tbuckley/cabot-search huggingface dataset:
Fracture Risk After Initiation of Use of Canagliflozin
Authors: Michael Fralick, Seoyoung C. Kim, Sebastian Schneeweiss, Dae Kim, Donald A. Redelmeier, Elisabetta Patorno
Journal: Annals of Internal Medicine (2018)

Background: Sodium–glucose cotransporter-2 inhibitors promote glycosuria, resulting in possible effects on calcium, phosphate, and vitamin D homeostasis. Canagliflozin is associated with decreased bone mineral density and a potential increased risk for fracture. Objective: To estimate risk for nonvertebral fracture among new users of canagliflozin compared with a glucagon-like peptide-1 (GLP-1) agonist. Design: Population-based new-user cohort study. Setting: Two U.S. commercial health care databases providing data on more than 70 million patients from March 2013 to October 2015. Patients: Persons with type 2 diabetes who initiated use of canagliflozin were propensity score–matched in a 1:1 ratio to those initiating use of a GLP-1 agonist. Measurements: The primary outcome was a composite end point of humerus, forearm, pelvis, or hip fracture requiring intervention. Secondary outcomes included fractures at other sites. A fixed-effects meta-analysis that pooled results from the 2 databases provided an overall hazard ratio (HR). Results: 79 964 patients initiating use of canagliflozin were identified and matched to 79 964 patients initiating use of a GLP-1 agonist. Mean age was 55 years, 48% were female, average baseline hemoglobin A1c level was 8.7%, and 27% were prescribed insulin. The rate of the primary outcome was similar for canagliflozin (2.2 events per 1000 person-years) and GLP-1 agonists (2.3 events per 1000 person-years), with an overall HR of 0.98 (95% CI, 0.75 to 1.26). Risk for pelvic, hip, humerus, radius, ulna, carpal, metacarpal, metatarsal, or ankle fracture was also similar for canagliflozin (14.5 events per 1000 person-years) and GLP-1 agonists (16.1 events per 1000 person-years) (overall HR, 0.92 [CI, 0.83 to 1.02]). Limitation: Unmeasured confounding, measurement error, and low fracture rate. Conclusion: In this study of middle-aged patients with type 2 diabetes and relatively low fracture risk, canagliflozin was not associated with increased risk for fracture compared with GLP-1 agonists. Primary Funding Source: Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.
Liver and/or lung metastasectomy after cetuximab or bevacizumab+FOLFIRI chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Sang-A Kim, Ji-Won Kim, Koung Jin Suh, Jin Won Kim, Heung-Kwon Oh, Jai Young Cho, Duck-Woo Kim, Keun-Wook Lee, Sukki Cho, Jee Hyun Kim, Kwhanmien Kim, Sung-Bum Kang, Sanghoon Jheon
Journal: Journal of Clinical Oncology (2018)

843 Background: Some mCRC pts who have liver and/or lung metastases (LLMs) could achieve cure after palliative chemotherapy and conversion surgery (CS) including metastasectomy. Though targeted agents including bevacizumab and cetuximab significantly improved outcomes in mCRC pts, the effect of targeted agents on cure rate after CS has not yet been thoroughly investigated. Methods: We analyzed clinical data of mCRC pts who initially had unresectable LLMs regardless of their size and number and underwent first-line cetuximab or bevacizumab+FOLFIRI. Pts who had metastasis other than liver and lung were excluded. Results: From January 2013 to May 2016, 87 pts (male, 56) were consecutively enrolled: liver-limited metastasis in 42 pts (48.3%), lung-limited metastasis in 17 pts (19.5%), and both liver and lung metastases in 28 pts (32.2%). Median age was 62 years (range, 37-85). K-RAS or N-RAS mutation was detected in 39 pts (46.4%) and B-RAF in 2 pts (3.1%) among mutation evaluated pts. Among them, 35 pts (40.2%) received cetuximab+FOLFIRI and the others (N = 52, 59.8%), bevacizumab+FOLFIRI. Median follow-up time was 20.0 months (range, 1.9-49.1). Response rate was 65.7% in the cetuximab group (CET) and 42.3% in the bevacizumab group (BEV) ( p= 0.032). Median progression-free survival was 19.1 months (95% confidence interval [CI], 11.2-27.1) in CET and 14.1 months (95% CI, 11.5-16.8) in BEV ( p= 0.249). CS was performed in 24 pts (27.6%) after median 8.7 months (range, 2.5-27.3) after initiation of chemotherapy. In CET, 11 pts (31.4%) including 8 pts with partial response (PR) and 3 pts with stable disease (SD) underwent CS and all (100%) attained R0. In BEV, 13 pts (25%) including 6 pts with PR and 7 pts with SD received CS and 11 of them (84.6%) achieved R0. Among pts with R0 resection, median disease-free survival (DFS) was 8.8 months (95% CI, 4.9-12.7) in CET and 3.2 months (95% CI, 0.0-7.4) in BEV ( p= 0.326). Conclusions: A substantial proportion of pts could receive CS after cetuximab or bevacizumab+FOLFIRI chemotherapy. CET tended to show higher rate of CS. However, the median DFS after R0 resection was not significantly different between the two groups.
Inferring clonal composition from multiple sections of a breast cancer.
Authors: C. Anthony Blau, Habil Zare, Junfeng Wang, Chaozhong Song, Alex Hu, Kris Weber, Josh Smith, Debbie Nickerson, Daniela Witten, William Noble
Journal: Journal of Clinical Oncology (2014)

11077 Background: Cancers arise from successive rounds of mutation and selection, generating clonal populations that vary in size, mutational content and drug responsiveness. Ascertaining the clonal composition of a tumor is therefore important both for prognosis and therapy. Methods: Mutation counts and frequencies resulting from next-generation sequencing (NGS) potentially reflect a tumor's clonal composition; however, deconvolving NGS data to infer a tumor's clonal structure presents a major challenge. We propose a generative model for NGS data derived from multiple subsections of a single tumor, and we describe an expectation-maximization procedure for estimating the clonal genotypes and relative frequencies using this model. Results: We demonstrate, via simulation, the validity of the approach, and then use our algorithm to assess the clonal composition of a primary breast cancer and associated metastatic lymph node. After dividing the tumor into subsections, we perform exome sequencing for each subsection to assess mutational content, followed by deep sequencing to precisely count normal and variant alleles within each subsection. By quantifying the frequencies of 17 somatic variants, we demonstrate that our algorithm predicts clonal relationships that are both phylogenetically and spatially plausible. Conclusions: Applying this method to larger numbers of tumors should cast light on the clonal evolution of cancers in space and time.
TAp73 Modifies Metabolism and Positively Regulates Growth of Cancer Stem–Like Cells in a Redox-Sensitive Manner
Authors: Tanveer Sharif, Cathleen Dai, Emma Martell, Mohammad Saleh Ghassemi-Rad, Mark Robert Hanes, Patrick J. Murphy, Barry E. Kennedy, Chitra Venugopal, Minomi Subapanditha, Carman A. Giacomantonio, Paola Marcato, Sheila K. Singh, Shashi Gujar
Journal: Clinical Cancer Research (2018)

Stem-like cancer cells, with characteristic self-renewal abilities, remain highly refractory to various clinical interventions. As such, stemness-inhibiting entities, such as tumor suppressor p53, are therapeutically pursued for their anticancer activities. Interestingly, similar implications for tumor suppressor TAp73 in regulating stemness features within stem-like cancer cells remain unknown.Experimental Design: This study utilizes various in vitro molecular biology techniques, including immunoblotting, qRT-PCR, and mass spectrometry-based proteomics, and metabolomics approaches to study the role of TAp73 in human and murine embryonal carcinoma stem-like cells (ECSLC) as well as human breast cancer stem-like cells (BCSLC). These findings were confirmed using patient-derived brain tumor-initiating cells (BTIC) and in vivo xenograft models.TAp73 inhibition decreases the expression of stem cell