tbuckley/cabot-search huggingface dataset:
Incidence of cardiovascular events in the real-world population of cancer patients treated with targeted therapies.
Authors: Jonathan G Zaroff, Douglas A Corley, Wei K Zhao, Lina Titievsky
Journal: Journal of Clinical Oncology (2014)

1605 Background: Population-based risks of cardiovascular events (CV) among cancer patients treated with targeted therapies (tyrosine kinase inhibitors (TKIs) or drugs with similar mechanism of action (MOA)) are not available. Most estimates derive from case-series or trials. The study objective was to estimate the incidence of specific CV events in this population. Methods: A population-based cohort study of Kaiser Permanente Northern California (KPNC) members. KPNC is an integrated health program with 3.2 million members (~30% of the insured population) in 14 Northern California counties. Inclusion criteria: Cancer registry diagnosis (1997-2009) of any solid tumor excluding non-melanoma skin cancer, and with treatment with any of the following: sunitinib, sorafenib, imatinib or bevacizumab. Main (adjudicated) outcome measures: Acute coronary syndrome, heart failure (HF), ischemic stroke, hemorrhagic stroke, cardiac arrest, hypertension (HTN), deep venous thrombosis (DVT), pulmonary embolus, and CV death. Statistical analysis: The incidence rate (IR) of each CV outcome was measured as the rate of events per 1000 person years (PY) and reported with 95% confidence intervals (CI). Two follow-up periods were defined: early (treatment duration of the targeted therapy plus 60 additional days) and unrestricted (at any time after a prescription until censoring or the end of follow-up). Results: In total, ~3,000 patients met inclusion criteria for this analysis including 294 patients with renal cell carcinoma (RCC) and 80 patients with gastointestinal stromal tumor (mean age=59.5 years, 66.8% White and 2005 as a median year of cancer diagnosis). Highest IRs were observed for HTN, DVT and HF for both the early and unrestricted follow-up periods for all cancer types. For early follow up, the IR of HTN was 0 for prostate cancer, 14.6 (95%CI: 9.7-22.0) for breast cancer, and 25.7 (95%CI: 17.0-38.6) for RCC. These IRs increased to 1.8 (95%CI: 0.2-10.4), 20.7 (95%CI: 14.6-29.2), and 30.6 (95%CI: 20.9-44.4), respectively, for unrestricted follow up. Conclusions: This was the first population-based study to estimate incidence of CV events among those treated with targeted therapy, by cancer type.
Phase I trial of patupilone (P) and RAD001 in patients (pts) with advanced solid tumors
Authors: M. N. Stein, B. Knox, E. Wesolowsky, M. Levitt, R. Moss, E. Poplin, J. Mehnert, M. Gounder, S. Goodin, R. DiPaola
Journal: Journal of Clinical Oncology (2009)

2529 Background: P is an epothilone with activity in solid tumors including docetaxel (D) resistant prostate cancer. R is an oral mTOR inhibitor that demonstrates synergy with P in pre-clinical models, possibly by decreasing resistance to apoptosis. This on-going phase I study is assessing the tolerability of P in combination with R in pts with advanced solid tumors. Methods: Eligible patients with ECOG PS 0–2, adequate organ function and no more than 3 prior chemotherapy treatment received P every 21 days and weekly R using a standard 3+3 dose escalation schema in a 21 day(d) cycle starting at 50% of the phase II dose of P and 60% of the standard weekly dosing of R. Dosing levels are (1) P 5mg/m2 D1, R 30mg D1; (2) P 7.5mg/m2 D1, R 30mg D1 (3) P 7.5mg/m2 D1 R 30mg D1, D8 (3A) P 7.5mg/m2 D1 R 30mg D1, D8, D15 (3B) P 8mg/m2 D1 R 50mg D1, D8 (4) P 10 mg/m2 D1, D8 R 30mg D1, D8 (5) P 10 mg/m2 D1, D8 R 50mg D1, D8. Pharmacokinetic (PK) levels of R