tbuckley/cabot-search huggingface dataset:
Preclinical model for combined effects of metformin and vitamin D3 on colitis-associated colon neoplasia.
Authors: Wan Li, Qi-Long Wang, Hong-Xia Li, Chun-Yang Li, Nathan A. Berger, Li Li, Yongjie Wu
Journal: Journal of Clinical Oncology (2013)

e14634 Background: Metformin and vitamin D each has been shown to have anti-colon carcinogenic effects in pre-clinical and epidemiologic studies. We tested the potential synergistic effects of Metformin and vitamin D3 against colorectal neoplasia in a DMH-DSS induced colitis-associated colon neoplasia mouse model. Methods: We randomized 182 5-week old ICR male mice into 7 groups: 1) normal controls; 2) DMH controls; 3) DSS controls; 4) DMH + DSS controls; 5) vitamin D3 (3 dosage groups), 6) metformin (3 dosage groups), and 7) vitamin D3 + metformin (3 dosage combinations). After 20 weeks of treatment, the mice were sacrificed and colon tissues were harvested and examined for multiplicity of adenoma/cancer, volume of each tumor, number and score of aberrant crypt foci (ACF). Results: Compared to the DMH + DDS controls, combination of vitamin D3 (200 IU/kg/day) and metformin (240 mg/kg/day) statistically significantly reduced the average number of adenoma/cancer per mouse formed (6.20 ± 3.68 vs. 2.20 ± 2.12, p&lt;0.01), volume (mm3 ) of tumor (115.46 ± 107.32 vs. 31.05 ± 38.26, p&lt; 0.05), number of ACF (0.46 ± 0.88 vs. 2.58 ± 1.93, p &lt;0.01), and ACF score (5.00 ± 3.26 vs. 1.23 ± 2.04, p &lt;0.01). Western blot and IHC show that vitamin D3 potentiates metformin in activating AMPK (phos-AMPK: 0.53 ± 0.01 vs. 0.70 ± 0.03, p &lt; 0.01), inhibiting AKT (phos-AKT: 0.39 ± 0.10 vs. 0.15 ± 0.04, p &lt; 0.01), S6P (phos-S6P: 0.36 ± 0.03 vs. 0.14 ± 0.04, p &lt;0.01), cyclin D1 (0.24 ± 0.02 vs. 0.06 ± 0.02, p &lt;0.01), ?-catenin (0.808 ± 0.142 vs. 0.010 ± 0.001, p &lt; 0.01), and VDR (0.182 ± 0.045 vs. 0.488 ± 0.081). Combination treatment also statistically significantly increases serum levels of IGFBP-3, with little effect on IGF-1, IGFBP-1 or IL-1?. Conclusions: Metformin and vitamin D3 synergistically inhibit the development of colorectal neoplasia in a colitis-associated mouse colon carcinogenesis model. Further study of the underlying mechanisms is warranted.
Lumen-apposing covered self-expandable metal stents for short-length gastrointestinal strictures: Will they take hold?
Authors: Todd Baron, Ian Grimm, Shayan Irani
Journal: Endoscopy (2017)

Benign strictures can occur throughout the gastrointestinal (GI) tract. Endoscopic therapy consists primarily of dilation with or without fluoroscopy. For esophageal and rectal strictures, this consists of balloon dilation and over-the-wire rigid (bougie) dilation. At other locations within the GI tract, through-the-scope balloon dilation is used. Endoscopic dilation is usually effective, though some patients may require one or more sessions to achieve an adequate response. Unfortunately, in a subset of patients, repeated dilation sessions are ineffective in maintaining an adequate lumen. Such refractory strictures are problematic, as there are few remaining options, and surgery is not often a simple matter in these patients. Electroincision is effective for short anastomotic and nonanastomotic strictures. Intralesional corticosteroid injection may have some efficacy in peptic esophageal strictures and inflammatory bowel disease-related strictures, but the outcome in short, anastomotic strictures often seems to benefit the endoscopist more than the patient, though it is often used as adjuvant therapy owing to its low risk and relatively low cost.
Restoration of pro-death function of BAX MSI mutation for selective chemotherapy in colorectal cancer cells.
Authors: Honghong Zhang, Bonnie Haferkamp, Jialing Xiang, Xin Wang
Journal: Journal of Clinical Oncology (2013)

