tbuckley/cabot-search huggingface dataset:
Restitution slope is principally determined by steady-state action potential duration
Authors: Michael J. Shattock, Kyung Chan Park, Hsiang-Yu Yang, Angela W. C. Lee, Steven Niederer, Kenneth T. MacLeod, James Winter
Journal: Cardiovascular Research (2017)

The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF.Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM - to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope.Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.
Morbidity and Mortality Associated With Meningioma After Cranial Radiotherapy: A Report From the Childhood Cancer Survivor Study
Authors: Daniel C. Bowers, Chaya S. Moskowitz, Joanne F. Chou, Claire M. Mazewski, Joseph P. Neglia, Gregory T. Armstrong, Wendy M. Leisenring, Leslie L. Robison, Kevin C. Oeffinger
Journal: Journal of Clinical Oncology (2017)

Purpose Little is known about neurologic morbidity attributable to cranial radiotherapy (CRT) -associated meningiomas. Materials and Methods From 4,221 survivors exposed to CRT in the Childhood Cancer Survivor Study, a diagnosis of meningioma and onset of neurologic sequelae were ascertained. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% CIs to evaluate the factors associated with neurologic sequelae after subsequent meningioma. Results One hundred ninety-nine meningiomas were identified among 169 participants. The median interval from primary cancer to meningioma diagnosis was 22 years (5 to 37 years). The cumulative incidence of a subsequent meningioma by age 40 years was 5.6% (95% CI, 4.7% to 6.7%). CRT doses of 20 to 29.9 Gy (HR, 1.6; 95% CI,1.0 to 2.6) and doses ≥ 30 Gy (HR, 2.6; 95% CI, 1.6 to 4.2) were associated with an increased risk of meningioma compared with CRT doses of 1.5 to 19.9 Gy ( P < .001). Within 6 months before or subsequent to a meningioma diagnosis, 20% (30 of 149) reported at least one new neurologic sequela, including seizures (8.3%), auditory-vestibular-visual deficits (6%), focal neurologic dysfunction (7.1%), and severe headaches (5.3%). Survivors reporting a meningioma had increased risks of neurologic sequelae > 5 years after primary cancer diagnosis, including seizures (HR, 10.0; 95% CI, 7.0 to 15.3); auditory-vestibular-visual sensory deficits (HR, 2.3; 95% CI, 1.3 to 4.0); focal neurologic dysfunction (HR, 4.9; 95% CI, 3.2 to 7.5); and severe headaches (HR, 3.2; 95% CI, 1.9 to 5.4). With a median follow-up of 72 months after meningioma diagnosis (range, 3.8 to 395 months), 22 participants (13%) were deceased, including six deaths attributed to a meningioma. Conclusion Childhood cancer survivors exposed to CRT and subsequently diagnosed with a meningioma experience significant neurologic morbidity.
Efficacy of a phosphoinositol 3 kinase (PI3K) inhibitor in gastrointestinal stromal tumor (GIST) models.
Authors: Thomas Van Looy, Agnieszka Wozniak, Raf Sciot, Giuseppe Floris, Paul W. Manley, Maria Debiec-Rychter, Patrick Schöffski
Journal: Journal of Clinical Oncology (2012)

