dose and safety of UDCA when added to standard therapy for mCRC. Methods: Trial Design: UDCA doses will be escalated using a 3+3 design which will stop at the MTD or at two levels above an Active Dose (AD), whichever is the lowest. The AD is defined as the dose that will activate FXR. After a 7 day run-in period of UDCA only, cytotoxic combination chemotherapy and antiangiogenic agent for mCRC will be given along with the UDCA. The use of a run-in period allows for metabolic studies to identify serum biomarkers of FXR activation and to determine an AD. Treatment or intervention planned: UDCA is given during a run-in period of 7 days. At the end of the run-in period, standard doses of 5-fluorouracil, leucovorin, oxaliplatin, and bevacizumab are added. Patients are treated until excessive toxicity, progression of disease, or surgical resection. Major eligibility criteria: Patients with mCRC are eligible. Patients with greater than 10% body weight loss within 6 months of entering the protocol, a diagnosis of diabetes and active diabetes treatment are excluded from the study. Results: Current enrollment: Cohorts 1, 2, 3 have been completed without DLT. Enrollment to Cohort 4 began in 12/2011. Conclusions: Continue dose escalation until MTD or 2 levels above AD.Clinical trial registry number: NCT00873275.
Multivariate analysis of factors affecting overall survival in minority-based population of young colorectal cancer patients: A single-institution experience.
Authors: Jain Shivi , Agrawal Kireet , Pattali Shinoj , Singh Abhijai , Agrawal Kamal , Cleveland Barbara , Mullane Michael Russell 
Published: March 2020

e14186 Background: Overall survival in colorectal cancer is influenced by obesity, age, gender and stage at diagnosis. However, in minority based populations, effect of the above factors on overall survival has not been studied in any detail. Hence, we undertook this retrospective study to evaluate effect of above factors on overall survival in young colorectal cancer patients. Methods: 1,195 subjects with colorectal cancer treated at John H. Stroger Hospital of Cook County between 2000 and 2008 were retrospectively analyzed. 179 subjects with age 50 years and younger were identified. 146 of 179 subjects with available Body Mass Index (BMI) in kg/m2 were included in the study. Effect of BMI, age, sex, race, LDH and CEA levels, stage, site of tumor, smoking and family history on overall survival was evaluated using standard statistical multivariate analysis. Results: In our population, 22 of 146(15%) were underweight (BMI<20), 56 of 146(38.4%) were normal weight (BMI 20-24.9), 46 of 146(31.5%) were overweight (BMI 25-29.9) and 22 of 146(15%) were obese (BMI >30). Male: female ratio was 1.4:1. 75 of 146(51.7%) were African American, 23 of 146(15.9%) were Caucasians. 50 of 146(34.2%) were stage IV colorectal cancer at diagnosis. On univariate analysis, BMI<20(p=0.031, HR 2.1, 95% CI 1.15-3.82), CEA >4ng/ml (p=0.005, HR 1.93, 95% CI 1.21-3.08) and stage IV colorectal cancer (p<0.001, HR 6.1, 95% CI 2.42-15.53) were significantly associated with decreased overall survival. LDH<200 U/L was significantly associated with improved overall survival (p 0.029, HR 0.6, 95% CI 0.391-0.950). On multivariate analysis, stage IV colorectal cancer was a single significant independent predictor of overall survival (p=0.001, 95% CI 2.47-27.78). CEA>4ng/ml was marginally significant for decreased overall survival (p=0.06, 95% CI 0.978-3.015). On the contrary, no statistically significant difference was found on overall survival with age, BMI>20, gender, race, tumor location, smoking and family history. Conclusions: Advanced stage and CEA >4ng/ml are independent prognostic variables for decreased overall survival in minority based population of young colorectal cancer.
A phase II study of biweekly paclitaxel and cisplatin chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma: Role of ERCC1 expression.
Authors: Huang Jing , Zhou Yi , Qu Tao , Zhang Hong-Tu , Mao You-Sheng , Zhu Hong-Xia , Quan Lan-Ping , Xing Pu-Yuan , Wang Jin-Wan , Jie He , Xu Ning-Zhi 
Published: March 2020

