tbuckley/cabot-search huggingface dataset:
Critical Appraisal of the Evidence That Dietary Fat Intake Is Related to Breast Cancer Risk in Humans
Authors: P J Goodwin, N F Boyd
Journal: JNCI Journal of the National Cancer Institute (1987)

A critical appraisal was undertaken of the evidence that dietary fat intake is related to breast cancer risk by application of the criteria for causal inference proposed by Bradford Hill to the published evidence that relates dietary fat to breast cancer risk in humans. These criteria concern the consistency, strength, and temporal relationships of possible causative associations and also require the existence of a biologic gradient and examine the extent to which the proposed causal association is in keeping with other biological and epidemiological knowledge. The published reports were inconsistent in their ability to detect a significant association between dietary fat and breast cancer risk, correlation studies that examined the effect of fat over large ranges being largely positive, and studies with stronger designs (case-control, cohort) that examined fat intake over much smaller ranges being largely negative. It was postulated that methodologic limitations associated with the design of the latter studies, in particular the small ranges of fat intake examined and inaccuracies in the measurement of fat intake, may have obscured any relationships between dietary fat and breast cancer that did exist. The remaining criteria, with the exception of temporality and epidemiological coherence, were not satisfied. Insufficient evidence existed to conclude a causal association existed between dietary fat and breast cancer risk in humans. A need for further study was identified in several areas, and it was concluded that intervention studies that examined the effect of fat over large ranges were most likely to yield the information required to determine whether dietary fat intake was causally related to breast cancer risk.
Initial safety results of an expanded access program (EAP) of erlotinib in non-small cell lung cancer (NSCLC)
Authors: M. Reck, R. Perng, H. Groen, H. Riska, R. Pirker, C. Sederholm, C. Caspar, M. Boyer, P. Berzinec, S. Allan
Journal: Journal of Clinical Oncology (2006)

7190 Background: Erlotinib is an orally active and selective inhibitor of HER1/EGFR tyrosine kinase. In the BR.21 phase III trial, erlotinib significantly prolonged survival, delayed symptom progression, and improved quality of life in NSCLC patients (pts) (Shepherd et al, NEJM, 2005;353:123). The EAP is an open label, non-randomized, multicentre phase IV trial. Methods: Eligibility criteria included stage III/IV NSCLC pts who failed or were unsuitable for chemotherapy. Pts were given oral erlotinib, 150 mg/d, for as long as treatment provided clinical benefit without unacceptable toxicity. Pts were monitored monthly. Results: In Dec 05, data were available for 1,140 pts from 25 countries, median age 64 y (range 25–91). Key base-line characteristics (% pts) were: males 58%; Caucasian/Oriental 82/15; non-smoker/former or current-smoker 26/73. The % pts with ECOG PS 0/1/2/3 were 20/52/20/8. Most pts (55%) had adenocarcinoma. The % pts receiving erlotinib as 1st/2nd/3rd-line treatment were 12/47/40. As expected, rash was a common adverse event (AE: any grade [gr]: 65%; gr 3/4: 9%). Full safety data were available for 581 pts. Unexpected erlotinib-related AEs were only seen in &lt;2% pts. Erlotinib-related AEs leading to treatment discontinuation were GI disorders in 21 pts (12 pts had gr 3/4 AEs) and skin disorders in 14 pts (6 pts had gr 3/4 rash). Only 10% of pts had dose reductions, mainly due to rash (66%; gr 3 in 8 pts) and diarrhea (17%; gr 3 in 2 pts). The median daily dose of erlotinib was 150mg. Serious erlotinib-related AEs were GI disorders (19 AEs; 11 gr 3/4), mainly diarrhea (8 AEs, 5 were gr 3). Pt accrual and analyses of response, survival data and assessment of various predictive biomarkers are ongoing. Response and survival data will be presented. Conclusions: These interim safety results of erlotinib in the real-life clinical setting in a large number of unselected pts with advanced NSCLC confirm the good tolerability observed in clinical trials. To date, the trial demonstrates that erlotinib is well tolerated, thus, allowing full dose administration to most pts. [Table: see text]
Usage trends of minimally absorbed vaginal estrogens in breast cancer patients versus patients with non-breast malignancies
Authors: M. Castiel, S. Masakhalia, M. Krychman, B. Stier, A. Amsterdam, M. Gemignani, N. Kauff
Journal: Journal of Clinical Oncology (2006)