10030 Background: PI3K signaling is crucial for GIST proliferation and survival. We assessed the efficacy of the PI3K inhibitor NVP-BEZ235 (BEZ), alone or in combination with imatinib (IM), in GIST xenografts. Methods: Nude mice were grafted bilaterally with human GIST, carrying either KIT exon 9 (GIST-BOE, dose-dependent IM resistant) or exon 11 (GIST-DFR, IM sensitive) mutations. Animals, randomized into four groups (n=8/group) were dosed orally for 2 weeks with either vehicle, IM (50mg/kg/bid), BEZ (10mg/kg/qd), or IM+BEZ. Treatment efficacy was assessed by tumor volume, histopathology and Western immunoblotting. Moreover tumor regrowth was evaluated for 3 weeks after treatment cessation. Results: As a single agent IM and BEZ stabilized tumor growth of both GIST-BOE and DFR. Moderate to significant tumor regression was observed in GIST-BOE under BEZ (by 27%), and IM+BEZ (66%), and also in GIST-DFR under IM (75%) and IM+BEZ (75%). In GIST-BOE significant reduction in mitotic index was observed under BEZ (8.5 fold) and IM+BEZ (8.5 fold) as compared to control. In GIST-DFR mitotic activity was virtually absent under all regimens. Apoptotic activity increased significantly after treatment with IM (5.5 fold) and IM+BEZ (14.0 fold) in GIST-DFR, whereas it was almost unaffected by BEZ as single agent, as well as in all treatment groups in GIST-BOE. By Western, PI3K signaling was incompletely inhibited in all groups in GIST-DFR, and after BEZ in GIST-BOE. Complete inhibition of PI3K signaling was observed only after combination treatment. After treatment cessation long-lasting growth-inhibition was observed in IM+BEZ treated GIST-DFR. Moreover, mitotic index after BEZ and BEZ+IM in GIST-DFR was lower than in control even after treatment withdrawal. Conclusions: BEZ shows significant efficacy in GIST xenografts. Furthermore, combination with IM shows synergistic and long-lasting effects even after treatment withdrawal, which is not the case with drugs routinely used for GIST treatment.
Cardiology monitoring substudy in the PERSEPHONE trial: 6 versus 12 months of trastuzumab.
Authors: Louise Hiller, Anne-Laure Vallier, Emma Ogburn, Andrew M. Wardley, David A. Cameron, David Miles, Janet Dunn, Helena Margaret Earl
Journal: Journal of Clinical Oncology (2014)

552 Background: PERSEPHONE is a randomised trial comparing 6month (6m) to 12month (12m) of trastuzumab in patients (pts) with HER2-positive early breast cancer. The trial has recruited 3,166 of 4,000 pts. We report the results of the cardiology monitoring substudy, which the iDSMC reviewed in June 2013 and recommended we release. Methods: Left ventricular ejection fraction (LVEF) was measured prior to trastuzumab, and then 3-monthly for 12 months (x5). Low LVEF was defined as either <50%, or reported as ‘low’. Results: 11,413 LVEF tests have been reported in 2,484 pts (see Table). Only 10% pts reported low LVEFs, similar across arms (p=0.19). In total, only 483 low LVEFs were reported. There was no difference in time to first low LVEF between treatment arms (log-rank p=0.49). On each treatment arm, there were statistically significant reductions in LVEF % at 6 and 12 months (all p<0.0001). Significantly more 12m pts reported delays (p=0.007) and discontinuations (p<0.0001) due to low LVEFs. Conclusions: Both PERSEPHONE arms are considered safe, with only small relative reductions in LVEF. Duration of treatment has no effect on numbers of pts reporting low LVEFs or time to first low LVEF. However the longer treatment suffers from more delays and discontinuation due to low LVEFs. Low LVEF may relate more to pt factors (e.g.pharmacogenetics), than length of treatment. The data support, and the iDSMC now recommend, less intensive cardiology monitoring during treatment. Clinical trial information: 52968807. 6 m trastuzumab 12 m trastuzumab No. pts 1,243 1,241 No. (%) pts reporting low LVEFs 110 (9%) 130 (10%) p=0.19 No. LVEF tests 5,462 5,951 No. (%) low LVEFs 213 (4%) 270 (5%) Time to first low LVEF Log-rank p=0.49 6 month low LVEF rates 7% 6% 12 month low LVEF rates 10% 11% Relative change from baseline Median (IQR), p Baseline to 6 month .96 (.90-1.02), p<0.0001 .97 (.91-1.03), p<0.0001 p=0.01 Baseline to 12 month .98 (.91-1.03), p<0.0001 .97 (.90-1.03), p<0.0001 p=0.07 Cardiology effect on treatment Trastuzumab doses 11,171 20,383 No. pts 1,233 1,231 Pts reporting delays 38 (3%) 66 (5%) p=0.007 Pts reporting discontinuations 20 (2%) 62 (5%) p<0.0001
The association between insurance status and survival in patients with stage III colon cancer.
Authors: Aabra Ahmed, Ryan W Walters, Ahmed Ibrahim Tahseen, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2017)

