tbuckley/cabot-search huggingface dataset:
Impact of 2013 ASCO/CAP guidelines on HER2 determination of invasive breast cancer: A single institution experience using frontline dual-color FISH.
Authors: Elisa Gasparini, Moira Ragazzi, Alessandra Bisagni, Elisabetta Kuhn, Cristina Bassano, Ione Tamagnini, Moira Foroni, Giuseppe Falco, Guglielmo Ferrari, Luca Braglia, Luisa Savoldi, Alessandra Bologna, Roberto di Cicilia, Giorgio Gardini, Giancarlo Bisagni
Journal: Journal of Clinical Oncology (2017)

1028 Background: ASCO/CAP new guidelines published in 2013 (AC2013) significantly modified the scoring criteria for HER2-FISH. We retrospectively evaluated the impact of AC2013 in a five-year cohort of consecutive invasive breast cancers (IBCs) underwent frontline dual-color FISH. Furthermore, we applied three different reflex tests and investigated clinical outcomes of patients with HER2-equivocal IBC. Methods: 2788 consecutive IBCs that underwent frontline HER2/CEP17 determination in our institution from January 2009 to December 2013 were reclassified based on the AC2013 guidelines. FISH HER2-equivocal cases underwent reflex tests: HER2-IHC, RARA-FISH, and SMS-FISH. Clinico-pathological correlation was performed. Results: Two hundred HER2-negative cases (7.2%) were classified differently based on the AC2013: 0.3% (8/2788) became HER2-positive and 6.9% (192/2788) HER2-equivocal. AC2013 equivocal-IBCs represented a subgroup of grade 3, luminal-like subtype IBCs, in patients with a higher age. After reflex tests, among 190 equivocal cases 102 (53.7%) were reclassified as HER2-positive, 51 (26.8%) negative and 37 (19.5%) equivocal. IHC resulted negative in 44.7% (85), whereas SMS-FISH showed the highest percentage of positive results (45.8%). No statistically significant differences were identified in the disease-free and overall survival. Conclusions: AC2013 compared with AC2007 significantly increased initial HER2-equivocal cases (6.9%vs1.6%, p &lt; 0.001). After reflex testing, 4.5% of patients not treated with anti-HER2 therapy (either HER2-positive or “ultimate equivocal”) resulted eligible to trastuzumab, but showed clinical outcome comparable with AC2007 HER2-positive patients, treated with trastuzumab. Our findings belittle the clinical impact of AC2013 HER2-equivocal reclassification; accordingly further studies are necessary to justify this category and the reclassification efforts by additional reflex tests.
beta-Blockers in treatment of hypertension.
Journal: BMJ (1978)

3).This deals with the time of onset of local compared with distant recurrence and the effect of radiotherapy on the time of onset of local recurrence.The error, which we acknowledge and for which we should like to apologise, is to have excluded from the life-table analysis patients who did not have recurrence.We should like to present amended data, dealing with these points, derived from a further analysis.Firstly, the time to onset of local recurrence is slightly longer than that to distant metastasis.The actuarial relapse rates for local recurrence at 2, 4, and 6 years are 15%, 23%, and 270% respectively, while for distant recurrence the rates are 23%/, 36%O, and 40%.For both groups there was a constant
Phase III study of lapatinib (L) plus trastuzumab (T) and aromatase inhibitor (AI) vs T+AI vs L+AI in postmenopausal women (PMW) with HER2+, HR+ metastatic breast cancer (MBC): ALTERNATIVE.
Authors: William John Gradishar, Roberto Hegg, Seock-Ah Im, In Hae Park, Sergei Tjulandin, Sarah Kenny, Severine Sarp, Lisa Williams, Miguel A. Izquierdo, Stephen R. D. Johnston
Journal: Journal of Clinical Oncology (2017)