e14707 Background: Microsatellite instability (MSI) is a common cause for a frameshift mutation in Bax the exon 3 microsatellite region leading to Bax-negative phenotype. However, we found that a unique Bax isoform (BaxΔ2) can be generated in combination of the deletion mutation (from G8 to G7) and alternative splicing. BaxΔ2 is a potent cell death inducer and specific to MSI tumors. Methods: The cell death assay, immunoblotting and immunohistochemisty are used for conducting the experiments. Results: The colon cancer cells with Bax G7, not G8, are selectively sensitive to certain chemotherapeutic drugs, such as 5-FU and Adriamycin. Unlike the parental Baxα, BaxΔ2 does not directly target to mitochondria, rather activates the caspase 8-dependent apoptotic pathway. Conclusions: Our data may provide an explanation that some colon cancer patients with “Bax negative” MSI tumor having a better prognosis and suggest that MSI colon cancer with Bax G7 mutation may potentially have a better response to selective chemotherapeutic drugs.
Clinical benefit of panitumumab after cetuximab failure in patients with metastatic colorectal cancer.
Authors: Sigurdis Haraldsdottir, Christina Sing-Ying Wu, Jeffrey Scott Rose
Journal: Journal of Clinical Oncology (2012)

e14178 Background: Panitumumab (Pmab) is a fully humanized monoclonal IgG-2 antibody against epidermal growth factor receptor (EGFR). It was approved by the FDA in September 2006 as 3 rd line therapy in metastatic colorectal cancer with disease progression on or following fluoropyrimidine (5-FU), oxaliplatin, and irinotecan chemotherapy regimens. Cetuximab (Cmab) is a chimeric monoclonal IgG-1 antibody and has been on the market since February 2004. It is unclear whether patients who have previously progressed on Cmab will benefit from therapy with Pmab. Methods: This is a retrospective analysis of 13 patients previously treated at OSUMC. The primary aim was to assess clinical benefit rate of Pmab in patients who failed Cmab. Patients were identified through our database from Sep 2006 until Dec 2011. Patient characteristics, length of treatment duration, response rate, and time elapsed from Cmab to Pmab were recorded. Clinical benefit (CR, PR, SD) was assessed by RECIST criteria. CEA was recorded. Results: Median age was 61 years (range 29-80), 8 males and 5 females. One patient had one FU-based line of chemotherapy while 12 patients had two FU-based lines of chemotherapy before starting Pmab. Five patients were KRAS wild-type, 8 were unknown. Five patients got Pmab as a single agent, 6 with FOLFIRI, 1 with irinotecan and 1 with capecitabine. Median time elapsed from stopping Cmab to starting Pmab was 4 months (range 0-25 months). One patient had a partial response to Pmab, 6 had stable disease, 2 had progressive disease and 4 patients did not have imaging studies. CEA decreased in 7 patients with mean decrease of 55% (SD +/- 34%). Median time to progression on Pmab was 5 months (range 1-13 months). Of 3 patients without clinical benefit to Cmab, 2 (67%) had clinical benefit from Pmab. Of 8 with clinical benefit to Cmab, 5 (63%) had clinical benefit from Pmab. Median duration of time from stopping Cmab to starting Pmab was similar for responders (3.5 months) and nonresponders (2.5 months). Conclusions: Our data suggest that Pmab can be given to patients previously treated on Cmab with clinical benefit seen in 2/3 of cases. Of interest, patients who did not have clinical benefit from Cmab did so with Pmab in 2/3 of cases.
Financial impact of cancer care on survivors: Results from the 2015 LIVESTRONG survey.
Authors: Aditi Narayan
Journal: Journal of Clinical Oncology (2017)