535 Background: Colon cancer is the third most frequent cancer diagnosis, and primary payer status has been shown to be associated with treatment modalities and survival in cancer patients. The goal of our study was to determine between-insurance differences in survival in patients with pathologic stage III colon cancer using data from the National Cancer Data Base (NCDB). Methods: We identified 130,998 patients with pathologic stage III colon cancer in the NCDB diagnosed between 2004 and 2012. Kaplan-Meier curves and multivariable Cox regression models were estimated to determine the association between insurance status and survival. Results: Private insurance patients were 41% less likely than Medicaid patients to die, 28% less likely to die than uninsured patients, and 14% less likely to die than those with Medicare (p&lt;0.01). Medicare patients were 18% were less likely to die compared to uninsured patients (p&lt;0.01) and 19% less likely to die compared to Medicaid patients (p&lt;0.01). Medicaid and noninsured patients had comparable likelihoods of dying (p=0.76). Those with no comorbidities were 36% less likely to die than those with 2+ comorbidities (p&lt;0.01). Each additional year in age added a 3% likelihood of dying (p&lt;0.01). Patients with chemotherapy were 57% less likely to die compared to patients not receiving chemotherapy (p&lt;0.01). Private insurance had the greatest percentage of patients receiving chemotherapy at 82%. Conclusions: Of all variables examined, chemotherapy provided the greatest increased chance of survival. Comorbidities were also a significant contributor to survival. Private and Medicare patients were likely to survive longer than uninsured and Medicaid patients. Furthermore, having Medicaid did not provide an advantage in survival over having no insurance. [Table: see text]
Did FDA safety warnings and CMS coverage restrictions improve guideline adherence for ESA use for patients with myelodysplastic syndromes?
Authors: Franklin Hendrick, Maria R. Baer, Steven Gore, Sheila Weiss Smith, Amy J. Davidoff
Journal: Journal of Clinical Oncology (2012)

e16519 Background: ESAs are used to treat anemia associated with MDS as an off-label indication. Our prior research demonstrated poor adherence to MDS treatment guidelines in US Medicare-insured patients. Concerns of adverse events including tumor progression led the FDA to release safety alerts and mandate label changes in early ‘07. In a rare move, CMS implemented a National Coverage Determination (NCD) in August ‘07, dramatically restricting ESA coverage based on specific clinical parameters (e.g. baseline hemoglobin). As MDS patients were not directly targeted by the NCD, we sought to examine if ESA use changed following these actions. Methods: We selected Medicare beneficiaries with MDS diagnostic codes and receiving a bone marrow aspirate based on 100% enrollment and claims data from 2004-2008. Patients were observed from diagnosis until death or end of study. Through procedures codes on claims we determined the receipt of any ESA within 6 months of diagnosis, whether serum EPO level was measured prior to ESA initiation, whether treatment was of therapeutic duration (&gt;=8 weeks), and whether patients had low transfusion needs (defined based on a measure of transfusion dependence) at ESA initiation. Logistic regression models tested the effect of time (half-year increments pre-post the August ‘07 CMS NCD implementation), controlling for demographics, health status, and supplemental insurance Results: The sample included 36,537 MDS patients; 23,351 (64%) with ESA use. Regression results indicate that relative to Jan-June 2005, ESA use increased through ‘06 (OR 1.22, 95% CI 1.12, 1.33), and declined beginning in August ‘07 (OR 0.71,CI:0.65,0.77). Assessment of serum EPO levels increased beginning in January ‘06, preceding the FDA/CMS actions, ESA use increased among transfusion-users throughout the study period (Jan-June ’08 OR 1.59; CI 1.43, 1.77) though the proportion of patients receiving therapeutic-duration episodes began declining in Jan ‘07 (OR 0.82; CI 0.73-0.91). Conclusions: These results suggest a mixed pattern of change in the face of the FDA safety warnings and CMS NCD in MDS.
Variations of <i>DICER1</i> sequence in Chinese women with <i>BRCA1/BRCA2</i> negative familial breast cancer.
Authors: Wenming Cao, Yun Gao, Hongjian Yang, Shang-Nao Xie, Xuli Meng, Zhi-Wen Pan, zhan-Hong Chen, Huang Jian, Wei-Wu Ye, Shao Xiying, Wang Xiao Jia
Journal: Journal of Clinical Oncology (2013)