1004 Background: Combination ofHER2-targeted therapy+AI improved clinical benefit in patients (pts) with HER2+, HR+ MBC vs AI alone in two previous trials, median progression free survival (mPFS) 4.8 vs 2.4 mo (TAnDEM), and 8.2 vs 3.0 mo (EGF30008). Dual HER2 blockade enhances clinical benefit vs single HER2 blockade. This study evaluated the safety and efficacy of dual vs single HER2 blockade (L+T vs T/L)+AI in HER2+, HR+ MBC progressing on (neo)adjuvant/first-line T+chemotherapy (CT). HER2 and HR status were assessed for eligibility at local lab. Methods: PMW were randomized 1:1:1 to receive T (8mg/kg followed by 6mg/kg IV Q3W)+L (1000mg/d)+AI or T+AI or L (1500mg/d)+AI. AI was per investigator’s choice. Pts were excluded if they were intended for CT. The primary endpoint was to assess superiority of PFS with L+T vs T. Secondary endpoints included PFS (L vs T), overall survival (OS), overall response rate (ORR), and safety. Results: 369 pts were enrolled; current analysis included 355 pts (data cutoff, March 11, 2016); L+T (n = 120), T (n = 117) or L (n = 118). Final PFS data were analyzed after 137 events. Baseline characteristics were balanced across all treatment (tx) arms. The primary endpoint was met; superior PFS was observed with L+T vs T (mPFS, 11 vs 5.7 mo; HR = 0.62, 95% CI [0.45, 0.88], P= 0.0064). This benefit of L+T was consistent in key subgroups. mPFS with L vs T was 8.3 vs 5.7 mo (HR = 0.71, 95% CI [0.51, 0.98], P= 0.0361). ORR with L+T, T, and L was 32%, 14%, and 19% respectively. OS data are immature. Most common adverse events (AEs) with L+T, T and L (≥15%, any arm) were diarrhea (69%, 9%, 51%), rash (36%, 2%, 28%), nausea (22%, 9%, 22%), and paronychia (30%, 0, 15%). Hepatic abnormalities of &gt; 3 ULN ALT/AST levels were noted in 4%, 6%, and 16% respectively. Incidence of tx-related SAEs was 5%, 2%, and 4% and on-tx deaths was 3%, 4%, and 5%, respectively. Conclusions: Dual HER2 blockade with L+T+AI showed superior PFS benefit vs T+AI, in pts with HER2+, HR+ MBC. Incidence of AEs was increased with L+T. This combination can potentially offer an effective CT-sparing tx option in subgroup of HER2+, HR+ pts without aggressive disease and who are not candidates for CT. Clinical trial information: 2010-019577-16.
Measurement of Hemoglobin A<sub>1c</sub> in Patients With Sickle Cell Trait
Authors: Curt Rohlfing, Steven Hanson, Randie R. Little
Journal: JAMA (2017)

