tbuckley/cabot-search huggingface dataset:
Inherited Mutations in Women With Ovarian Carcinoma
Authors: Barbara M. Norquist, Maria I. Harrell, Mark F. Brady, Tom Walsh, Ming K. Lee, Suleyman Gulsuner, Sarah S. Bernards, Silvia Casadei, Qian Yi, Robert A. Burger, John K. Chan, Susan A. Davidson, Robert S. Mannel, Paul A. DiSilvestro, Heather A. Lankes, Nilsa C. Ramirez, Mary Claire King, Elizabeth M. Swisher, Michael J. Birrer
Journal: JAMA Oncology (2015)

Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized.To determine the frequency and importance of germline mutations in cancer-associated genes in OC.A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay.Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status.Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations.Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.
Gemcitabine (G) /carboplatin (C) surveillance study in patients with advanced or metastatic non-small cell lung cancer (NSCLC): Survival update of a phase II study of a 21 versus 28-day schedule
Authors: C. K. Obasaju, Z. Ye, J. Jorge, A. Hatfield
Journal: Journal of Clinical Oncology (2004)

7134 Background: The combination of G and C is active and widely used for advanced NSCLC. For Gemzar administered on days 1,8 and 15 dose-limiting toxicity was thrombocytopenia. This study compared two different combinations of C with G (days 1,8) to identify a schedule with superior therapeutic index. Methods: 499 chemonaive patients with stage IIIB-IV NSCLC were accrued at 80 centers between June 1999 and June 2000. Patient characteristics are tabulated below. Therapy: Arm A: G 1100mg/m2 d 1,8 + C AUC 5 d 8 q 28 d or Arm B: G 1000 mg/ m2 d 1,8 + C AUC 5 d 1 q 21 d. Each physician put 3 patients on Arm A and 2 patients on Arm B in any order of choice. Data was collected using a web-based program. Results: Grades 3 and higher toxicities in Arms A/B were: anemia (4.8%/6.9%), neutropenia (9.1%/10.7%), and thrombocytopenia (8.0%/14.4%). Platelet transfusions occurred in (34pts/43pts) respectively. A total of (62units/91units) of platelets were given but no bleeding episodes occurred. 404 were evaluable for response and 473 for toxicity. The overall response rate was 22.7% in Arm A and 32.6% in Arm B. Median, 1-year and 2-year survival was 9.4 months, 35.5% and 13.2%, respectively in Arm A and 10.2 months, 44.4% and 12%, respectively in Arm B. Dose intensity was similar for both arms. Conclusions: In this largest US-based trial the G/C combination demonstrates comparable efficacy to other platinum doublets. Either schedule can be recommended although Arm B appears to have a slight efficacy advantage. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co.; Lilly Oncology Eli Lilly
More complaints should be resolved locally, says health ombudsman
Authors: Jacqui Wise
Journal: BMJ (2015)

The parliamentary and health service ombudsman, Julie Mellor, has said that she sees too many complaints that could have been resolved locally, resulting in people being left waiting for answers and delays in improving services.

The ombudsman’s office investigates complaints about government departments, other public organisations, and the NHS in England. It investigates around 4000 complaints a year and upholds around 37%.

The ombudsman’s new report1 is a snapshot of 192 complaints, including 116 about the NHS in England, that were investigated …
Monitorization of primary therapy (PT) by additional imaging methods in locally advanced breast cancer (LABC)
Authors: M. Margelí, B. Cirauqui, V. Vallejos, C. Sánchez, A. Mariscal, E. Castellà, M. Rull, A. Torrente, M. Fraile, A. Barnadas
Journal: Journal of Clinical Oncology (2006)