e14502 Background: Recurrent or metastatic esophageal cancer has poor prognosis. Currently, the standard of care for esophageal cancer includes treatment with triweekly cisplatin-based chemotherapy. However, not all patients benefit from the treatment. To improve the response and identify specific marker for patient-personalized treatment, we designed this study to assess the efficacy and safety of biweekly paclitaxel and cisplatin combination for patients with recurrent or metastatic esophageal squamous cell carcinoma. The excision repair cross-complementation group 1 (ERCC1) expression to predict response is also assessed. Methods: Forty-six eligible patients were enrolled. Paclitaxel was given at 150 mg/m2 over 3 hours on day 1 and cisplatin was given at 50 mg/m2 on day 2, every 2 weeks as one cycle. ERCC1 protein expression was assessed by immunohistochemistry staining. Results: The overall response rate was 56.5% (26/46, 95% CI 42.2 %- 70.8%). Progression-free survival was 5.6 months (95% CI, 2.8-8.4 months) and the median actuarial survival time was 17.0 months (95% CI, 12.3-21.7months). There was a significant difference in median actuarial survival between the patients with a response compared to the non-responders (22.8 months vs. 7.4 months, p<0.0001). Overall survival at 1 year was 65.0%, and at 2 years was 34.0%, respectively. The most frequent toxicity for all patients was neutropenia (37.0% and 23.9% for grades 3 and 4, respectively). Patients with ERCC1 negative tumors had a higher treatment response than the ERCC1 positive group (radiological response rates; 92.3% vs.50%, p=0.013). Conclusions: Biweekly chemotherapy with paclitaxel and cisplatin was found to be active and generally well-tolerated. Our study indicates that expression of ERCC1 evaluated by immunohistochemistry is a promising predictive marker for response in patients with metastatic ESCC receiving cisplatin-paclitaxel regimen.
Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGF-i) following stereotactic body radiotherapy (SBRT).
Authors: Barney Brandon M. , Markovic Svetomir , Laack Nadia N. , Miller Robert C. , Sarkaria Jann Nagina , Macdonald Orlan Kenneth , Olivier Kenneth R 
Published: March 2020

e14507 Background: Serious gastrointestinal injury (SGI) is a rare but documented side effect that can occur independently with agents that affect the vascular endothelial growth factor (VEGF) receptor or with stereotactic body radiotherapy (SBRT). The risk of SGI in patients treated with the combination of SBRT sequentially followed by a VEGF inhibitor (VEGF-i) is not yet quantified. We explored the incidence of SGI in patients treated with SBRT with or without VEGF-i therapy at a single institution. Methods: From May 2008 to August 2011, 76 patients with 84 primary or metastatic intraabdominal lesions underwent SBRT (median dose, 50 Gy in 5 fractions). Twenty of these patients (26%) received a VEGF-i within two years of completing SBRT (bevacizumab, n=14; sorafenib, n=4; pazopanib, n=1; sunitinib, n=1). The most common site treated with SBRT was the liver (n=43, 57%), and the most common histology was colorectal adenocarcinoma (n=18, 24%). Other common histologies included melanoma of the skin (n=14, 18%) and non-small cell lung cancer (n=10, 13%). The incidence of SGI (CTCAE v4.0 grade 3 to 5 ulceration or perforation) after SBRT was obtained, and the relationship between SGI and VEGF-i was examined. Other factors that could potentially contribute to SGI, such as radiotherapy dose to bowel, were also analyzed. Results: Seven patients (9%) experienced SGI at a median 4.6 months (range, 3-17 months) after SBRT. All seven had received a VEGF-i prior to SGI and within 13 months of completing SBRT, and five received the VEGF-i within three months of SBRT. The six-month estimate of SGI in patients receiving a VEGF-i within three months of SBRT was 38%. No SGI was noted in the 63 patients not receiving VEGF-i therapy after SBRT. The Log-Rank test showed a significant correlation between SGI and VEGF-i therapy within three months of SBRT (p=0.0006) but not between SGI and maximum radiotherapy bowel dose (p=0.20). Conclusions: The combination of SBRT and VEGF-i therapy results in a much higher risk of SGI than would be expected with either treatment given independently. Local therapies other than SBRT should be considered if a patient is likely to be treated with a VEGF-i in the future.
Cost-effectiveness of treating patients with advanced progressive pancreatic neuroendocrine tumors with everolimus versus sunitinib in the United States.
Authors: Chulikavit Maruit , Casciano Roman , Perrin Allison , Liu Zhimei , Wang Xufang , Babigumira Joseph , Grzegorzewski Kris , Garrison Louis P 
Published: March 2020