10620 Background: To determine if differences exist in the use of minimally absorbed vaginal estrogens in a breast cancer population versus one with non-breast malignancies. Methods: A retrospective review of all patients with documented malignancy who were prescribed vaginal 17-β-estradiol tablets (Vagifem, Novo-Disc, Princeton, New Jersey) through the General Gynecology Service from July 1, 2003 to June 30, 2004. Data were accessed from the pharmacy health information computerized system. All patients complained of dyspareunia, and examination was consistent with vaginal atrophy. Comparison between groups was performed using the Fisher Exact Test and t-test. Results: 152 patients were identified_81 patients with breast cancer diagnoses and 71 with non-breast malignancies. There was no difference in the mean age of patients in either group, 56.9 vs. 55.1 years. (p = 0.30). Overall, 60 of the 152 patients refilled their prescriptions through the time of last follow-up. There was no difference in the proportion of breast versus non-breast cancer patients who continued vaginal estradiol, 39.5% (32/81) versus 39.4% (28/71) respectively. When the cohorts were stratified by age ≤ 50 or &gt;50 at the time of initial consultation, 79% (11/14) of breast cancer patients age ≤ 50 years refilled their prescriptions at follow-up compared to 31.3% (21/67) of patients &gt;50 (p = 0.002). In women with non-breast malignancies there was no age-related difference in the proportion who obtained refills: 35% (7/20) ≤ 50 years versus 41.2 % (21/51) &gt;50 years (p = 0.79). Conclusions: Minimally absorbed vaginal estrogens appear to be viewed favorably amongst the younger breast cancer patient population. The older breast cancer population does not appear to continue vaginal estradiol use long-term. This may be due to differences in relationship status, interval from menopause to diagnosis, prior exposure to estrogen, or relief of symptoms with alternative therapies. These findings are different than those observed for similar patients with non-breast malignancies. Further studies looking at the use of minimally absorbed vaginal estrogens are needed to further evaluate the usage trends in differing patient populations. No significant financial relationships to disclose.
Are Genetic Tests for Atherosclerosis Ready for Routine Clinical Use?
Authors: Nina P. Paynter, Paul M Ridker, Daniel I. Chasman
Journal: Circulation Research (2016)

In this review, we lay out 3 areas currently being evaluated for incorporation of genetic information into clinical practice related to atherosclerosis. The first, familial hypercholesterolemia, is the clearest case for utility of genetic testing in diagnosis and potentially guiding treatment. Already in use for confirmatory testing of familial hypercholesterolemia and for cascade screening of relatives, genetic testing is likely to expand to help establish diagnoses and facilitate research related to most effective therapies, including new agents, such as PCSK9 inhibitors. The second area, adding genetic information to cardiovascular risk prediction for primary prevention, is not currently recommended. Although identification of additional variants may add substantially to prediction in the future, combining known variants has not yet demonstrated sufficient improvement in prediction for incorporation into commonly used risk scores. The third area, pharmacogenetics, has utility for some therapies today. Future utility for pharmacogenetics will wax or wane depending on the nature of available drugs and therapeutic strategies.
Randomized phase III trial comparing weekly docetaxel (D)-cisplatin (P) combination with triweekly D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): An intergroup trial of JCOG0803/WJOG4307L.
Authors: T. Abe, A. Yokoyama, K. Takeda, Y. Ohe, S. Kudoh, Y. Ichinose, H. Okamoto, N. Yamamoto, H. Yoshioka, K. Minato, T. Sawa, Y. Iwamoto, H. Saka, J. Mizusawa, T. Shibata, S. Nakamura, M. Ando, K. Nakagawa, N. Saijo, T. Tamura
Journal: Journal of Clinical Oncology (2011)