transcription factors Oct4, Nanog, and Sox-2, as well as tumorsphere formation capacity in ECSLCs. In vivo, TAp73-deficient ECSLCs and BCSLCs demonstrate decreased tumorigenic potential when xenografted in mice. Mechanistically, TAp73 modifies the proline regulatory axis through regulation of enzymes GLS, OAT, and PYCR1 involved in the interconversion of proline-glutamine-ornithine. Further, TAp73 deficiency exacerbates glutamine dependency, enhances accumulation of reactive oxygen species through reduced superoxide dismutase 1 (SOD1) expression, and promotes differentiation by arresting cell cycle and elevating autophagy. Most importantly, the knockdown of TAp73 in CD133HI BTICs, separated from three different glioblastoma patients, strongly decreases the expression of prosurvival factors Sox-2, BMI-1, and SOD1, and profoundly decreases their self-renewal capacity as evidenced through their reduced tumorsphere formation ability.Collectively, we reveal a clinically relevant aspect of cancer cell growth and stemness regulation through TAp73-mediated redox-sensitive metabolic reprogramming.
Coordinating cancer care: What organizations do to deliver high-quality breast cancer care.
Authors: Nina A. Bickell, Ann Scheck McAlearney, Alexandra Moss
Journal: Journal of Clinical Oncology (2014)

6628 Background: Hospitals are reorganizing how they coordinate care. Little is known about how cancer care is effectively coordinated particularly for patients at high risk of underuse. Methods: We interviewed 75 key informants (48 clinical; 14 administrative; 11 clerical; 2 other) from 9 inner-city safety net hospitals with a high proportion of minority breast cancer patients. We used fuzzy set Qualitative Comparative Analysis focusing on defined coordination approaches, calibrating each approach between 0 and 1 based on sites’ coordination processes and assessed their relationship to adjuvant underuse. Results: Five organizational factors appear salient to coordinating adjuvant breast cancer care: 1) better performing sites had someone designated to track and re-contact no-shows; 2) handoffs include exchange of clinical information (drs speaking directly to drs) as well as clerical transfer of responsibility (clerks scheduling appointments); 3) organizational attention to clinic patients: some sites separated private & clinic patients tolerating hectic, understaffed clinics; 4) all high quality sites had integrated Electronic Medical Records - doctors could see patients’ tests and treatments across specialties; 5) organizations with a culture of patient-centeredness worked for their patients, not vice-versa. Conclusions: Organizational factors can affect care coordination & cancer care quality. Higher quality sites had a fully integrated EMR, were better at tracking no shows, managing handoffs, paying attention to clinic patients & fostering a patient-centered culture. As care coordination across sites and specialties is encouraged by federal law and regulation, specialty care silos and rigid communication systems still pose barriers to change. Improving organizational factors may increase appropriate delivery of adjuvant breast cancer therapies, particularly for vulnerable women. Site: adj underuse (%) No-show tracking Handoffs Org. attn. to clinic Integrated EMR Culture A (7.7) 1.0 0.9 0.9 1.0 1.0 B (8.3) 0.8 0.6 0.8 0.7 1.0 C (9.7) 1.0 1.0 0.7 0.7 1.0 D (10.5) 0.6 0.4 0.2 0.5 0.6 E (11.8) 0.8 0.6 0.4 0.6 0.6 F (14.3) 1.0 1.0 0.6 0.9 0.8 G (15.2) 0.0 0.3 0.2 0.2 0.2 H (20.7) 0.4 0.8 0.2 0.2 0.6 I (25.5) 0.7 0.5 0.2 0.3 0.4
Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era
Authors: Yucai Wang, Umar Farooq, Brian K. Link, Mehrdad Hefazi, Cristine Allmer, Matthew J. Maurer, Thomas E. Witzig, Thomas M. Habermann, Stephen M. Ansell, James R. Cerhan, Grzegorz S. Nowakowski
Journal: Blood (2018)
Results of a multicenter phase I/II trial of abiraterone acetate plus BEZ235 in metastatic, castration-resistant prostate cancer (mCRPC).