e14525 Background: Everolimus and sunitinib were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). This analysis examined the projected cost-effectiveness of everolimus versus sunitinib in this disease setting from a US payer perspective. Methods: A lifetime (20-year) Markov model was developed to simulate a cohort of advanced, progressive pNET patients and to estimate the cost per life-year (LY) gained and quality-adjusted life-year (QALY) gained when treating with everolimus as compared to sunitinib. Absent head-to-head trials, efficacy data were based on a weight-adjusted indirect comparison of the two agents using the respective phase 3 trial data. Disease or health states considered in the model included: stable disease with no adverse events, stable disease with adverse events, disease progression, and death. Costs of anti-tumor therapies, symptomatic care drugs, and post-progression therapy were based on wholesale acquisition cost. Other costs including physician visits, tests, infusions, hospitalizations, adverse event costs, and end-of-life care costs were obtained from literature and/or standard sources such as the Healthcare Cost & Utilization Project and Medicare reimbursement rates. Utility inputs were based on a time trade-off study conducted in the United Kingdom. Sensitivity analyses were conducted to test the model’s robustness. Results: In the base case analysis, the estimated gain of everolimus over sunitinib was 0.448 LYs (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LY ($41,702/QALY gained), which fell within the cost per QALY range for many other widely used oncology drugs. The ICER was most sensitive to the uncertainty of the sunitinib trial outcomes: however, a probabilistic sensitivity analysis found consistent results across simulations. Conclusions: While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies rather than a single head-to-head trial, everolimus is projected to be cost-effective relative to sunitinib in advanced pNET.
CONKO-008: Oxaliplatin (O)/folinic acid (FA)/5-fluorouracil (5-FU) (24h) in combination with lapatinib as second-line therapy in pancreatic cancer after gemcitabine failure: A phase I trial.
Authors: Stieler Jens , Pelzer Uwe , Sinn Marianne , Striefler Jana Kaethe , Dörken Bernd , Riess Hanno 
Published: March 2020

e14533 Background: ErbB-1 and ErbB-2 as its enhancer are expressed in pancreatic cancer. Based on the results of the 2nd-line chemotherapy (CT) with Oxaliplatin, 5-FU and Folinic acid (OFF) (CONKO-003; ASCO 2008) and the activity of EGFR- tyrosine kinase inhibition in pancreatic cancer (Moore JCO 2007), this trial aims to further improve therapeutic options for patients after Gemcitabine failure by combining OFF with lapatinib, a combined ErbB-1 and ErbB-2 tyrosine kinase inhibitor which showed preclinical synergy with 5-FU (Kim PloS One 2009). Methods: The daily dose of lapatinib combined with oxaliplatin 85 mg/m2 (2-4 h infusion d 8, 22), 5-FU 2000 mg/m2 (24 h continuous infusion d1,8,15,22 q d 42) and FA 200 mg/m2 (30 min infusion d1,8,15,22 q d 42). was expected to be between 750 to 1,500 mg, further dose intensification was not planned. Starting dose for lapatinib was set on 1,000 mg/day, with a minimum of 3 pts. on each level and extension to 6 pts. in case of a dose limiting toxicity (DLT). Maximum tolerated dose (MTD) was defined as a dose level (DL) below the level where 2/6 patients would show DLTs during cycle 1. Results: 18 Pts (12m/6w). have been enrolled in the trial.7 pts. were treated on 1,000 mg/d (DL 1), 5 pts. on level 1,250 mg/d (DL 2), and 6 pts. on 1,500 mg (DL 3). DLTs were met on DL 3 with diarrhea CTC grade 4 and concomitant neutropene enterocolitis in one patient and diarrhea CTC grade 3 in another patient. MTD is thus limited to 1,250 mg lapatinib in combination with OFF. Conclusions: With diarrhea as most prominent cumulative toxicity of the regimen, the maximum dose of lapatinib in combination with OFF is 1,250 mg. This dose may find further use in future phase II trials.
Dosing patterns of octreotide LAR among elderly patients with neuroendocrine tumors: Analysis of the SEER-Medicare database.
Authors: Xu Ying , Shih Ya-Chen T. , Leary Colleen , Shen Chan , Yao James C. 
Published: March 2020

e14550 Background: Octreotide LAR is used for treatment of hormonal syndromes associated with NETs and may delay tumor progression. Although various dosages and schedules of administration have been reported, a systematic analysis has not been performed. Methods: Using the SEER-Medicare database, we identified patients diagnosed with NETs between July 1999 and December 2007. We then excluded those patients with poorly differentiated histology, under age 65 at diagnosis, enrolled in HMOs, and who did not have continuous Part A & B enrollment between NET diagnosis and the end of 12 months after the initial octreotide LAR use. HCPCS codes, J2352 and J2353, were used to identify octreotide LAR from Medicare claims. For each patient, mean octreotide LAR dose per month was calculated and classified into five dosing categories, ≤ 10, 11-20, 21-30, 31-40, >40 mg, for the initial 3 months and every subsequent 3 months during the first year. Results: A total of 3,543 octreotide LAR treatments were observed among 355 patients during their first year of therapy. Dose given on a single day ranged from 10 mg to 90 mg. 86 (24.2%) patients required a ≥ 30% escalation in dose during the first year of therapy. The distributions of the mean monthly doses by dosing categories for the initial 3 months and the highest use 3 months during the first year are included in the Table below. 134 (37.7%) patients required doses greater than 30 mg per month. Conclusions: Our analyses showed that patients frequently required the escalation of octreotide LAR dose during their course of illness. A substantial number of patients required doses greater than the FDA approved dose of 30 mg per month. [Table: see text]
MEK/ERK pathway characterization and its prognostic implication in gastric cancer (GC).
Authors: Martin-Richard Marta , Tibau Ariadna , Ferre Malena , Castillo-Martin Mireia , Colomer Anna , Erill Nadine , Sancho Francesc , Gich Ignasi , Barnadas Agust 
Published: March 2020