were obtained D1, D2 and PBMC were obtained to assess phospho-S6 and to assess markers of apoptosis and autophagy. Results: A total of 24 pts have been enrolled and 23 pts are evaluable for toxicity (tumor types: colon-7, prostate-6, lung-3, ampulla-3, leiomyosarcoma-2, cervical cancer-1). DLTs of grade(g) 3 diarrhea, g3 colitis and g3 fatigue were observed in dose levels 5, 4 and 1 pt in cohort 3A with a colostomy. Cohorts 1–3 were well tolerated with the common AEs of g1 diarrhea, g2 neuropathy after cycle 7, g1/g2 anemia, g1 triglycerides. In pts with prostate cancer (all previously pretreated with D) PSA declines of &gt;50% occurred in 3/5 pts treated with &gt;2 cycles; 1/7 pts with colon cancer had a PR and 3/7 pts with colon cancer had stable disease (SD) &gt; 8 cycles; 1/3 pts with ampullary ca had a PR and a pt with cervical ca had SD x10 cycles. Conclusions: P 7.5mg/m2 and R 30mg D1, D8 is safe and well tolerated. Encouraging evidence of clinical activity is observed in prostate, colon and other tumor types. Enrollment to cohort 3A is ongoing. [Table: see text]
Association of Tissue Abiraterone Levels and <i>SLCO</i> Genotype with Intraprostatic Steroids and Pathologic Response in Men with High-Risk Localized Prostate Cancer
Authors: Elahe A. Mostaghel, Eunpi Cho, Ailin Zhang, Mohammad Alyamani, Arja Kaipainen, Sean Green, Brett T. Marck, Nima Sharifi, Jonathan L. Wright, Roman Gulati, Lawrence D. True, Massimo Loda, Alvin M. Matsumoto, Daniel Tamae, Trevor N. Penning, Steven P. Balk, Phillip W. Kantoff, Peter S. Nelson, Mary-Ellen Taplin, R. Bruce Montgomery
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Germline variation in solute carrier organic anion (SLCO) genes influences cellular steroid uptake and is associated with prostate cancer outcomes. We hypothesized that, due to its steroidal structure, the CYP17A inhibitor abiraterone may undergo transport by SLCO-encoded transporters and that SLCO gene variation may influence intracellular abiraterone levels and outcomes. Experimental Design: Steroid and abiraterone levels were measured in serum and tissue from 58 men with localized prostate cancer in a clinical trial of LHRH agonist plus abiraterone acetate plus prednisone for 24 weeks prior to prostatectomy. Germline DNA was genotyped for 13 SNPs in six SLCO genes. Results: Abiraterone levels spanned a broad range (serum median 28 ng/mL, 108 nmol/L; tissue median 77 ng/mL, 271 nmol/L) and were correlated (r = 0.355, P = 0.001). Levels correlated positively with steroids upstream of CYP17A (pregnenolone, progesterone), and inversely with steroids downstream of CYP17A (DHEA, AED, testosterone). Serum PSA and tumor volumes were higher in men with undetectable versus detectable tissue abiraterone at prostatectomy (median 0.10 vs. 0.03 ng/dL, P = 0.02; 1.28 vs. 0.44 cc, P = 0.09, respectively). SNPs in SLCO2B1 associated with significant differences in tissue abiraterone (rs1789693, P = 0.0008; rs12422149, P = 0.03) and higher rates of minimal residual disease (tumor volume &amp;lt; 0.5 cc; rs1789693, 67% vs. 27%, P = 0.009; rs1077858, 46% vs. 0%, P = 0.03). LNCaP cells expressing SLCO2B1 showed two- to fourfold higher abiraterone levels compared with vector controls (P &amp;lt; 0.05). Conclusions: Intraprostatic abiraterone levels and genetic variation in SLCO genes are associated with pathologic responses in high-risk localized prostate cancer. Variation in SLCO genes may serve as predictors of response to abiraterone treatment. Clin Cancer Res; 23(16); 4592–601. ©2017 AACR.
Correlates of fever in patients (pts) receiving combined dabrafenib (GSK2118436) plus trametinib (GSK1120212) for V600 BRAF-mutant metastatic melanoma (MM).