7509 Background: Tri-weekly D is one of the standard treatment regimens for elderly advanced NSCLC pts. To investigate whether the addition of a modified platinum agent might improve the survival in these patients, we conducted a phase III trial comparing weekly DP with tri-weekly D. Methods: Eligibility criteria were: chemotherapy-naïve; unfit for bolus P administration; stage III/IV or relapsed NSCLC; age≥70; PS 0-1. Pts were randomized to receive either DP or D by the minimization method, balancing for site, age (<75/≥75), and stage (III/IV). DP comprised administration of D (20 mg/m2) and P (25 mg/m2) iv on days 1, 8, and 15 every 4 weeks. D comprised administration of D (60 mg/m2) iv on day 1 every 3 weeks. The primary endpoint was overall survival (OS). The planned sample size was 190 pts in each arm, to provide an 80% power to detect a 0.752 hazard ratio for DP to D in regard to the OS, and a 5% one-sided alpha. Results: Between Oct 2008 and Sep 2010, 276 pts were randomized (D/DP: 137/139). The first planned interim analysis was performed on 221 assessable pts (D/DP: 108/113, <75/≥75: 22/78%, male/female: 70/30%, PS 0/1: 35/65%, III/IV or relapse: 32/68%). Information time, defined as the proportion of interim events to planned events, was 24% (=73/304). The median survival times of the DP and D groups were 13.3 and 17.3 months, respectively (hazard ratio [95% CI]: 1.557 [0.976-2.485]). The predictive probability that DP would be superior to D at the time of the final analysis was 0.996%, which led to early termination of the trial. The major grade 3-4 toxicities were (%D/DP): neutropenia 88/11%, anemia 3/16%, anorexia 1/10%, febrile neutropenia 17/0%, pneumonitis 3/2%. Treatment-related death occurred in 3 pts of the DP arm. The proportion of pts with an improved symptom score (FACT-L lung symptom subscale) after 3 courses of treatment was higher in the D arm. Conclusions: This study failed to demonstrate any advantage of the addition of weekly P to single-agent D in first line chemotherapy for elderly advanced NSCLC pts.
Addition of bevacizumab or sunitinib to biweekly cetuximab and irinotecan as salvage therapy in patients with metastatic colorectal cancer after failure to CetIri
Authors: P. Pfeiffer, T. L. Joergensen, B. V. Jensen, C. Qvortrup, K. Skougaard, J. K. Bjerregaard, T. P. Hansen, E. Høgdal, D. Nielsen
Journal: Journal of Clinical Oncology (2009)

e15011 Background: The combination of cetuximab and irinotecan (CetIri) given biweekly has shown remarkable efficacy in patients with chemo-resistent metastatic colorectal cancer (mCRC). At the time of PD to CetIri many patients are still in an excellent performance status and they are often requesting further therapy. Preclinical and clinical studies have shown an additive effect of inhibiting both the EGFR and the VEGF pathways. The Danish National Board of Health (DNBH) launched a national programme for experimental cancer therapy in 2004. According to this programme, non-proven therapy may be offered after approval by an expert panel appointed by DNBH that subsequently finances the cost of treatment. Inspired by BOND-2, we have offered dual-modulated therapy with a combination of biweekly CetIri with either bevacizumab 5 mg/kg (CIB) or sunitinib 25 mg/day continuously (CIS). Methods: Observational study designed to evaluate the toxicity and safety of CIB or CIS. From January 2007 to April 2008, 51 patients received either CIB (n=24) or CIS (n=27) at two oncologic departments. Therapy was approved by DNBH in each case. All patients had mCRC resistant to 5-FU, oxaliplatin, irinotecan and CetIri. CIB or CIS was offered independently of KRAS status and EGFR expression. Results: Results were updated December 1st 2008. Median duration of therapy was 30 weeks/10 weeks, response rate was 8%/0%, median PFS was 8.7/3.2 months and median OS was 12.1/8.7 months, respectively for CIB/CIS. Toxicity was comparable except for patients receiving CIS where fatigue and diarrhea were more common. Conclusions: Modulation of the VEGF pathway in combination with biweekly CetIri is a promising and tolerable treatment option for patients with mCRC refractory to CetIri. Some patients had extraordinary long PFS and OS. We are currently performing translation research into predictive markers. [Table: see text]
Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia
Authors: Chien-Hung Yeh, Xue Tao Bai, Ramona Moles, Lee Ratner, Thomas A. Waldmann, Toshiki Watanabe, Christophe Nicot
Journal: Molecular Cancer (2016)

Epigenetic regulators play a critical role in the maintenance of specific chromatin domains in an active or repressed state. Disruption of epigenetic regulatory mechanisms is widespread in cancer cells and largely contributes to the transformation process through active repression of tumor suppressor genes. While mutations of epigenetic regulators have been reported in various lymphoid malignancies and solid cancers, mutation of these genes in HTLV-I-associated T-cell leukemia has not been investigated. Here we used whole genome next generation sequencing (NGS) of uncultured freshly isolated ATL samples and identified the presence of mutations in SUZ12, DNMT1, DNMT3A, DNMT3B, TET1, TET2, IDH1, IDH2, MLL, MLL2, MLL3 and MLL4. TET2 was the most frequently mutated gene, occurring in 32 % (10/31) of ATL samples analyzed. Interestingly, NGS revealed nonsense mutations accompanied by loss of heterozygosity (LOH) in TET2 and MLL3, which was further confirmed by cloning and direct sequencing of DNA from uncultured cells. Finally, direct sequencing of matched control and tumor samples revealed that TET2 mutation was present only in ATL tumor cells. Our results suggest that inactivation of MLL3 and TET2 may play an important role in the tumorigenesis process of HTLV-I-induced ATL.
Review: More- vs less-intensive BP-lowering regimens reduce major CV events
Authors: Saurav Chatterjee, Partha Sardar, Anasua Chakraborty, Sanjay Chatterjee
Journal: Annals of Internal Medicine (2016)