10 Background: The cost of cancer care in the U.S. was $124.5 billion in 2010, and is projected to increase by 27% to $158 billion in 2020. With an estimated 1.7 million new cancer cases every year, it is imperative to understand the financial impact of cancer care on survivors’ decision-making and daily living. Methods: In August of 2015, LIVESTRONG conducted an online survey to learn more about the financial impact of treatment on cancer survivors and their loved ones. Two similar surveys were distributed for survivors (n = 1,704) and loved ones (n = 739). Our analyses focus on the results from the survivor survey. Results: Fifty-nine percent of survivors reported that they experienced a lot of or some financial problems as a result of cancer. Eighty-five percent of survivors reported that their provider did not discuss the costs of care with them, and 12% reported that they would have altered decisions about treatment if they had known then what they know now about the financial impact of cancer. Most survivors (59%) reported that they spent less than $10,000 on out-of-pocket costs while 27% reported that they spent between $10,000 and $24,999 on out-of-pocket costs. The majority of respondents reported that they paid out-of-pocket for doctor visit co-pays (77%), transportation (60%) and medications (51%) (Table 1). Additionally, 61% of survivors reported that they had to make financial sacrifices such as using retirement savings and spending less on day-to-day living expenses. Conclusions: With costs of cancer care expected to continue rising for the foreseeable future, there is a need for more and better communication between patients and healthcare teams related to the potential financial impact of cancer care prior to treatment. Cancer institutions should consider including financial counselors as a part of care teams to inform patients of costs based on insurance status and type, and help them make educated and well-informed decisions related to their care. [Table: see text]
Combination of gemcitabine and adoptive cell therapy of autologous anti-tumor CTL induces clinical activities in patients with refractory lung cancer
Authors: U. Toh, T. Fujii, S. Takamori, M. Fukunaga, E. Ogo, N. Seki, H. Yamana, K. Shirouzu
Journal: Journal of Clinical Oncology (2007)

3053 Background: Cytotoxic T cells selectively kill autologous tumor cells is powerful for adoptive cell therapy of cancer. Gemcitabine (GEM) is able to induce molecular changes in cancer cells that make them to induce an antigen specific CTL response. This study was to evaluate the anti-tumor and the immunological activity using the CTL in combination with GEM. Methods: The 50Gy irradiated autologous tumor cells were cocultured with PBMCs and CTLs was developed with RPMI 1640 and rIL-2 (50 u/ml) for 7–14 days. Nine pts with non small cell lung cancer failed their prior chemotherapy were enrolled this pilot study. GEM regimen [intravenous (iv.) GEM (1000mg/m 2 ) - day 1, 8 and 15 ] was started without CTL administration for 1st cycle. GEM was administered at least 2 cycles with a 1-week interval and combined with iv. CTL therapy (0.9 x 10 8 - 4.6 x 10 8 cells/injection + IL-2 0.4 MIU; biweekly for 6 to 12 injections) from 2nd cycle. The mean total administered T cells were reached to 3.9 x 10 9 - 5.6 x 10 9 . PBMCs were analyzed their surface markers by Flow Cytometry and the cytokine productions of IFN-γ etc. in the serum were measured by ELISA before and after 1 st cycle of GEM administration and 3 rd cycles of CTL injection. Results: After finishing 2 cycles of GEM and 3 injections of CTL, the ratio of CD4/CD8 in PBMCs increased in 7/9 pts. In contrast, CD3/CD19 decreased in 6/9 pts. The cytokine production of IFN-γ in the serum revealed an increase after treatment, the levels of TGF-β were decreased simultaneously. There was no remarkable change in the levels of NKG2D in the PBMCs and MIG, IP10 in the serum. The clinical response showed PR/SD/PD was 2/5/2. The tumor marker proteins (CEA) were also decreased significantly in 4 of 9 pts. The adverse effects were tolerable with grade &lt;2 fever, nausea and fatigue and no bone marrow suppression was observed. Conclusions: These results suggested the synergistic enhancement of antitumor effect might be induced between CTLs and anti-cancer agent GEM. Marked clinical responses were observed in two pts after the treatment. Thus this chemo-immunotherapy will be applicable for the patients with refractory lung cancer. No significant financial relationships to disclose.
Abstract 13161: Serial Follow-Up of Clinical Condition and Ventricular Function in Patients After Repair of Tetralogy of Fallot: We Know When to Operate, Do We?
Authors: Saskia E Luijnenburg, Willem A Helbing, Adriaan Moelker, Lucia J Kroft, Maarten Groenink, Jolien W Roos-Hesselink, Yolanda B de Rijke, Mark G Hazekamp, Ad J Bogers, Hubert W Vliegen, Barbara J Mulder
Journal: Circulation (2011)