Authors: Clara Inkyung Lee, Alexander M. Menzies, Lauren Haydu, Arthur Clements, Richard Kefford, Georgina V. Long
Journal: Journal of Clinical Oncology (2012)

e19011 Background: Dabrafenib is an effective targeted treatment of oncogenic BRAF-mutant MM. 20-30% of pts experienced drug-related fever in phase I and II trials of dabrafenib, but not trametinib. The combination of dabrafenib and trametinib reduces skin AEs seen with either drug alone, but dabrafenib-related fever persists as a common AE. We investigated correlates of fever in pts from a single institution enrolled in the BRF113220 phase I/II study of combined dabrafenib and trametinib. Methods: Demographics, BRAF genotype, extent and burden of disease, RECIST response, PFS and OS were collected on all pts enrolled into BRF113220 at Westmead Hospital between Nov 2010 and Nov 2011. Data were collected, including the number and severity of febrile episodes, associated symptoms, haematologic and biochemical alterations, the treatment and prophylaxis of fever, and the efficacy of these measures. Results: 23 pts were enrolled. 9 pts (39%) developed fever defined as ≥38.5°C, 5 had associated rash and 6 had rigors. Fever was not associated with pt age, sex, BRAF genotype (V600E vs V600K), M-stage, sites of distant metastases, baseline LDH and baseline tumor volume (RECIST target lesions). Fever did not predict RECIST response, PFS or OS. Fever recurred in 6 pts, and was repetitive (&gt;2 episodes) in 2 (6 and 7 episodes). Neither dose reduction of either drug, nor anti-pyretic therapy (acetaminophen, NSAIDs) were effective in fever prophylaxis, but corticosteroids were effective in all cases. 8 of 9 pts had biochemical assessment at first fever, and all had a rise in AST (median 100%), ALT (79%), ALP (40%) and LDH (40%) compared to those without fever (p&lt;0.05). At time of first fever, there was no significant change in neutrophil or lymphocyte counts, GGT or CRP, yet lymphopaenia had developed in the 4 pts subsequently requiring corticosteroid prophylaxis. Conclusions: Fever is not predictive of response or clinical outcome, and there are no clinical characteristics which predict fever. Febrile episodes are associated with transient elevation of ALT, ALP, LDH and especially AST. Corticosteroids are the only effective fever prophylaxis.
David Oliver: Taking carers for granted
Authors: David Oliver
Journal: BMJ (2017)

BerkshireDavid Mowat, the health minister, raised a few eyebrows earlier this year when he said that people had the same duty to look after their ageing parents as they did to look after their children. 1 Mowat, who was giving evidence to the communities and local select committee, acknowledged the current problems in the care system and its future sustainability.He then added, "No one ever questions that we look after our children-that is obvious.No one says that is a caring responsibility, it is what we do."Some of that logic and some of the way we think about that . . .will have to impinge on the way that we think about caring for our parents.Because it is a responsibility in terms of our life cycle which is similar."Mowat isn't the first politician or commentator to make this kind of plea.The health secretary, Jeremy Hunt, said in 2013 that we should "adopt the Asian culture of caring for the elderly." 2 Yet, even in countries such as China and Japan, urbanisation, falling birth rates, increasing longevity, changing gender roles, and working lives mean that Hunt's stereotype decreasingly holds true. 3 4 Carers are often spouses rather than offspring.Around two million are over 65, and half a million are over 80
Concordance between formalin-fixed paraffin-embedded biopsy samples and surgically resected snap-frozen samples in multiplexed molecular profiling of lung cancers.