Source Citation Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2015;Nov 7. [Epub ahead of print.] 26559744
Do patients with larger prostates have greater toxicity after external beam radiotherapy for localized prostate cancer?
Authors: M. Pinkawa, K. Fischedick, B. Asadpour, M. D. Piroth, B. Gagel, B. Krenkel, J. Klotz, M. J. Eble
Journal: Journal of Clinical Oncology (2007)

15577 Background: To aim of the study was to assess the impact of prostate volume (PV) on health-related quality of life (HRQOL) before and at different points in time after conformal radiotherapy for prostate cancer. Methods: A group of 180 patients has been surveyed prospectively before (time A), at the last day (B), two months after (C) and sixteen months (median) after (D) radiotherapy (70.2- 72Gy) using a validated questionnaire (Expanded Prostate Cancer Index Composite). Patients in this analysis (n=165) met the prerequisite of responding to the first and last questionnaire. The multi-item scale scores were transformed lineary to a 0–100 scale, with higher scores representing better HRQOL. The group has been divided into a subgroup with a small PV (median 32cc; range 11–45; 83 patients) and a subgroup with a large PV (median 59cc; range 46–151; 82 patients). Results: Treatment plans for large prostates implied a larger planning target volume (averagely 396 vs. 305cc; p&lt;0.01) with a significantly larger dose to the bladder and rectum at all volume levels. Patients with large prostates presented with lower urinary bother (averagely 76 vs. 83; p=0.04), but higher bowel bother scores (averagely 95 vs. 90; p&lt;0.01) before the beginning of treatment. At time B, urinary bother scores decreased stronger for patients with large prostates (averagely 22 vs. 16 points). Comparing posttreatment scores to baseline scores, no significant decrease resulted for urinary function or bother scores for both groups at time C and D. At time D, urinary function scores even increased significantly for patients with large prostates (averagely 4 points). Bowel function and bother scores were still significantly lower for both groups at time C and D (averagely 3–8 points). HRQOL scores did not differ significantly between both patient groups at time D. Conclusions: In spite of a higher dose-load to the organs at risk, lower urinary bother scores before treatment and a higher decrease of urinary scores at the end of radiotherapy for patients with larger prostates, long-term HRQOL scores did not differ significantly between patients with large and small prostates. An improvement of urinary function suggests a regression of hyperplastic prostatic tissue. No significant financial relationships to disclose.
Comparative Study of Autoantibody Responses between Lung Adenocarcinoma and Benign Pulmonary Nodules
Authors: Jie Wang, Shilpa Shivakumar, Kristi Barker, Yanyang Tang, Garrick Wallstrom, Jin G. Park, Jun-Chieh J. Tsay, Harvey I. Pass, William N. Rom, Joshua LaBaer, Ji Qiu
Journal: Journal of Thoracic Oncology (2016)
Abstract P285: Pattern of Atrial Fibrillation and Risk of Outcomes: The Loire Valley Atrial Fibrillation Project
Authors: Amitava Banerjee, Sophie Taillandier, Jonas B Olesen, Deirdre A Lane, Benedicte Lallemand, Gregory Y Lip, Laurent Fauchier
Journal: Circulation (2012)