Introduction: Pulmonary valve replacement (PVR) is often considered in patients with pulmonary regurgitation (PR) after tetralogy of Fallot (TOF) repair. Timing of PVR remains controversial, in part because the course of biventricular remodeling after TOF repair is difficult to predict. We aimed to study the course of biventricular size and function in patients after TOF repair in relation to clinical parameters and to identify independent predictors for outcome variables. Methods: We prospectively included 78 nonPVR patients, age 25 (10-66) years at final follow-up (FU). Biventricular size and function (MRI), peak oxygen uptake (VO2 max.), and QRS duration were assessed at baseline and after 5 years. Results were compared to those of 52 PVR patients, age 28 (13-51) years, who had these studies in a 5-year interval before and after PVR. Results: In nonPVR patients, PR and right ventricular (RV) volumes increased during FU (RV enddiastolic volume (EDV) 130 ± 30 ◊ 138 ± 34 ml/m2, p < 0.001); RV ejection fra...
Survival in veterans with lung cancer: Cancer cachexia and the importance of weight.
Authors: Sheetal Malhotra, Kan Huang, Kosana Simeunovic, Ravi Vinnakota, Tatjana Gavrancic, Nicholas Villanueva, Donny Dietz, Kathleen Fenn, Kristen Beck, Courtney Coker, Yeun-Hee Anna Park, Swarnali Acharyya
Journal: Journal of Clinical Oncology (2015)

e20608 Background: About 50%- 60% lung cancer patients develop cancer cachexia. Knowledge of cancer cachexia trends and outcomes in different types of lung cancers can help target patients most at risk of decreased survival. In our study, we examined weight loss trends in lung cancer patients and survival according to percentage (%) weight loss as well as cancer stage involved. Methods: We conducted a chart review of lung cancer patients from 2007-2013 at a Veterans Affairs Medical Center. Data on demographics, date of diagnosis, type and Stage of cancer, date of death or end point were obtained. Body mass index (BMI) and weight before, during and after treatment were recorded and % weight loss and survival days were calculated. Patients were also categorized according to % weight loss ( < 5%, ≥ 5 and ≤ 10%, > 10%, weight gain) to assess associations between % weight loss with stage and type of cancer. Survival for the different stages and subtypes of cancer was also assessed. Descriptive statistics, t-tests, ANOVAs, and regression analysis were used for data analysis to assess differences and relationships between percentage weight loss and survival for sub-groups. Results: Data from 197 male patients were available for the study. Patient average age was 68 (SD ±8.9) years; 55% of the patients were White and 35%, African American. Of the total patients, 94 (47%) had AdenoCa, 87 (44%) had squamous cell cancer, and 16 (8%) small cell lung cancer and; 42 (21%) had stage I cancer, 11 (6%) had stage II cancer, 55 (28%) had stage III cancer and 89 (45%) had stage IV cancer. In our study, 51% of stage IV patients had lost > 10% weight compared to 13% stage I patients, 6% stage II patients, and 29% stage III patient. Total % weight loss was significantly higher (P < 0.01) and survival was significantly lower (P < 0.001) in higher stage patients as compared to those with lower stage There were no significant differences in weight loss, % weight loss or survival based on subtype of cancer. In the regression analysis, stage of the cancer (P < 0.001) and baseline BMI (P < 0.05) were significant factors predicting survival in these patients. Conclusions: Survival in veterans with lung cancer is related to percentage weight loss and stage of cancer rather than the subtype of lung cancer.
Guidelines for the definitions of time-to-event endpoints in randomized clinical trials: Results of the DATECAN Project for Breast Group.
Authors: Sophie Gourgou, Tienhan Sandrine Dabakuyo, Bernard Asselain, David Azria, David A. Cameron, Fatima Cardoso, Philip M. Poortmans
Journal: Journal of Clinical Oncology (2013)

1094 Background: With the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients, surrogate endpoints of overall survival (OS) are increasingly being used in cancer RCTs. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. The objective of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. Here, we present results for BREAST cancer. Methods: We relied on the modified Delphi consensus method, a validated formalized consensus process for the development of practice guidelines. International experts with various backgrounds and expertises were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints, events of interest and the existence of guidelines in adjuvant and metastatic settings. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee. Results: The consensus process involved 2 rounds of scoring (31 experts) and 1 in-person meeting (in parallel to ASCO'12). Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death from breast cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 150 events had to be scored for the 11 selected endpoints. Consensus was reached for 57% of the events after the 2 rounds of scoring. After the in-person meeting, consensus was reached for all the remaining events except one. Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect.
Clinical and analytical performance of non-small cell lung cancer biomarkers.
Authors: Steven M. Anderson, Li Cai, James H. Tepperberg, Hawazin Faruki
Journal: Journal of Clinical Oncology (2013)