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Abstract DPOC-008: LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION
Authors: Holly R. Harris, Megan S. Rice, Amy L. Shafrir, Elizabeth M. Poole, Jonathan L. Hecht, Kathryn L. Terry, Shelley S. Tworoger
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND: One recent model of ovarian cancer development divides ovarian cancer into two types. Type II tumors are fast growing, potentially arising from the fallopian tubes, and characterized by tubal precursor lesions with p53 mutations. Type I tumors are slow–growing, arising from the ovary, and characterized by KRAS, BRAF, and PTEN mutations. The purpose of this study was to evaluate the association between selected lifestyle and reproductive risk factors and risk of ovarian cancer defined by expression of p53 (as a marker of Type II disease) and mitogen–activated protein kinase (MAPK), which is upregulated by KRAS and BRAF (as a marker of Type I disease). METHODS: Epithelial ovarian cancer cases with available tumor blocks and cancer–free controls were identified from the Nurses' Health Study (NHS) and NHS II prospective cohorts, and from the population–based New England Case–Control (NECC) study of ovarian cancer. We performed immunohistochemical assays for p53 and MAPK expression. Age– and multivariable–adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the association between each lifestyle or reproductive risk factor (e.g. parity, oral contraceptive use, tubal ligation, age at menarche, menopausal status, age at menopause, hormone therapy use, and family history of ovarian cancer) and ovarian cancer using polytomous logistic regression. RESULTS: 249 cases and 1051 controls from the NHS/NHS II and 77 cases and 857 controls from the NECC study were included in the analyses. Overall there were few significant differences in lifestyle or reproductive risk factors by p53 or MAPK tumor expression. Increasing parity was associated with a greater decreased risk of p53 negative tumors (OR=0.40; 95% CI=0.26–0.62) than p53 positive tumors (OR=0.85; 95% CI=0.46–1.57) (pheterogeneity=0.03). Family history of ovarian cancer was associated with risk of developing MAPK negative (OR=1.87; 95% CI=1.28–2.74) but not MAPK positive tumors (OR=0.76; 95% CI=0.46–1.23) (pheterogeneity&amp;lt;0.01). When p53 and MAPK expression were cross–classified family history was most strongly associated p53+/MAPK– expression (OR=2.46; 95% CI=1.42–4.28). CONCLUSIONS: These findings provide evidence that parity and family history may be associated with tumor subtypes defined by p53 and MAPK expression. However, in future studies other immunohistochemical markers that more clearly define these subtypes should be considered. Citation Format: Holly R. Harris, Megan S. Rice, Amy L. Shafrir, Elizabeth M. Poole, Jonathan L. Hecht, Kathryn L. Terry, Shelley S. Tworoger. LIFESTYLE AND REPRODUCTIVE RISK FACTORS AND OVARIAN CANCER RISK BY p53 AND MAPK EXPRESSION [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-008.
N-acyl Taurines and Acylcarnitines Cause an Imbalance in Insulin Synthesis and Secretion Provoking β Cell Dysfunction in Type 2 Diabetes
Authors: Michaela Aichler, Daniela Borgmann, Jan Krumsiek, Achim Buck, Patrick E. MacDonald, Jocelyn E. Manning Fox, James Lyon, Peter E. Light, Susanne Keipert, Martin Jastroch, Annette Feuchtinger, Nikola S. Mueller, Na Sun, Andrew Palmer, Theodore Alexandrov, Martin Hrabe de Angelis, Susanne Neschen, Matthias H. Tschöp, Axel Walch
Journal: Cell Metabolism (2017)
TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM).
Authors: Rachel A. Freedman, Rebecca Sue Gelman, Michelle E. Melisko, Carey K. Anders, Beverly Moy, Kimberly L. Blackwell, Roisin M. Connolly, Polly Ann Niravath, Catherine H. Van Poznak, Shannon Puhalla, Sarah Farooq, Anne Cropp, Christine M Cotter, Minetta C. Liu, Ian E. Krop, Julie R. Nangia, Nadine M. Tung, Antonio C. Wolff, Eric P. Winer, Nancy U. Lin
Journal: Journal of Clinical Oncology (2017)

1005 Background: Evidence-based treatments (tx) for metastatic, HER2+ BCBM are limited. We previously found a central nervous system (CNS) objective response rate (ORR) of 8% (95% CI 2-22%) for the irreversible, EGFR/HER2-targeted kinase inhibitor, neratinib. To enhance CNS activity, we evaluated the combination of neratinib + capecitabine in a subsequent cohort, and report results here. Methods: Pts with measurable BCBM (≥ 1 cm in longest dimension) and no prior lapatinib or capecitabine were eligible. All but 3 had CNS progression after local CNS tx. During 21 day cycles, pts received capecitabine 750 mg/m2 twice daily x 14 days followed by 7 days off + neratinib 240 mg orally once daily. Loperamide prophylaxis (16 mg total daily) was recommended during cycle 1. Brain MRI and non-CNS imaging were repeated every 2 cycles until 18 wks, then every 3 cycles. The primary endpoint was composite CNS ORR, requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions (central review, VORR), no progression of non-target or non-CNS lesions, no new lesions, no escalating steroids, and no progressive neurologic signs/symptoms. We used a two-stage design with hypotheses ORR 15% and 35% (error rates 5% and 20%), responses in ≥5/19 pts to enter 2 nd stage; responses in ≥9/35 [26%] pts to be promising. Results: 39 pts enrolled between 4/2014-11/2016 (2 withdrew before tx, 37 analyzed); median age 51, median prior metastatic lines 2 (range 0-6), 65% had prior WBRT. As of 11/15/16, 23 (62%) patients are alive and 7 remain on protocol tx; median number of cycles initiated = 5 (range 1-26). 18 women (49%) had a VORR (95% CI 32-66%, neurologic exams not yet available on all pts). Overall 12-month survival is 63% (95% CI 43%-77%); 4/7 pts still on protocol therapy have not yet reached 6 cycles. No pts had grade 4 toxicity; 18 (49%) had grade 3 toxicity, with diarrhea most common (32%), and 6 pts discontinued tx for toxicity. Conclusions: The combination of neratinib and capecitabine is active for BCBM with VORR in nearly half of pts, supporting further development of the regimen for BCBM. Updated results will be presented at the meeting. Clinical trial information: NCT01494662.
Overall survival results from the randomized phase II study of palbociclib (P) in combination with letrozole (L) vs letrozole alone for frontline treatment of ER+/HER2– advanced breast cancer (PALOMA-1; TRIO-18).
Authors: Richard S. Finn, John Crown, Istvan Lang, Katalin Boer, Igor Bondarenko, Sergey O. Kulyk, Johannes Ettl, Ravindranath Patel, Tamas Pinter, Marcus Schmidt, Yaroslav V. Shparyk, Anu Thummala, Nataliya L. Voytko, Camilla Fowst, Xin Huang, Sindy Kim, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2017)