Authors: Adam Phillip Siegel, Alan Haruo Bryce, Amy M. Lin, Terence W. Friedlander, Andrew Caleb Hsieh, Evelyn Hang, Vivian K. Weinberg, Charles J. Ryan
Journal: Journal of Clinical Oncology (2014)

e16042 Background: Prostate cancer progression and development of resistance to abiraterone acetate (AA) is associated with loss of PTEN-mediated negative regulation of the PI3K and mammalian target of rapamycin (mTOR) signaling pathways. BEZ235 is a novel small molecule, pan-class I PI3K and mTOR signaling inhibitor which has been associated with radiologic response in patients with other advanced solid-tumor malignancies. The primary objective of the phase I portion of this study was to evaluate the feasibility, safety, and MTD of BEZ235 coadministered with the androgen synthesis inhibitor AA in the treatment of patients with mCRPC. Methods: Chemotherapy-naïve patients with mCRPC and with or without prior AA exposure were eligible. BEZ235 was administered orally via sachet per 3+3 dose escalation at a starting dose of 200 mg BID coadministered with AA 1000 mg daily and prednisone 5 mg BID until radiographic disease progression or DLT. Results: Six men were enrolled, with median age 71 (range 59-75), median baseline PSA 110.45 (26.7-233.6), median duration of prior AA treatment of 7 months (range 2-19), and baseline ECOG performance status of 0 or 1. All patients received BEZ235 at the starting dose of 200 mg BID. DLTs were experienced in 1/3 of the initial patients treated with BEZ235 200 mg BID (mucositis, gr 3), prompting cohort expansion to a total of 6 patients. Subsequently, 2 additional patients experienced DLTs (hypotension, gr 3; pneumonitis, gr 4). The most common AEs of any severity were mucositis (n = 5, 83%), diarrhea (n = 4, 67%), fatigue (n = 2, 33%), and anorexia (n = 2, 33%). The trial was terminated after 3 of the 6 patients experienced DLTs within the first 12 weeks of study participation. Conclusions: Although PI3K signaling pathway inhibition may ultimately hold promise for treatment of mCRPC, DLTs precluded administration of BEZ235 at a starting dose of 200 mg BID. Clinical trial information: NCT01717898.
A Clinical Study of Tomaralimab (OPN-305), a Toll-like Receptor 2 (TLR-2) Antibody, in Heavily Pre-Treated Transfusion Dependent Patients with Lower Risk Myelodysplastic Syndromes (MDS) That Have Received and Failed on Prior Hypomethylating Agent (HMA) Therapy
Authors: Guillermo Garcia-Manero, Elias J. Jabbour, Marina Y. Konopleva, Naval G. Daver, Gautam Borthakur, Courtney D. DiNardo, Prithviraj Bose, Parita Patel, Rami S. Komrokji, Aditi Shastri, Gail J. Roboz, Robert Matthew Miller, Sarah Arbe-Barnes, Mary Reilly, Peter McGuirk, Tara Kearney, Brian Keogh, Hagop M. Kantarjian
Journal: Blood (2018)
Molecular profiling of non-small cell lung cancer by histologic subtype.