Authors: Hirotsugu Kenmotsu, Masakuni Serizawa, Yasuhiro Koh, Mitsuhiro Isaka, Toshiaki Takahashi, Haruyasu Murakami, Tateaki Naito, Tetsuhiko Taira, Takehito Shukuya, Akira Ono, Hiroaki Akamatsu, Hisao Imai, Keita Mori, Masahiro Endo, Takashi Nakajima, Yasuhisa Ohde, Nobuyuki Yamamoto
Journal: Journal of Clinical Oncology (2013)

e18556 Background: The results of comprehensive genome-wide characterization of lung cancer have recently been reported. However, the concordance of driver mutations between formalin-fixed paraffin-embedded (FFPE) and surgically resected snap-frozen samples is unclear. We conducted the Shizuoka Lung Cancer Mutation Study to analyze driver mutations in patients with lung cancer. Methods: Based on the biobanking system in conjunction with the clinic including the pathology lab, we developed a multiplexed mutational panel designed to assess 23 mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN and HER2), EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications, and EML4-ALK translocations, using pyrosequencing plus capillary electrophoresis, qRT-PCR, and RT-PCR, respectively.DNA concentration in FFPE samples was analyzed by measuring absorbance at 260 nm (A260) in a spectrophotometer. Results: Between July 2011 and July 2012, sixty-five lung cancer patients with both FFPE and snap-frozen samples were included in this study. Patient characteristics were as follows: median age (range) 70 (38-92) years; female 68%; never-smoker 34%; histology adenocarcinoma/squamous cell carcinoma/small cell carcinoma/other 52/29/6/13 %. FFPE samples included 64 transbronchial biopsies and one pleural biopsy. We detected driver mutations in 58% of all cases. Mutations found: EGFR 28%, KRAS 12%, PIK3CA 6%, NRAS 2%, HER2 5%, EGFR amplification 5%, PIK3CA amplification 12%, FGFR1amplification 2%. Complete concordance of driver mutations between FFPE and snap-frozen samples was shown in 65%. Median DNA concentration in FFPE samples was 72.7 ng/ul (range; 2.4 - 472.4 ng/ul). Exploratory analyses using an ROC curve, done to evaluate the useful cutoff of DNA concentration in FFPE samples, showed low AUC (AUC; 0.5326). Conclusions: These results suggest that the rate of complete concordance of driver mutations between FFPE and snap-frozen samples might be acceptable, and DNA concentration in FFPE samples might not be correlated with concordance.
Abstract 15231: Oncostatin M Receptor Deletion Decreases FGF23 After Transaortic Constriction in Mice and Receptor Activation Correlates With Increased FGF23 in Patients With Aortic Stenosis
Authors: Manfred H Richter, Hans-Jürgen Lautze, Yunlong Hou, Ranganath Maringanti, Adalbert Skwara, Markus Schönburg, Ayse Cetinkaya, Andres Beiras-Fernandez, Isabella Werner, Hendrik Nolte, Soraya Hölper, Thomas Braun, Thomas Kubin, Sawa Kostin, Thomas Walther
Journal: Circulation (2015)

Objectives: Fibroblast growth factor 23 (FGF23) is becoming increasingly recognized as biomarker for heart failure (HF). We have previously shown that oncostatin M (OSM) is the strongest cytokine which induces FGF23 secretion from cultured cardiomyocytes. Although the bone is regarded as the source of FGF23, we have also demonstrated that cardiomyocytes of patients with end-stage HF strongly express FGF23. In this study we tested the hypothesis that the hypertrophied, non-failing heart is a source of circulating FGF23 via OSM receptor (Oβ) activation. Methods: Transaortic constriction (TAC) was performed in WT and Oβ knock-out mice (OβKO). Sham operated mice served as control. We have analysed myocardial biopsies and serum from patients with aortic stenosis (AS) with preserved ejection fraction. Patients with kidney disease were excluded from the study. Serum from healthy volunteers served as a control. Proteome and transcriptome profiling of serum and tissue samples in mice and AS patients were performed by mass spectrometry, multiplex assays, RT-PCR, ELISA, confocal microscopy (CM) and Western blots (WB). Results: Four weeks after TAC, WT mice animals showed significant increases in circulating FGF23 in comparison to sham-operated mice (583±117 (n=10) vs 218±36 pg/mL (n=10); p&lt;0.05). Furthermore, CM, WB and RT-PCR analysis consistently revealed up-regulation of FGF23 expression and increased Oβ mRNA levels (100±10% (n=8) vs 284±26% (n=8); p&lt;0.01) in cardiomyocytes. Conversely, TAC-OβKO showed reduction of circulating FGF23 to Sham levels (215±39 pg/mL (n=11); p&lt;0.02) and significantly decreased myocardial FGF23 expression as compared to TAC in WT mice. Similarly, AS patients showed a 2.7-fold higher expression of Oβ in comparison to control tissue (269±77 (n=8) vs 100±28% (n=4); p&lt;0.05). FGF23 serum levels were elevated 4-fold in comparison to serum from volunteers (85±47 (n=19) vs 23±2 (n=16) RU/mL; p&lt;0.01). Conclusions: Our data demonstrate that Oβ activation is responsible for the cardiac release of FGF23 into the circulation in TAC animals. Activation of Oβ and increased levels of FGF23 in patients with AS indicates that FGF23 is a potential biomarker in AS patients with compensated hypertrophy before the onset of HF.