1001 Background: Preclinical data identified a synergistic role for P and hormone blockade in blocking growth of ER+ breast cancer (BC) cell lines. PALOMA-1 was an open-label phase II trial comparing progression-free survival (PFS) in patients (pts) with advanced ER+/HER2– BC treated with P+L or L alone. Median PFS increased with addition of P to L to 20.2 mos (vs 10.2 mos with L alone; HR = 0.488), with an acceptable safety profile, leading to accelerated approval by the US FDA. These results were confirmed in the phase 3 PALOMA-2 trial. At the time of the final PFS analysis, overall survival (OS) data were immature with only 61 events in both arms and a median follow-up of &lt; 30 mos with a trend in favor of P+L vs L (37.5 vs 33.3 mos; HR = 0.813; P= 0.211). Here we present final OS results. Methods: PALOMA-1 was a 2-part study evaluating P+L in ER+/HER2– advanced BC. Part 1 enrolled postmenopausal pts with this subtype using only ER+/HER2– while Part 2 enrolled pts of this subtype additionally screened for CCND1 amplification and/or loss of p16. The primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate, OS, safety, and correlative biomarker studies. A total of 165 pts were randomized; 66 in Part 1 and 99 in Part 2. Baseline characteristics were balanced between treatment arms. In both parts, pts were randomized 1:1 to receive P+L or L alone. OS data were collected as well as post-study therapy. Results: As of Dec 2016, there were 116 OS events. Median OS was 37.5 mos (95% CI: 31.4, 47.8) with P+L vs 34.5 mos (95% CI: 27.4, 42.6) for L (HR = 0.897 [95% CI: 0.623, 1.294]; P= 0.281). Median OS was 37.5 vs 33.3 mos (HR = 0.837; P= 0.280) for Part 1 and 35.1 vs 35.7 mos (HR = 0.935; P= 0.388) for Part 2. 78.6% of pts in the P+L arm received post-study systemic therapy vs 86.4% in the L arm. More pts in the L arm received ≥3 lines of therapy (37% vs 18%). Further subgroup analyses and details on post-study therapies will be presented. Conclusions: In PALOMA-1, P+L provided a statistically non-significant trend towards an improvement in OS. Survival data from the phase III, PALOMA-2 study is awaited. Sponsor: Pfizer; Clinical trial information: NCT00721409.
Abstract 1254: Novel Insights In Arrhytmogenesis Of Catecholaminergic Ventricular Tachycardia From The First Knock In Model Of Homozygous Calsequestrin Mutation
Authors: Nicoletta Rizzi, Nian Liu, Diego Arcelli, Tom Rossenbacker, Alessandra Nori, Mario Scelsi, Carlo Napolitano, Pompeo Volpe, Silvia G Priori
Journal: Circulation (2007)