11070 Background: A variety of biomarkers are currently used to help guide treatment decisions for patients with non-small cell lung cancer (NSCLC). These include mutation analysis for the EGFR and KRAS genes, along with gene rearrangement analysis for the ALK and ROS1 loci. In this study we have evaluated the clinical and analytical performance features of these assays in a series of formalin-fixed paraffin-embedded (FFPE) tissue samples. Methods: FFPE samples submitted for analysis of the EGFR, KRAS, ALK and ROS1 genes were evaluated using molecular and FISH assays. EGFR mutation analysis was performed using Sanger nucleic acid sequencing methods for exons 18-21. KRAS mutations were detected using allele specific PCR or pyrosequencing methods. Rearrangements involving the ALK gene were detected using break-apart FISH probes (Abbott Molecular). Genetic alterations involving the ROS1 gene were determined using FISH probes (Kreatech Diagnostics). Over 6,200 test results for these 4 markers are included in this analysis. Results: Mutations in the EGFR gene were detected in 10.1% of samples evaluated (n=3,872). A slightly higher percentage of samples from female patients (13%) had a detectable mutation compared to samples from males (7%) (chi-square p&lt;0.0001). Deletions in exon 19 (51%) were the most common alterations detected, followed by point mutations in exon 21 (35%). KRAS mutations were detected in approximately 22% of specimens. ALK gene rearrangements were observed in 3.1% of samples (n=1,524). Specimens from individuals &lt;50y of age were more likely to provide a positive result (11%) compared to samples from individuals &gt;50y of age (2.5%) (chi-square p&lt;0.0001). Gene amplification for the ALK gene was a common finding in the NSCLC samples evaluated. ROS1 alterations were detected in 2.8% of the specimens. In this cohort, no specimens were positive for both an EGFR mutation and an ALK gene rearrangement. Conclusions: Biomarker testing is well established in clinical practice for NSCLC, with results from the tests used to guide important therapy decisions. Assays for biomarkers such as EGFR, KRAS, ALK and ROS1 are robust, allowing for the analysis of multiple analytes in FFPE samples, even when the amount of tissue may be limiting.
Chronic medical conditions in adult survivors of retinoblastoma.
Authors: Danielle Novetsky Friedman, Joanne F. Chou, Kevin C. Oeffinger, Jennifer Ford, Charles A. Sklar, Yuelin Li, Mary S. McCabe, Leslie L. Robison, Ruth Kleinerman, Brian Marr, David H. Abramson, Ira J. Dunkel
Journal: Journal of Clinical Oncology (2013)

10019 Background: Increased risk of second malignant neoplasms (SMN) in retinoblastoma survivors (RBS) is well documented, but little is known about their long-term burden of chronic non-visual morbidity. Methods: RBS treated in NYC were asked to complete a comprehensive questionnaire, adapted from the Childhood Cancer Survivor Study (CCSS) surveys; frequencies of chronic conditions, excluding SMN, in 470 RBS and 2,377 CCSS siblings were calculated. A severity score, based on the NCI CTCAE v4 (ranging from grade 1 [mild] to grade 4 [disabling/life-threatening]) was assigned to each condition. Logistic regression was used to estimateodds ratios of chronic condition risk in RBS vs CCSS siblings, adjusted for age, sex, and race/ethnicity, reported as relative risks (RR) and 95% confidence intervals (CIs). Results: RBS and CCSS siblings were mean ages of 43 years (SD 11) and 38 years (SD 9), respectively, at the time of questionnaire completion. 53.6% of RBS had bilateral disease. After excluding SMN, 70.2% of RBS had at least one non-visual chronic condition while 14% had a grade 3-4 condition. The adjusted RR of a non-visual chronic condition in a survivor compared to siblings was 1.5 (95% CI, 1.2-1.8); for a grade 3-4 condition, the risk was 1.5 (95% CI, 1.1-2.1). The most common grade 3-4 non-visual conditions in RBS were hearing loss (3.6%; bilateral 5.6%, unilateral 1.3%, p=0.023) and thyroid nodules requiring partial or full thyroidectomy (3.4%; bilateral 5.6%, unilateral 0.9%, p=0.008). Rates of grade 3-4 thyroid nodules and hearing loss did not differ significantly when stratified by treatment received. Rates of all conditions in RBS are reported in the Table. Conclusions: RBS have a modestly increased risk of non-visual chronic conditions when compared to individuals of comparable age, sex and race/ethnicity. [Table: see text]