Authors: Solange Peters, Andreas Voss, Kenneth Russell, Sherri Z. Millis, Elisabeth Brambilla
Journal: Journal of Clinical Oncology (2014)

8057 Background: A substantial proportion of NSCLC has been shown to harbour specific molecular alterations affecting tumour proliferation and resulting in sensitivity to inhibition of the corresponding activated oncogenic pathway by targeted therapies. Comprehensive tumor profiling can diagnose such alterations and may identify new alterations opening additional treatment options for all distinct NSCLC subtypes. Methods: Over 6,700 non-small cell lung cancer cases referred to Caris Life Sciences between 2009 and 2014 were evaluated; clinical diagnoses and detailed tumor pathology were collected from referring physicians. Specific profiling was performed per physician request and included a combination of sequencing (Sanger, NGS or pyrosequencing), protein expression (IHC), gene amplification/rearrangement (CISH or FISH), and/or RNA fragment analysis within potential cancer-related genes and pathways. Results: Patients were grouped into cohorts according to histological subtype – adenocarcinoma (AD) (n=4,286), squamous cell carcinoma (SCC) (n=1,280), large cell carcinoma (LCC) (n=153) and bronchioalveolar carcinoma (BAC) (n=94). Protein overexpression of cMET (>2+ in >50% cells) was higher in AD (35.9%) compared to other subgroups (12-20%) while RRM1 and TOP2A levels were lower in AD. ALK or ROS1 were rearranged in 5.3% of patients with AD compared to 3.7% of patients with LCC and 1.2% of patients with SCC. EGFR mutations were found at low prevalence in both the LCC (0%) and SCC cohorts (2.8%) compared to 21% in AD. Similar lower rates of BRAF mutations were observed in the LCC and SCC cohorts compared to AD (0%, 1.1% and 5.1%). Pathway analysis showed activating mutations in the ERK pathway in 40% of patients with AD. Only 10-12% of patients with LCC or SCC had activating mutations in the ERK pathway. Conclusions: Despite the limitations of this retrospective series, we report comprehensive profiling of the largest cohort of NSCLC. Tumor profiling reveals that ADs may be more addicted to the ERK pathway than other histological subtypes. Drugs which target cMET may also have most utility in AD. Full analysis by histological subtype and additional correlative data on protein expression, gene copy number and mutations will be presented.
Timing of angiotensin system inhibitor use and overall survival in patients on tyrosine kinase inhibitors for renal cell carcinoma.
Authors: Anthony P. Lam, John Allen, Sandy Srinivas
Journal: Journal of Clinical Oncology (2014)

e15587 Background: Recent studies have identified an association between angiotensin system inhibitors (ASIs) and improved outcomes in patients on tyrosine kinase inhibitors (TKIs) for renal cell carcinoma (RCC). However, ASI use is often a result of treatment-related hypertension (HTN), which itself is associated with improved outcomes. We set out to confirm the association between ASI use and overall survival (OS) in this patient population. We then examined whether ASI use prior to a TKI is also associated with improved OS. Methods: We included all patients with metastatic RCC treated with a TKI at the Stanford Cancer Center. Adjusted hazard ratios (HRs) were calculated using Cox regression for overall mortality by ASI use. This was repeated by ASI subtype and time of ASI use (before/after TKI). Lastly, Kaplan-Meier (KM) curves were constructed to compare OS. Results: In total, 190 patients were included and received a TKI between June 2005 to August 2013. Mean age was 61.2 years, with 72.6% male, 86.4% clear cell pathology, 84.9% ECOG PS 0-1, 71.6% prior nephrectomy and 49.0% prior HTN. After adjusting for gender, age, ethnicity, ECOG PS, prior nephrectomy and HTN, ASI use was associated with decreased mortality (HR=0.51, p<0.005). This association persisted after stratifying by ASI subtype (ARB: HR=0.65, p=0.09; ACEI: HR=0.52, p<0.005). In total, 38 patients (48%) started ASI prior to a TKI. The adjusted HR for ASI use before TKI was 0.40 (p=0.006), and ASI after TKI was 0.49 (p=0.004). KM curves for the 2 groups compared to no ASI use were constructed (Median survival 16.5 months for no ASI, 18.2 months for ASI before TKI, 34.0 months for ASI after TKI). Conclusions: Our study confirmed the association of ASI and improved OS in patients with RCC treated with a TKI. ASI use prior to TKI was also associated with improved OS. This observation argues against TKI-induced HTN as a confounder. Furthermore, our adjusted HRs suggest that the favorable effects of ASI use may possibly be greater if the medication was started prior to the initiation of a TKI.