Background: The risk of stroke and thromboembolism (TE) in patients with non-valvular atrial fibrillation (NVAF) can be classified in commonly-used stroke risk stratification scores. The role of the pattern of atrial fibrillation in risk prediction is unclear in contemporary ‘real world’ cohorts. Methods: Patients diagnosed with NVAF in a four-hospital-institution between 2000 and 2010 were identified and included. Event rates of stroke/TE were calculated according to pattern of AF, i.e. paroxysmal, persistent and permanent, defined by consensus guidelines. Independent risk factors of stroke/TE were investigated by Cox regression. Results: Among 7156 patients with NVAF, 4176 (58.4%) patients with paroxysmal, 376 (5.3%) with persistent and 2604 (36.3%) with permanent NVAF patterns were included. In non-anticoagulated patients, the overall stroke/TE event rate per 100 person-years was 1.29 (95% CI 1.13–1.47). Paroxysmal NVAF patients were more likely to be female (p&lt;0.001). Persistent NVAF patients were less likely to have prior history of stroke (p–0.002) and vascular disease (p&lt;0.001), and more likely to have hypertension (p&lt;0.001) and vitamin K antagonist therapy (p&lt;0.001). Permanent NVAF patients were more likely to have diabetes (p&lt;0.001), heart failure therapy (p&lt;0.001) and less likely to have dyslipidaemia (p&lt;0.001). Compared with paroxysmal NVAF, rates of stroke/TE (p=0.001), bleeding (p&lt;0.001) and all-cause mortality (p&lt;0.001) were significantly higher in permanent NVAF patients but not in persistent NVAF patients. In multivariate analyses, only previous stroke (hazard ratio, HR 2.58, 95% CI 2.08–3.21), vascular disease (HR 1.34,1.12–1.61), heart failure (HR 1.20,1.00–1.44), age≥75 years (HR 2.75, 2.16–3.50) and age 65–74 years (HR 1.60,1.22–2.09) increased stroke/TE risk, but persistent (HR1.13, 0.76–1.70) and permanent (HR 1.44,0.96–2.16) patterns of NVAF did not. Conclusion: In this large ‘real world’ cohort of NVAF patients, there were significant differences in rates of stroke, TE, death and bleeding between patterns of NVAF, however only previous stroke, age, heart failure and vascular disease (not pattern of NVAF) independently increased the risk of stroke/TE, death and bleeding in multivariate analyses. Therefore, the risk of stroke is similar across all patterns of NVAF and antithrombotic therapy should be based on clinical risk factors not NVAF pattern.
Telangiectasia macularis eruptiva perstans (TMEP): A form of cutaneous mastocytosis with potential systemic involvement
Authors: Maella Severino, Marie-Olivia Chandesris, Stéphane Barete, Emilie Tournier, Béatrix Sans, Camille Laurent, Pol André Apoil, Laurence Lamant, Claire Mailhol, Michel Laroche, Sylvie Fraitag, Katia Hanssens, Patrice Dubreuil, Olivier Hermine, Carle Paul, Cristina Bulai Livideanu
Journal: Journal of the American Academy of Dermatology (2016)
Abstract 38: A Decoy Peptide Selectively Inhibiting Dephosphorylation of Phospholamban
Authors: Woo Jin Park, Jae Gyun Oh, Dongtak Jeong, Roger J Hajjar
Journal: Circulation Research (2012)

Cardiac sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) plays a crucial role in Ca2+ handling in cardiomyocytes. Phospholamban (PLB) is an endogenous inhibitor of SERCA2a and its inhibitory activity is enhanced by dephosphorylation by protein phosphatase 1 (PP1). Therefore, blocking PP1-mediated dephosphorylation of PLB would be an efficient strategy for restoration of the reduced SERCA2a activity in failing hearts. We sought to develop a decoy peptide that mimics the phosphorylated PLB and thus competitively inhibits the PP1-mediated dephosphorylation of PLB. The phosphorylation sites, Ser16 and Thr17, are located within the flexible extra-membrane loop (amino acids 14-22) of PLB. We therefore synthesized a 9-mer pseudo-phosphorylated peptide derived from this region with a replacement of Ser16 with Glu (ψ-PLB-SE). Two other 9-mer peptides with wild type PLB sequence (ψ-PLB) or with a replacement of Ser16 with Ala (ψ-PLB-SA) were also synthesized. These peptides were coupled to a cell-permeable peptide TAT to facilitate cellular uptake. Treatment of adult rat cardiomyocytes with TAT-ψ-PLB-SE, but not with TAT-ψ-PLB or TAT-ψ-PLB-SA, significantly elevated the phosphorylation level of PLB, concomitant with an increase in contractile parameters in vitro. Perfusion of isolated rat hearts with TAT-ψ-PLB-SE significantly restored the left ventricular developed pressure that was suppressed by ischemia-reperfusion (Fig. 1). These data indicate that ψ-PLB-SE prevented dephosphorylation of PLB by acting as a decoy for PP1 and it would provide effective modality to regulate SERCA2a activity in failing hearts.