10580 Introduction: The response of locally advanced breast cancer (LABC) to Primary therapy (PT) may be monitored clinically and by mammography (MG). Magnetic resonance (MR) and 99mTc-sestamibi scintimammography (SMM) are increasingly being used. The aim of this study was to determine whether MG, MR and SMM are accurate indicators of tumour response to PT and whether they are predictors of histological response. Patients and Methods: A prospective observational study was approved at our institution and 52 patients( p) with core biopsy diagnostic of LABC and written consent were enrolled (mean age 52 years, SD 13) All p had clinical, MG, MR, SM assessment pre- and post- PT. Primary chemotherapy based on anthracyclines was administered as follows: 19 p FEC, 17 p AC-Docetaxel, 8 p Gemcitabine- Doxorubicine- Paclitaxel, 1 p FEC- Docetaxel and 1 p Carboplatin- VP16. 6 p were treated with hormone-therapy. RECIST criteria were considered for clinical response assessment and the same criteria was adapted for imaging and pathologic response. Results: After PT 33 tumours were considered not suitable for breast-conserving surgery. Based on histopathological findings, 10 (19%) lesions showed complete pathologic response, 30 (58%) partial response, 12 (23%) stabilization. No progression was detected. Clinical assessment of tumour complete response agreed with pathology in 40 of 52 tumours (78%), and with MG in 39 (78%). Correlation between MG and pathological findings was observed in 42 p (84%). Correlation between MR and pathological findings was observed in 42 p (82%). Correlation between SMM and pathological findings was observed in 31 p (66%). Among patients with complete pathologic remission, 9 of ten patients achieve a complete response by MR and SMM. Conclusion: In conclusion, our results don’t show that MR and SMM add any benefit to the diagnostic arsenal for predicting histopathological complete response to PT. However these new diagnostic methods should be considered in selected cases. No significant financial relationships to disclose.
P315Wt1 regulates the expression of inhibitory chemokines during heart development.
Authors: V Velecela, LA Lettice, YY Chau, QD Gunst, M Van Den Hoff, M Reina, FO Martinez, ND Hastie, OM Martinez-Estrada
Journal: Cardiovascular Research (2014)

The embryonic epicardium is an important source of cardiovascular precursor cells and paracrine factors that are required for adequate growth and complete formation of the heart. WT1 is expressed in the embryonic and neonatal heart in mammals; however it becomes quiescent in the adult heart. Recently, a great deal of attention has been given to the signalling pathways regulated by WT1 that promote heart development. It has been demonstrated that WT1 can regulate epicardial EMT and the release of growth factors; however there is little information on the signalling pathways regulated by WT1 that could act in a negative manner. Transcriptome analysis of Wt1KO epicardial cells reveals an unexpected role for WT1 in repressing the expression of interferon-regulated genes that could be involved in a negative regulation of heart morphogenesis. We showed that WT1 is required to repress the expression of the chemokines Ccl5 and Cxcl10 in epicardial cells. We observed an inverse correlation of Wt1 and the expression of Cxcl10 and Ccl5 during epicardium development. Chemokine receptor analyses of hearts from Wt1(gfp/+) mice demonstrate the differential expression of their chemokine receptors in GFP(+) epicardial enriched cells and GFP(-) cells. Functional assays demonstrate that CXCL10 and CCL5 inhibit epicardial cell migration and the proliferation of cardiomyocytes respectively. WT1 regulates the expression levels of Cxcl10 and Ccl5 in epicardial cells directly and indirectly through increasing the levels of IRF7. As epicardial cell reactivation after myocardial damage is linked with WT1 expression, the present work has potential implications in the field of adult heart repair.
A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide.
Authors: C P Belani, M J Egorin, J S Abrams, D Hiponia, M Eisenberger, J Aisner, D A Van Echo
Journal: Journal of Clinical Oncology (1989)

Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75% of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater carboplatin dosage administered, greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15% (90% confidence +/- 9%). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.
Nicastrin mutations in familial acne inversa impact keratinocyte proliferation and differentiation through the Notch and phosphoinositide 3-kinase/AKT signalling pathways
Authors: X. Xiao, Y. He, C. Li, X. Zhang, H. Xu, B. Wang
Journal: British Journal of Dermatology (2015)

Summary Background Acne inversa (AI) is a chronic inflammatory skin disease with an autosomal dominant inheritance pattern. Mutations of the gene encoding nicastrin (NCSTN), a cofactor subunit of γ-secretase, are responsible for familial AI. However, whether deficiency of nicastrin is functionally implicated in the biological behaviours of human keratinocytes and related molecular mechanisms remains unknown. Objectives To study alterations of biological traits and related signalling pathways modulated by nicastrin knockdown in keratinocytes. Methods A human immortalized keratinocyte cell line (HaCaT) was treated with efficient small interfering (si)RNA-targeted NCSTN. Cell proliferation was measured by CCK-8 assay; cell-cycle and cell apoptosis analyses were detected by flow cytometry. Microarray analysis was applied to uncover impacts of NCSTN silencing on whole-genome expression of HaCaT cells. Altered signalling pathways were further confirmed by real-time polymerase chain reaction, Western blotting and immunohistochemistry in both HaCaT cells and lesions of a patient with AI with NCSTN mutation. Results NCSTN knockdown in HaCaT cells impaired γ-secretase activity, leading to increased cell proliferation and S-phase population. Microarray data also showed that numerous genes and pathways implicated in proliferation and differentiation of keratinocytes were statistically changed. Among these genes, expression levels of several Notch pathway molecules, known as γ-secretase substrates, were validated to be significantly attenuated in both nicastrin-silencing HaCaT cells and the lesion of the patient. Furthermore, a remarkable elevation of expression of phosphoinositide 3-kinase (PI3K), AKT and its activated form pAKT was illustrated in siRNA-treated HaCaT cells. Conclusions Deficiency of the NCSTN in familial AI may regulate proliferation and differentiation of keratinocytes mainly through the Notch and PI3K/AKT signalling pathways.
Abstract 11940: Mineralocorticoid Receptor Dysregulation by MicroRNA-135a in Bradycardic Arrhythmogenic Remodeling
Authors: Eric Duong, Jiening Xiao, Khai Le Quang, Patrice Naud, Yan- F Shi, Jean- C Tardif, Dobromir Dobrev, Stanley Nattel
Journal: Circulation (2014)