Racial differences in radiation-induced toxicity and cytokine expression levels.
Authors: Jeremy Walston, Richard C. Zellars
Journal: Journal of Clinical Oncology (2014)

e17570 Background: African American (AA) breast cancer patients treated with breast conserving therapy reportedly have more treatment related toxicity and worse clinical outcomes than their Caucasian (CA) counter parts. Etiology for these differences is unknown. One hypothesis is that there is differential activation of the inflammatory pathway between these groups which results in different toxicity profiles. To test the premise and the hypothesis we compared toxicity profiles and pro-inflammatory cytokine expression levels between AA and CA patients receiving radiation as part of breast conserving therapy. Methods: Women receiving adjuvant whole breast radiation for breast cancer were eligible. Radiation toxicities assessed included: dermatitis, pruritis, hyperpigmentation, fatigue, subcutaneous fibrosis, and pneumonitis using standard CTCAE criteria. Cosmetic outcome was assessed using the standard Harvard scale. Serum levels of cytokines IL-6, PDGF, TNFR-1 were also assessed using multiplexed sandwich- based ELISA. All samples were run in duplicate with standard. Blood draws and toxicity assessments were obtained before (baseline), during weeks 2 and 3, and 6 months after radiation. The difference in cytokine levels between cohorts was estimate using GEE model in which the cytokine level was dependent variable and race and time were independent variables and interaction between race and time was included. Results: There are 57 patients (27 AA and 30 CA) who have completed the 6-month follow-up. Grade 1 hyperpigmentation only during the 2nd week of therapy was worse in AA than in CA (57% vs. 0% p=0.002). There was no statistically significant difference between AA and CA patients with respect to any of the other toxicity parameters assessed. Additionally, IL-6, PDGF, and TNFR1serum levels did not significantly differ between AA and CA at any of the studied time points. Conclusions: In this limited sample size, there appears to be little difference in treatment related toxicity or serum cytokine expression between AA and CA women during radiation therapy for breast cancer. This research is sponsored by The Breast Cancer Research Foundation.
Successful implementation of a cost management strategy for an outpatient oncology infusion center.
Authors: Benjamin Marshall Parsons, Misty M Abrams, Amber M Woodrum
Journal: Journal of Clinical Oncology (2014)

e17533 Background: According to the US Census Bureau, almost 1 million Americans were underinsured in 2009. Oncology medications present financial difficulties for both patients and infusion centers. Our goal was to implement cost management strategies to contain costs while maintaining an excellent level of care and provide treatment to those patients that are underinsured. Methods: The primary objectives were to identify patients that were underinsured through a review process in a timely manner; and provide those identified with drug assistance through free product replacement, copay assistance or grants. When new orders are sent to the infusion center, the information is forwarded to our utilization review department depending on insurance/non-insurance type. If the patient is underinsured, the Medication Assistance Nurse and Oncology Pharmacist are notified and drug assistance applications are completed. Once approved and drug/grant assistance is provided, the patient’s account is credited. Results: We were able to verify benefits, or lack of benefits in every patient that utilized our infusion center. In 2011 we secured 1.91 million dollars in drug and grant assistance by utilizing only the Oncology Pharmacist. In 2013, a Medication assistance nurse was added to the team to work full time with patient assistance, which allowed us to secure 5.85 million dollars in drug and grant assistance by the end of the fiscal year. By streamlining the process and dividing the workload depending on insurance type, we improved our turn-around-time to 48 hours maximum. Conclusions: Drug assistance and grant programs are an excellent way to provide treatment to patients that are underinsured while containing costs and delivering significant savings to the infusion center. It is a very laborious process and requires significant interaction among several departments. It is imperative that the process be streamlined to ensure efficiency and timely treatment.