e14552 Background: MEK/ERK pathway is considered one of the main controllers of cell proliferation and survival and its deregulation has been involved in several tumors. Different mechanisms have been described leading to ERK activation and nuclear translocation including mutations on genes encoding pathway constituents', or upstream factors overexpression. Little is known about the status of this pathway in GC. The aim of our study was to evaluate the expression of different factors of this pathway in GC and their correlation with patient outcome. Methods: Fifty-eight patients with localized stage Ib-III GC who underwent radical surgery followed by adjuvant chemoradiotherapy were selected. ERK and its activated form (pERK) expression were analyzed by IHC, and KRAS and BRAF mutations were determined by PCR. Additionally, expression of upstream factors such as EGFR, HER2, VEGFR and downstream factor such as MST2 was evaluated by IHC. Finally, EGFR and HER2 copy number alterations were analyzed by FISH. Association of these markers to overall survival was assessed using the log rank test, and survival curves were plotted with Kaplan-Meier methodology. Results: Among the 58 tumors analyzed, 7% arose from the cardias and 33% corresponded to signet ring cell carcinomas. ERK and pERK expression was observed in the majority of tumors (86 and 64%, respectively, p=0.002). Cytoplasmic pERK expression did not show any association with the clinico-pathological characteristics. Notably, nuclear pERK (pERKnc) expression was observed in 12% of the cases and it showed a significant correlation with patient survival (p=0.05), conferring a worse prognosis. Moreover, EGFR overexpression (p=0.03) correlated with pERKnc. Finally, multivariate Cox analysis for survival confirmed that stage (HR 0.31, p=0.01) and pERKnc (HR 2.7, p=0.04) are unique independent prognostic factors. Conclusions: MEK/ERK pathway is commonly activated in localized GC, backed up by ERK and pERK being highly expressed in these tumors. Moreover, EGFR expression correlates with nuclear ERK expression, suggesting that ERK translocation to the nucleus could be mediated by this factor. More importantly, nuclear ERK has appeared as an independent marker of poor prognosis.
Treatment outcomes of peritoneal carcinomatosis arising from gastric cancer with no measurable disease using systemic chemotherapy.
Authors: Lee Guk Jin , Hong Sook Hee , Roh Sang Young , Hong Young Seon , Song Kyo Young , Park Cho Hyung , Lee Myung Ah , Kang Jin Hyoung , Lee Hee Yeon , Hong Ji Hyung , Jung Yun Hwa , You Si Young 
Published: March 2020

e14558 Background: Although many clinical trials of newly developed chemotherapeutic drugs have been conducted, limited studies have focused on gastric cancer patients specifically diagnosed with peritoneal carcinomatosis (PC) without measurable regions. In the current study, we characterized the outcomes of systemic chemotherapy and prognostic factors for patients with gastric cancer PC, particularly in cases without measurable disease. Methods: Clinical data from 211 gastric cancer PC patients (137 without and 74 with measurable disease) subjected to systemic chemotherapy between January 2000 and December 2010 at a single center were reviewed. Results: Median OS rates of gastric cancer PC patients with no measurable disease were significantly longer than those of patients with measurable disease (18.2 vs 12.0 months, p=0.011). In multivariate analysis, poor PS (Hazard ratio (HR) = 2.33, 95% CI, 1.42-3.8, P=0.001), presence of metastatic lymphadenopathy (LAP) (HR=2.23, 95% CI, 1.42-3.5, p=0.002) and high-grade PC (HR=1.82, 95% CI, 1.09-3.04, p=0.025) were associated with significantly decreased OS. Combined with clinical PC grade and measurability of disease, median OS of patients with low-grade PC without measurable disease was 19.6 months (95% CI, 15.5-23.7 months). Median OS rates of 12.6, 13.7 and 6.8 months were estimated in high-grade PC without measurable disease, low-grade PC with measurable disease, and high-grade PC with measurable disease, respectively. Median OS of low-grade PC patients with no measurable disease was significantly higher than that of patients in all other groups (p=0.001, p=0.029 and p<0.001, respectively). Conclusions: Gastric cancer PC is a heterogeneous disease entity. In our study, clinically low-grade PC without measurable disease was associated with better outcomes than other groups following systemic chemotherapy. According to the carcinomatosis grade, specific groups of patients may benefit from systemic chemotherapy. Despite the difficulties of response assessment, further clinical trials for newer treatment strategies and molecular studies focusing on the heterogeneity of gastric cancer PC should be introduced.