Introduction: Complete atrioventricular block (CAVB) causes arrhythmogenic remodeling and increases the risk of Torsades de Pointes (TdP) arrhythmias. MicroRNAs (miRs) are key regulators of gene expression that contribute to cardiac remodeling. Here, we assess microRNA changes after CAVB and their potential significance in arrhythmogenic cardiac remodeling. Methods: CAVB was induced in mice via His bundle ablation. Expression of miRs was evaluated by pan-microRNA microarray with qPCR confirmation on samples from controls and at 24 hrs and 4 wks post-CAVB. Arrhythmias were detected by continuous monitoring. MicroRNA target prediction algorithms were used to identify potential target genes. Biological confirmation of targets was by luciferase assay and overexpression (OE) studies in HEK and H9c2 cells respectively. Results: TdP occurred within 24 hrs in 6/17 CAVB mice, vs no controls. Ventricular tachyarrhythmia episodes were frequent at 4 wks CAVB (212±83 per 24 hrs) and were not seen in controls. CAVB was followed by increased left ventricular (LV) dimension (by 31%, ***p&lt;.001), LV mass (by 33%, *p&lt;.05) and LV fractional shortening (by 33%*) at 4 wks. Of &gt;400 miRs assayed, only miR-135a was altered at 24 hrs (downregulated by 96%***, Fig. A), with 70% decrease at 4 wks. TargetScan predicted miR-135a regulation of the mineralocorticoid receptor (MCR), encoded by the NR3C2 gene. miR-135a OE suppressed NR3C2 3’UTR reporter activity 3.2-fold* (n=5, Fig. B). miR-135a OE did not affect NR3C2 mRNA (Fig. C) but significantly reduced NR3C2 protein expression (n=4, Fig. D). Coexpression with anti-miR-135a eliminated the NR3C2 downregulating effect of miR-135a OE. Conclusions: The mineralocorticoid receptor, encoded by the NR3C2 gene, is translationally regulated by miR-135a, a microRNA that is downregulated in the heart following CAVB in mice. These results implicate miR-135a/mineralocorticoid modulation in arrhythmogenic ventricular remodeling caused by CAVB.
Phenotyping atopic dermatitis in children by filaggrin status. The COPSAC clinical birth cohort study
Authors: Charlotte Giwercman Carson, Morten Arendt Rasmussen, Jacob P. Thyssen, Torkil Menné, Hans Bisgaard
Journal: European Respiratory Journal (2011)

Background:  Filaggrin null mutations result in an impaired skin barrier function and are associated with atopic dermatitis. Clinical observations suggest a distinct phenotype for patients with the filaggrin null genotype.   Objective:  To characterize and compare the clinical presentation and course of atopic dermatitis within the first 7 years of life in children with and without filaggrin null mutations.   Method:  The COPSAC cohort is a prospective, longitudinal, birth cohort study of 397 Caucasian children born to mothers with a history of asthma, followed for 7 years with scheduled visits every 6 months as well as visits for acute exacerbations of dermatitis. Atopic dermatitis was defined in accordance with international guidelines and dermatitis reactions were accurately described at every visit using 35 predefined localizations and 10 different characteristics.   Results:  A total of 170 (43%) of 397 children suffered from atopic dermatitis before age 7. The R501X and 2282del4 filaggrin null mutations were associated with a higher number of acute visits (3.6 vs. 2.7; p=0.04), more severe dermatitis (moderate-severe SCORAD 44% vs. 31%; p=0.14), more widespread dermatitis (10% vs. 6% of the body, p   Conclusion:  Filaggrin mutations represent a genetically defined endophenotype, characterized by early onset and a more severe dermatitis with particular predilection to the exposed areas of the body.
SNaPshot multigene assay to detect mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs).
Authors: B. A. Waltman, D. Dias-Santagata, A. K. Cosper, M. Mino-Kenudson, D. R. Borger, P. Fidias, A. T. Shaw, A. J. Iafrate, J. A. Engelman, L. V. