tbuckley/cabot-search huggingface dataset:
The lipogenic phenotype reprograms the epigenome in sarcomas.
Authors: Warren Allen Chow, Min Guan
Journal: Journal of Clinical Oncology (2015)

10555 Background: The “lipogenic phenotype of cancer” enhances the metastatic potential of cancers by promoting the de novo synthesis of fatty acids (FAs) to maintain their enhanced metabolism. Further, epigenetic reprogramming also promotes the malignant sarcoma phenotype. We hypothesized that development of the “lipogenic phenotype” reprograms the sarcoma epigenome to enhance their malignant potential. Methods: Soft-tissue (STS) and bone sarcoma cell lines (SK-UT-1 leiomyosarcoma, HT1080 fibrosarcoma, and Saos-2 osteosarcoma) were transduced with a fatty acid synthase (FASN)-expressing retrovirus. FASN catalyzes the synthesis of long-chain FAs from acetyl-CoA. Acetyl-CoA is generated from pyruvate, the excess end-product of aerobic glycolysis, better recognized as the “Warburg effect.” FASN-expressing clones were subjected to proliferation, migration, and immunoblot assays. Transcriptome-wide sequencing and DNA methylation arrays were also performed. Finally, FASN expression was detected in STS clinical specimens by immunohistochemistry (IHC). Results: FASN overexpression increased sarcoma proliferation (35-47%), enhanced migration (scratch-wound assay), and increased methylation and acetylation of selected histone 3 lysines (H3K9me3 and H3K27ac). Whole transcriptome sequencing demonstrated multiple up- and downregulated genes, which generally correlated with the methylation status of their respective promoters. Finally, FASN expression was detected 1-3+ by IHC in 14/18 STS tumors by a blinded pathologist. Conclusions: FASN overexpression induces histone modifications that repress and induce genes that may enhance the malignant phenotype in sarcoma cell lines. Further, FASN is variably expressed in a majority of STS. Therapeutic targeting of FASN and epigenetic reprogramming may be a novel therapeutic approach to recurrent sarcomas.
Clinical and molecular characteristics of pediatric gastrointestinal stromal tumors (GISTs)
Authors: V. Price, M. Zielenska, C. Smith, S. Chilton-Macneill, D. Malkin, A. Pappo
Journal: Journal of Clinical Oncology (2004)

8537 Background: GISTs are the most common mesenchymal tumors of the gastrointestinal tract in adults and are characterized by c-KIT expression (CD117). The natural history and molecular characteristics of these tumors in children are virtually unknown. Objective: Describe clinical characteristics, treatment, outcome, and molecular features of pediatric GISTs. Methods: Retrospective study of 6 patients with GIST seen at HSC over an 11-year period. DNA was extracted from tumor and amplified by exon 11 specific primers to determine mutational status. Analysis of other coding sequences of the gene is being performed and will be presented at the meeting Results: The characteristics of the patients are depicted in the table.The median age at diagnosis was 13.6 years (range 6.9–14.8 years).Four patients were female. Iron deficiency anaemia secondary to gastrointestinal (GI) hemorrhage was a presenting feature in all patients. The common primary site was the stomach. Five patients presented with localized disease; one had disseminated disease to omentum. Two patients had evidence of Carney's triad. All tumors were diffusely positive for CD117 and CD34. None of the three samples available for molecular analysis revealed an exon 11 c-KIT mutation. All of the tumors were surgically resected and none of the pts received chemotherapy. Disease recurred in 1 pt, 2 were lost to follow-up, and 4 remain alive.Conclusion: GISTs should be considered in the differential diagnosis of pediatric pts presenting with anaemia secondary to a GI hemorrhage. GISTs in the pediatric population preferentially occur in the second decade of life, arise in the stomach, and do not exhibit an exon 11 c- KIT mutation. The latter findings suggest that pediatric GISTs may have biological differences compared to adult GISTs. Multicenter trials are needed to better elucidate the natural history, molecular phenotype, and therapies for these pts. No significant financial relationships to disclose.
A multicenter phase 2 clinical trial testing a combination of oxaliplatin, bolus 5-fluorouracil, leucovorin and capecitabine in patients with metastatic colorectal cancer (MCRC)
Authors: N. K. LoConte, K. D. Holen, J. Eickhoff, T. Dzelak, K. Richie, K. Teeter, D. Warren, A. J. Jumonville, R. W. Kwong, D. L. Mulkerin
Journal: Journal of Clinical Oncology (2007)

14526 Introduction: The combination of oxaliplatin (OX) with bolus and infusional 5FU has shown high activity in MCRC. Substituting capecitabine (CAPE) for 5FU in a novel high-dose schedule designed to mimic FOLFOX-6 is a feasible and well tolerated treatment (Hegeman, ASCO, 2005, #2058). A multicenter phase 2 study of this combination was performed to evaluate efficacy in first-line treatment of MCRC. Methods: Eligible patients have ECOG PS 0–2, no grade 2 or higher neuropathy, and no prior systemic treatment for metastatic cancer. Patients are treated with OX 100 mg/m2, leucovorin (LV) 20 mg/m2 and 5FU 400 mg/m2 IV bolus followed by CAPE 1500 mg/m2 PO Q8H x 6 doses, repeated every two weeks. The primary endpoint was confirmed antitumoral response. Patients were allowed to come off study to pursue surgical resection, if feasible. Results: 36 out of a planned 45 patients have been enrolled since 6/04. Survival (OS) and time to progession (TTP) data are available for all 36 patients. Toxicity and efficacy data is available for 33 patients. The median age of enrolled patients is 65.5 years (range 42–78). 16 (44%) of patients are male. 94% of patients are ECOG PS 0 or 1. Toxicity data is presented in the table . 14/33 (42%) of patients had a grade 3/4 toxicity (see table ). The response rate was 33% (95% confidence interval [CI] 18–52%): 11 patients achieved a partial response (33%), 14 (42%) had stable disease, and 8 (24%) had progressive disease. Median overall survival was 17.1 months (M) (CI 0.7+-27.5+ M). The one-year survival rate was 67%. The median TTP/TTF was 4.1 M (CI 0.3–14.3 M). Four (11%) patients have come off of the study protocol to pursue metastatectomy. Conclusion: OX, infusional 5FU, LV and CAPE is active and well tolerated in MCRC. This regimen had fewer episodes of grade 3–4 hand-foot syndrome and mucositis than prior regimens including longer durations of capecitabine. Study supported by sanofi-aventis. [Table: see text] [Table: see text]
Potential drug-drug interaction events in patients treated with abiraterone acetate plus prednisone or enzalutamide.
Authors: Dominic Pilon, Ajay S. Behl, Bruno Emond, Yongling Xiao, Patrick Lefebvre, Christopher J. Kane
Journal: Journal of Clinical Oncology (2017)

44 Background: The treatment of patients with advanced cancer generally requires multiple medications, and the consideration of potential drug-drug interactions (DDIs) is important to avoid unintended consequences; therefore, this study assessed potential DDIs in patients treated with oral metastatic castrate-resistant prostate cancer (mCRPC) therapies (abiraterone acetate plus prednisone [AA+P] and enzalutamide [ENZ]). Methods: The MarketScan databases from 03/2012 to 10/2015 were used to conduct a retrospective analysis, in which patients initiated on AA+P or ENZ after 09/2012 (index date) with ≥6 months of continuous eligibility prior to index date and ≥1 PC diagnosis were included. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Weighted Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare the occurrence of potential DDIs. Potential DDI was defined as having a claim for a drug that can interact with the index drug (AA+P or ENZ) during the exposure to index treatment (i.e., the time between the first and last claim [plus days of supply] of the index treatment). Interaction drugs were selected based on the prescribing information for each drug and included strong CYP3A4 inducers and CYP2D6 substrates for AA+P and strong CYP3A4 inducers, CYP2C8 inhibitors, CYP2C9 substrates, CYP3A4 substrates, and CYP2C19 substrates for ENZ. Results: A total of 2,540 AA+P and 1,265 ENZ patients were identified. IPTW resulted in balanced baseline demographic, comorbidities, and disease characteristics. At 3, 6, 9, and 12 months post-index, patients initiated on ENZ were more likely to have a potential DDI during their exposure to ENZ treatment when compared to patients initiated on AA+P (ENZ vs. AA+P, KM rates at 12 months: 30.3% vs. 1.5%, hazard ratio [95% confidence interval]: 28.9 [14.5, 57.4], p &lt; 0.0001). Conclusions: This study showed that mCRPC patients treated with ENZ were more likely to be exposed to a potential DDI during their treatment than those treated with AA+P.
Timing of PSA response to guide cessation of docetaxel in prostate cancer.
Authors: Peter D. Dickinson, Jahangeer Malik, Finbar Slevin, Ananth Sivanandan, Noel W. Clarke, Ananya Choudhury, Tony Elliott
Journal: Journal of Clinical Oncology (2013)

e16069 Background: Docetaxel plus prednisolone is an established treatment for men with advanced prostate cancer. Clinicians need to be able to identify men who are not benefiting from chemotherapy, and a key unanswered question is how many cycles of docetaxel should men receive before this assessment is made. We investigated the prognostic significance of a PSA response to docetaxel chemotherapy and the number of cycles after which an absence of PSA response could reliably predict future non-response. Methods: Data was collected for men who received one to ten cycles of docetaxel for castrate refractory prostate cancer between 2005 and 2011. PSA was monitored during treatment. All men were treated at a single centre, The Christie NHS Foundation Trust, UK. Survival is defined as the interval between the first dose of docetaxel and the date of death. Results: Data was available for 320 patients. At the commencement of chemotherapy, median age was 67 years (range 49-81yrs) and median PSA was 207ng/ml. All patients had a Karnofsky Performance Status ≥ 70%. There were 239 deaths and the median survival of the whole group was 403 days. 140 (44%) patients received 6 cycles of docetaxel and 23 patients (7%) received 10 cycles. Median survival was significantly longer in men who had any fall in PSA during chemotherapy compared to those whose PSA did not fall (462 days vs 268 days, p&lt;0.001). Any PSA fall occurred during the first 4 cycles of docetaxel for 95.1% of men. Median survival was significantly longer in men who had a 50% fall in PSA during chemotherapy compared to those who did not (491 vs 357 days, p&lt;0.001). The 50% fall in PSA occurred during the first 5/6 cycles of chemotherapy in 91.5% and 97.7% of men respectively. Conclusions: A patient’s clinical condition is of paramount importance when assessing them during docetaxel chemotherapy. Our data suggest that a fall in PSA following docetaxel is an indicator of improved overall survival. PSA response could help clinicians decide when to stop docetaxel; patients are unlikely to have a fall in PSA if it has not occurred during the first 4 cycles of chemotherapy and they fall into a poor prognostic group. These patients should be considered for alternative treatment in order to improve outcomes and spare them unnecessary toxicity.
Dramatic response of metastatic peripheral nerve sheath sarcoma to cetuximab combined with doxorubicin-based chemotherapy: Report of a case
Authors: J. P. Holmes, T. J. Reid
Journal: Journal of Clinical Oncology (2006)

19503 Background: Soft tissue sarcomas are aggressive tumors that often show poor response to conventional chemotherapy agents. Some of these tumors over express epidermal growth factor receptor (EGFR) which is thought to promote tumor growth. Cetuximab, a monoclonal antibody to EGFR, is FDA approved for use in colon cancer. We report a case here of use in a patient with an aggressive soft tissue sarcoma. Case Report: A 32 yr male presented in April 2005 for routine follow up three months after completing adjuvant radiotherapy for retroperitoneal soft tissue sarcoma. At this time the patient was found to have recurrence of disease on routine surveillance scans. During workup of the recurrent masses, he developed acute bowel obstruction and went emergently to the OR. Multiple masses were removed and he was rendered grossly disease free. Adjuvant adriamycin and ifosfamide were planned; however, bulky masses were again noted on a pre-chemo staging study. After a single cycle of chemotherapy, he presented with abdominal pain, and an urgent CT scan ordered showed progressive disease. Immunohistochemical stains demonstrated strong expression of EGFR on his tumor. Cetuximab was added to his chemotherapy regimen. Repeat studies showed dramatic (&gt;30%) decrease in his tumor burden after only two doses. As cycle three began, the patient developed acute abdominal pain and fever; emergent scans showed free air within the abdomen. The majority of his tumor burden had continued to decrease. The perforation could not be surgically managed and the patient was discharged to hospice. He expired ten days after discovery of the perforation. Conclusions: Addition of cetuximab to therapy for an aggressive soft tissue sarcoma which overexpressed EGFR resulted in dramatic decrease in tumor burden. Unfortunately, the patient suffered perforation of abdominal viscera and subsequently expired. Rapid tumor shrinkage likely contributed to the perforation. Use of cetuximab in patients with aggressive tumors expressing EGFR should be explored in the setting of clinical trials. No significant financial relationships to disclose.
Clinical characteristics and natural history of patients with squamous cell lung carcinoma with FGFR1 amplification.
Authors: Marc Christiaan Allardt Bos, Masyar Gardizi, Lukas Carl Heukamp, Hans-Ulrich Schildhaus, Lucia Nogova, Yon-Dschun Ko, Andreas Schlesinger, Michael Brockmann, Monika Heidi Serke, Ulrich Gerigk, Khosro Hekmat, Erich Stoelben, Marcel Reiser, Walburga Engel-Riedel, Roland Schnell, Stephan H. Schmitz, Konrad Frank, Reinhard Buettner, Juergen Wolf, Thomas Zander
Journal: Journal of Clinical Oncology (2012)

1533 Background: FGFR1 amplifications have been described as a promising oncogenic target in squamous cell lung cancer. Here we aimed at describing the clinical characteristics and natural history of FGFR1amplified squamous cell lung cancer patients. Methods: From 01/2011 to 01/2012 we screened 553 squamous cell lung cancer patients in our Network for Molecular Screening of Lung Cancer for the presence of FGFR1 amplifications by FISH analysis in accordance with the local ethics committee. FGFR1 was defined as amplified if the ratio of FGFR1 copies to centromeric copies was above 2 or if more than 50% of tumor cells showed 5 copies or if more than 15% of tumor cells demonstrated clusters of FGFR1. Clinical data were collected by extracting information from medical records, the local cancer registry and by questioning treating physicians and patients. Results: FGFR1FISH analysis could be performed in 95% of the cases and was amplified in 16%. Of the amplified cases 75 % were male and 25% female without significant enrichment for male or female. The median age of the patients at diagnosis was 67 yrs (range 46 - 82). Stage at presentation was: 16% I; 17.3% II; 26.7% IIIa, 40% IIIb/IV. 97,3% of the patients were former or active smokers with a median of 40 pack years. The median progression free survival of patients with stage IIIb/IV disease was 11 months (95% CI 8-14; n=14). The median overall survival was not yet reached after a median follow-up time of 14 months (95% CI 11 - 17; n=24). We further screened for co-existing genetic lesions such as mutations in EGFR, BRAF, KRAS, PIK3CA as well as translocations of ALK and amplifications of ERBB2. Two patients demonstrated co-occurring PIK3CA mutations and one a BRAFmutation. Conclusions: Screening for FGFR1 is feasible under routine clinical conditions. By implementation of a regional molecular screening network the ability to screen for FGFR1 amplification was successfully expanded to non-academic centers and private practices. FGFR1 amplifications in squamous cell cancer of the lung are frequent (16%) and associated with smoking history. Screening for FGFR1 might pave the way for the application of new FGFR1 directed targeted drugs in squamous cell lung cancer.
Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial
Authors: Shahin Lockman, Michael Hughes, Kate Powis, Gbolahan Ajibola, Kara Bennett, Sikhulile Moyo, Erik van Widenfelt, Jean Leidner, Kenneth McIntosh, Loeto Mazhani, Joseph Makhema, Max Essex, Roger Shapiro
Journal: The Lancet Global Health (2017)

Co-trimoxazole prophylaxis reduces mortality among HIV-infected children, but efficacy in HIV-exposed but uninfected (HEU) children in a non-malarial, low-breastfeeding setting with a low risk of mother-to-child transmission of HIV is unclear.HEU children in Botswana were randomly assigned to receive co-trimoxazole (100 mg/20 mg once daily until age 6 months and 200 mg/40 mg once daily thereafter) or placebo from age 14-34 days to age 15 months. Mothers chose whether to breastfeed or formula feed their children. Breastfed children were randomly assigned to breastfeeding for 6 months (Botswana guidelines) or 12 months (WHO guidelines). The primary outcome, analysed by a modified intention-to-treat approach, was cumulative child mortality from treatment assignment to age 18 months. We also assessed HIV-free survival by duration of breastfeeding. This trial is registered with ClinicalTrials.gov, number NCT01229761.From June 7, 2011, to April 2, 2015, 2848 HEU children were randomly assigned to receive co-trimoxazole (n=1423) or placebo (n=1425). The data and safety monitoring board stopped the study early because of a low likelihood of benefit with co-trimoxazole. Only 153 (5%) children were lost to follow-up (76 in the co-trimoxazole group and 77 in the placebo group), and 2053 (72%) received treatment continuously to age 15 months, death, or study closure. Mortality after the start of study treatment was similar in the two study groups: 30 children died in the co-trimoxazole group, compared with 34 in the placebo group (estimated mortality at 18 months 2·4% vs 2·6%; difference -0·2%, 95% CI -1·5 to 1·0, p=0·70). We saw no difference in hospital admissions between groups (12·5% in the co-trimoxazole group vs 17·4% in the placebo group, p=0·19) or grade 3-4 clinical adverse events (16·5% vs 18·4%, p=0·18). Grade 3-4 anaemia did not differ between groups (8·1% vs 8·3%, p=0·93), but grade 3-4 neutropenia was more frequent in the co-trimoxazole group than in the placebo group (8·1% vs 5·8%, p=0·03). More co-trimoxazole resistance in commensal Escherichia coli isolated from stool samples was seen in children aged 3 or 6 months in the co-trimoxazole group than in the placebo group (p=0·001 and p=0·01, respectively). 572 (20%) children were breastfed. HIV infection and mortality did not differ significantly by duration of breastfeeding (3·9% for 6 months vs 1·9% for 12 months, p=0·21).Prophylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV.US National Institutes of Health.
Tigit, CD226 and PD-L1/PD-1 Are Highly Expressed By Marrow-Infiltrating T Cells in Patients with Multiple Myeloma
Authors: Mahesh Yadav, Cherie Green, Connie Ma, Alberto Robert, Andrew Glibicky, Rin Nakamura, Teiko Sumiyoshi, Ray Meng, Yu-Waye Chu, Jenny Wu, John Byon, Joseph Woodard, Joanne Adamkewicz, Jane Grogan, Jeffrey M. Venstrom
Journal: Blood (2016)
Feasibility of collecting routine information for clinical and research purposes via electronic format questionnaire.
Authors: Yuchen Li, M Catherine Brown, Kathryn Estey, Gursharan Gill, Mindy Liang, Andrea Cosio Perez, Michael Borean, Kishan Shani, Penelope Ann Bradbury, Frances A. Shepherd, Natasha B. Leighl, Doris Howell, Geoffrey Liu
Journal: Journal of Clinical Oncology (2017)

167 Background: Patient demographics, lifestyle factors, and past medical history enable clinicians to optimize care plans, and be useful for health services research. Unfortunately, these data are often recorded inconsistently in the medical chart. In 2015, we tested a paper-form questionnaire to collect such data systematically in the outpatient setting. This current study assessed the feasibility (applicability, acceptability, practicality) of administering the questionnaire via electronic format (iPad). Objectives: To examine whether the electronic format of the questionnaire was (1) applicable (reliable and complete data); (2) acceptable to patients; and (3) practical for clinic utilization. Methods: New adult cancer patients visiting the thoracic cancer clinic at Princess Margaret Cancer Centre in summer, 2016 were asked to complete a Patient Health Questionnaire via iPad devices. This questionnaire was developed through trial testing in addition to literature review, expert opinion, and prior paper-based testing. Results: In 62 new patients (57% male, mean age 66 years old), this electronic questionnaire took on average 25 minutes to complete. The electronic questionnaire was applicable (89% completed the questionnaire, reliable data) and acceptable (69% were happy to complete, 69% found questionnaire useful, 61% thought it asked the right questions, 71% did not think it made clinic visits more difficult). For practicality, although the data were easily interpretable by clinicians, 48% of patients failed to complete the questionnaire before they were seen by their clinicians. Conclusions: Though feasible to collect electronically standardized demographics, lifestyle, and past medical history routinely, timeliness was an issue. Earlier arrival times or completion at home may be necessary to improve clinical utility of the questionnaire.