The efficacy of subclinical lymphedema detection in high-risk breast cancer survivors.
Authors: Atilla Soran, Lori DeGore, Kandace P. McGuire, Marguerite Bonaventura, Priscilla F. McAuliffe, Emilia Diego, Gretchen M. Ahrendt, Ronald Johnson
Journal: Journal of Clinical Oncology (2013)

9643 Background: Lymphedema (LE) is associated with profound functional, psychosocial and medical consequences. Early intervention may decrease morbidity from LE. Bioimpedance spectroscopy (BIS) allows subclinical diagnosis by detecting subtle differences in extracellular fluid volume between the limbs. In our lymphedema program, we prospectively monitor BIS in patients (pts) undergoing axillary lymph node dissection (ALND). The aim of this study is to investigate whether early diagnosis of LE after ALND using BIS can allow early intervention. Methods: BIS in the “Pre-Operative Group,” measurements using L-Dex U400 were obtained pre-operatively (n=123) and at 3-6 month intervals thereafter. In the “Follow-up Group" pts who had ALND previously (n=89) had baseline measurements and monitoring at the same intervals. Age, BMI, dominant hand use, side of ALND, type of breast surgery, receipt of radiation therapy, and number of LN removed were recorded. L-Dex values &gt; 10 units or increase &gt; 10 units above the initial measurement was treated with LE education, an over-the-counter compression sleeve, less intensive physical therapy sessions and daily exercise. Results: The mean age was 58 (27-90). The mean BMI was 28.5 (17.1-65.7)kg/m 2 . ALND was on the side of the dominant hand in 56% of pts (n=119). The mean number of LNs removed was 16 (5-49). The majority of pts underwent mastectomy (59%; n=126), 73% (n=55) received RT, and 80% (n=191) received neo- or adjuvant chemotherapy. 87 pts (41%) were followed for more than 1 year from initial measurement. Since the monitoring began, 18% (n=22) in the Preoperative Group and 23% (n=20) in the Follow-up group were diagnosed with subclinical LE and received early intervention. 41 pts (97.6%) remain stable with no worsening of LE 1 yr after diagnosis. One pt advanced to stage 2 LE but declined further monitoring at 6 mo. Conclusions: Subclinical detection of LE with BIS and timely intervention reduced the incidence of late-stage LE among women undergoing ALND to &lt;3% compared with historical incidence of &gt;25%. Periodic monitoring of women at high risk for LE can minimize costly and intensive LE treatment such as custom made sleeves, pump and surgery while anticipating elimination of more advanced LE.
Alvocidib Potentiates the Activity of Venetoclax in Preclinical Models of Acute Myeloid Leukemia
Authors: Clifford J. Whatcott, James M Bogenberger, Wontak Kim, Hillary Haws, Nanna Hansen, Devora Delman, Lisa Sproat, Jeanne Palmer, Ruben A. Mesa, Peter Peterson, Adam Siddiqui-Jain, Steven Weitman, David J. Bearss, Steven L. Warner, Raoul Tibes
Journal: Blood (2016)
Improving the measurement of clinician response to symptom screening: Auditing the symptom management of cancer patients in Ontario.
Authors: Gillian Hurwitz, Nicole Montgomery, Lesley Moody, Colleen Bedford, Lisa Catherine Barbera
Journal: Journal of Clinical Oncology (2017)

218 Background: Since 2007, Cancer Care Ontario has provincially mandated symptom screening of cancer patients using the Edmonton Symptom Assessment Scale (ESAS). Screening rates are the primary performance metric used across 14 Regional Cancer Centres (RCCs), however this indicator does not detail how symptoms are managed during the clinic visit. The objective is to share our accomplishments using a chart audit process and share upcoming changes aimed to improve the measurement of clinician response to symptom screening. Methods: The initial chart audit tool was created by regional stakeholders who oversee cancer symptom management. The tool measures the concordance between clinician response to the patient symptom screen and best practices outlined in the Cancer Care Ontario Symptom Management Guides. RCCs conduct an annual chart audit for seven of the ESAS symptoms, and sample at least 20 patients with high symptom scores (&gt;=4). Chart documentation is analyzed to determine whether the patient received appropriate assessment and interventions. Results: 7,952 chart audits have been completed since 2012. Patients reporting symptom burden in FY 2015/16 often received an assessment (72-93%) and intervention (48-79%) during the clinic visit, depending on the symptom. Annual provincial aggregate results are intended to support quality improvement, inform clinician symptom management education, and provide a snapshot of resource utilization. Shortcomings of the audit have been identified over time. These highlight the need for more actionable items and a standardized process to ensure representative sampling, as aggregate results can be biased when RCCs co-opt the audit to measure local projects. This prompted an overhaul of the audit process: new audit tool created; results linkable to administrative data; and objectives clearly defined to balance local and provincial needs. Conclusions: Measuring the frequency of symptom screening is important, but the most clinically relevant question is whether the patient’s symptoms are being managed. Changing the chart audit process will ease the burden on auditors, improve data quality, and ensure data utility at all levels.
Accuracy of breast MRI in predicting pathologic tumor size.
Authors: Kimberly Anne Caprio, Anees B. Chagpar, Regina Hooley, Fattaneh Tavassoli, Helen Honarpishe, Donald R. Lannin, Brigid K. Killelea, Nina Ruth Horowitz
Journal: Journal of Clinical Oncology (2012)

1109 Background: MRI use as a preoperative planning tool is increasing in women with breast cancer, yet the correlation between MRI and pathologic size of cancers is unclear. The purpose of this study was to determine the accuracy of MRI in predicting pathologic tumor size, and factors that affect this correlation. Methods: Clinicopathologic and imaging data from 84 patients diagnosed with invasive or in situ breast cancer from September 2010 to October 2011 who had preoperative MRI were reviewed. 12 patients who had neoadjuvant chemotherapy were excluded. MRI detected 147 lesions in the remaining 72 patients. Concordance between MRI and pathology size was determined using Spearman rho coefficients, and factors affecting the accuracy of MRI in predicting tumor size within +/- 0.5 cm were determined. Results: There was a modest correlation between MRI and pathology size for all MRI detected lesions (benign or malignant) with a Spearman coefficient of 0.53. Of the 147 MRI detected lesions, 45 (30.6%) had pathologic and MRI size correlating within +/- 0.5 cm; 76 (51.7%) were overestimated (&gt;0.5cm) by MRI, and 26 (17.7%) were underestimated (&gt;0.5cm). 101 (68.7%) of the 147 lesions were found to be malignant (either with invasive disease or DCIS). In this subgroup, 35 lesions (34.7%) had an MRI size within +/- 0.5 cm of the pathologic size; 40 (39.6%) were overestimated by MRI and 26 (25.7%) were underestimated. Patient age, tumor histology, LVI and grade did not predict concordance between pathologic and MRI size. However, small MRI lesion size more accurately correlated with pathologic tumor size. While 51.1% of tumors that had concordant MRI and pathologic findings within 0.5 cm were &lt;1 cm on MRI, no tumor found to be &gt; 5 cm on MRI was within +/-0.5 cm on final pathology (p=0.001). Conclusions: MRI accurately predicts pathologic tumor size only when the size of the lesion on MRI is &lt;1 cm.