e12557 Background: Germline mutations in identified breast cancer susceptibility genes account for less than 20% of Chinese familial breast cancers. Dicer is an essential component of the microRNA producing machinery and germline mutations of DICER1 gene have been confirmed in familial pleuropulmonary blastoma, ovarian sex cord-stromal tumor and so on. Moreover, low expression of DICER1 is frequently detected in breast cancer. However, whether germline mutations of DICER1 occur in familial breast cancers remains unknown. Methods: 65 breast cancer probands from BRCA1/BRCA2 negative Chinese breast cancer families were used for screening of germline mutations in DICER1. In addition, 100 unrelated healthy females were enrolled as the controls. Polymerase chain reaction (PCR)-sequencing assay was employed to screen mutations in the entire coding regions and exon-intron boundaries of DICER1. Genotype and haplotype analyses were studied by widely available programs. Results: No deleterious mutations were identified in the 65 breast cancer probands. However, we found 12 germline variations and 4 of which were novel. In addition, the G allele frequency of rs2297730 (IVS12-91 A&gt;G) was higher in familial breast cancer patients group than that in healthy controls group (OR = 1.873, 95% CI: 1.174-2.988, P = 0.008), and the A/G genotype were significantly associated with familial breast cancer (OR = 3.133; 95% CI: 1.562-6.287, P = 0.004). According to the minimum value of Akaike’s Information Criterion (AIC), the best genetic model was dominant. In addition, the haplotype GCGGAT was significantly associated with familial breast cancer (OR = 2.17, 95% CI: 1.20-3.91, P = 0.011). Conclusions: Although none of deleterious mutations were identified in the DICER1 gene, the current study provided a haplotype analysis of the DICER1 gene polymorphisms. We showed a significantly increased risk of BRCA1/BRCA2 negative familial breast cancer for DICER1 IVS12-91 A&gt;G variant. It might be a potential risk marker for breast cancer in thus population.
Systematic Review Links the Prevalence of Intraductal Carcinoma of the Prostate to Prostate Cancer Risk Categories
Authors: Laura H. Porter, Mitchell G. Lawrence, Dragan Ilic, David Clouston, Damien M. Bolton, Mark Frydenberg, Declan G. Murphy, Carmel Pezaro, Gail P. Risbridger, Renea A. Taylor
Journal: European Urology (2017)
Re: Johann S. de Bono, Matthew R. Smith, Fred Saad, et al. Subsequent Chemotherapy and Treatment Patterns After Abiraterone Acetate in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302. Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2016.06.033
Authors: Robert J. van Soest, Ronald de Wit
Journal: European Urology (2016)
Mortality associated with the treatment of HCV with direct-acting antivirals
Authors: Anne Laurain, Laura Kramer, Philippe Sultanik, Anaïs Vallet-Pichard, Philippe Sogni, Stanislas Pol
Journal: Gut (2017)

We read with interest the study by Welzel et al 1 confirming the high efficacy of oral direct-acting antiviral agents (DAAs) for the treatment of chronic HCV infection.2 Results about safety are less clear, since in these patients who have a high risk of hepatic decompensation or death within 12 months, the rate of death was 7.8% during treatment and the 12 weeks post-treatment. These deaths and most safety events were associated with advanced liver disease and not considered treatment related. The largest phase III studies (COSMOS, ION1 and ION3, SAPPHIRE) did not report any death during DAA treatment and severe adverse events occurring during therapy were considered to be unlikely related to DAAs.3 In real-life clinical settings, mortality has been observed in around 0.5% (0.3% for the French ANRS CO22 HEPATHER cohort and 0.6% for the US TARGET cohort).