Cardiac Calsequestrin (CASQ2) is a high affinity low capacity calcium binding protein essential in the regulation of intracellular Ca storage and release. Mutations in CASQ2 have been linked to the recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVTr). To elucidate the mechanisms of arrhythmogensis in CPVTr, we generated a knock-in mouse model carrier of the R33Q mutation identified in one of our patients (pts) with a severe CPVT phenotype. Continuous ECG recording (DSI implantable monitors) showed that homozygous (CASQ2 R33Q/R33Q ) mice develop bidirectional and polymorphic VT upon exposure to adrenergic triggers (noise, physical contact). CASQ2 R33Q/R33Q mice have no sign of structural cardiac abnormality (normal heart/body weight ratio, histology no fibrosis nor myofibrillar disarray). Calcium-binding affinity of CASQ2 R33Q/R33Q is identical to that of wild type (WT) CASQ2, its localization evaluated with confocal microscopy is superimposable to that of WT. Western blot analysis shows that CASQ2 R33Q/R33Q content in myocytes is reduced by 40% but Real Time PCR showed that levels of mRNA are not reduced suggesting an abnormal protein turn-over. Evaluation of electrophysiological properties of isolated CASQ2 R33Q/R33Q myocytes revealed that pacing (1–5 Hz) induces delayed afterdepolarizations (DADs; 18/32 cells 56%) and triggered activity (TA; 9/31 29%) addition of adrenalin (200 nM) enhances DADs and TA (DADs 15/16 cells 93%; TA 8/17 cells 47%) and also elicits (25% of myocytes) early after depolarizations (EADs) and EADs-mediated TA. Our data demonstrate that in analogy with our knock-in model of the dominant form of CPVT due to mutations in the cardiac ryanodine receptor (RyR2) the CASQ2 R33Q/R33Q mice 1) do not present signs of cardiomyopathy, 2) develop DADs and TA in vitro and bidirectional and polymorphic VT in vivo. At variance with RyR2 mice, CASQ2 R33Q/R33Q mice 1) present a more malignant phenotype, lower threshold for DADs, TA and VT; 2) EADs concur to arrhythmogenesis 3) overcoming with a knock-in the limitations of previous in vitro and in vivo models overexpressing mutant CASQ2 on the background of the WT protein we demonstrated that a reduction in CASQ2 is implicated in the arrhythmogenesis of recessive CPVT.
Polypill is not just for cardiovascular disease
Authors: Fay H Cafferty, Ruth E Langley
Journal: BMJ (2017)

Viera’s article on the polypill focused exclusively on cardiovascular benefits.1 Yet several candidates for inclusion in such a formulation, such as aspirin and metformin, have shown anticancer activity in recent years.

Randomised trials show that aspirin prevents the development of colorectal cancer,23 and long term follow-up from vascular trials indicates that aspirin inhibits development of …
Frontal Fibrosing Alopecia Severity Index ( <scp>FFASI</scp> ): a call for a more inclusive and globally relevant severity index for frontal fibrosing alopecia
Authors: N.C. Dlova, O.E. Dadzie
Journal: British Journal of Dermatology (2017)

We read with interest the article by Holmes et al,1 published in the February 2016 edition of the British Journal of Dermatology, and associated comments by Saceda-Corralo et al.2

We would like to congratulate all the above authors for addressing this important topic. Nevertheless, we would like to raise a few additional points about the proposed severity index for Frontal Fibrosing Alopecia (FFA), which may assist in making it more culturally inclusive and globally relevant, especially for patients of African and/or South Asian descent.

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The need for preventive and curative services for malaria when the military is deployed in endemic overseas territories: a case study and lessons learned
Authors: Sumadhya Deepika Fernando, Rahuman Booso, Priyani Dharmawardena, Arunagirinathan Harintheran, Kugapiriyan Raviraj, Chaturaka Rodrigo, Manjula Danansuriya, Rajitha Wickremasinghe
Journal: Military Medical Research (2017)

Sri Lanka has been free from indigenous malaria since November 2012 and received the WHO certificate for malaria-free status in September 2016. Due to increased global travel, imported malaria cases continue to be reported in the country. Military personnel returning home from international peace-keeping missions in malaria endemic countries represent a key risk group in terms of imported malaria. The present study intended to characterize the potential causes of a malaria outbreak among the Sri Lankan security forces personnel deployed in the Central African Republic (CAR). Data were collected from a cross-sectional survey distributed among Sri Lankan Air Force personnel who had returned from United Nations peace-keeping missions in the CAR region. A pre-tested questionnaire was used for the data collection, and focus group discussions were also conducted. One hundred twenty male Air Force personnel were interviewed (out of a group of 122 officers and airmen). All participants were deployed in the CAR for 14 months and were aware of the existence of chemoprophylaxis against malaria. The majority of the subjects (92.5%, 111/120) also knew that prophylaxis should be started prior to departure. However, the regular use of chemoprophylaxis was reported by only 61.7% (74/120) of the sample. Overall, 30.8% of the participants (37/120) had 44 symptomatic episodes of malaria during deployment, and one person succumbed to severe malaria. All cases were associated with noncompliance with chemoprophylaxis. Better coordination with overseas healthcare services and the establishment of directly observed chemoprophylaxis may help to avoid similar outbreaks in the future.