In our tertiary care …
First-in-human investigation of the oral first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640.
Authors: Andrew Jacob Brenner, Daniel D. Von Hoff, Jeffrey R. Infante, Manish R. Patel, Suzanne Fields Jones, Howard A. Burris, Chris Rubino, William McCulloch, Valentina Zhukova-Harrill, George Kemble
Journal: Journal of Clinical Oncology (2015)

TPS2615 Background: FASN is a central mediator of neoplastic lipogenesis. It catalyzes the production of palmitate, the building block of long chain fatty acids needed to support cancer cell signaling and proliferation. Tumor cells have more dependence on de novo lipogenesis than normal cells, and express higher levels of FASN. Several studies have shown a correlation between high levels of FASN expression and both advanced disease stage and poorer prognosis in patients. The combination of these observations provides the rationale for FASN inhibition as an antitumor therapy. TVB-2640 is a potent, reversible and selective fatty acid synthase (FASN) inhibitor currently in its first Phase 1 study (3V2640-CLIN-002) in patients with refractory solid tumors (NCT02223247), EORTC 2014 Abstract number: 3 LBA. Methods: TVB-2640 is administered in monotherapy orally once daily continuously on a 21 day cycle to assess dose-limiting toxicities (DLT). An accelerated dose-escalation method was used initially with single-patient cohorts and 100% dose escalations planned until NCI-CTCAE toxicity ≥ Grade 2 was encountered. Thereafter, the classical "3 + 3" design was used. Additionally, exploration of combination therapy using TVB-2640 co-administered with a taxane has begun. Eligibility includes adult patients with adequate bone marrow, hepatic and renal function and other standard Phase I characteristics. Patients with significant cardiovascular, ophthalmological disease, or any conditions that might interfere with oral absorption are excluded. In addition to standard safety assessments and pharmacokinetic (PK) sampling (over 24 hours on Days 1 and 8), specialist ophthalmological examinations and 24-hour Holter monitoring for QTc assessments are required. Tumor tissue (archival and/or fresh) is being obtained to assess the consequences of FASN inhibition on neoplastic lipogenesis and a pharmacodynamic effect has been evaluated by measuring metabolite changes in patient sera. Clinical trial information: NCT02223247.
Effect of baseline QTc interval prolongation on oncology clinical trial enrollment.
Authors: Carolina Moreno, Jill M. Weber, Maya Guglin, Larry Roy, Jonathan R. Strosberg
Journal: Journal of Clinical Oncology (2012)

2612 Background: An increasing number of clinical trials in oncology require normal or near-normal intervals of electrocardiographic corrected QT (QTc) as an eligibility criterion. However the normal QTc reference range (conventionally defined as ≤450ms) has been developed in broad populations of patients, and it is unclear whether average QTc intervals are higher in adult cancer patients. Methods: All electrocardiograms (ECGs) performed for any indication at the Moffitt Cancer Center during a one-week period were reviewed. The QTc interval for each patient was calculated according to the Bazett and Fridericia formulas. Mean and median QTc intervals were calculated along with standard deviations. The percentage of QTc intervals above 450ms, 470ms, and 500ms were calculated and graded accordingly to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4.0). The effects of gender on the QTc interval were also evaluated. Results: 257 patients underwent ECGs over a one-week period. A total of 90 patients (35%) had abnormally prolonged QTc. 50 patients (20%) had QTc prolongation &gt;450 (≥ grade 1), 32 (12%) had QTc prolongation &gt; 470 (≥grade 2) and 8 patients (3%) had QTc prolongation &gt;500ms (≥grade 3) using the Bazett formula. The corresponding numbers according to the Fridericia formula were 23 (9%), 13 (5%) and 2 (1%) . The median QTc interval was 441 (Bazett) and 422 (Fridericia) with a standard deviation of 30 and 28 respectively. Women had a mean QTc of 438 (Bazett) versus 443 for men. Conclusions: A very large percentage of patients seen at a comprehensive cancer center have QTc intervals above the normal reference range on routine ECGs. The growth in number of trials requiring a normal QTc interval as an eligibility criteria suggests that an ever-larger number of patients are excluded from trial participation. Regulatory agencies may need to reconsider eligibility criteria that substantially restrict trial enrollment and that accrue patients who are not reflective of the general patient population.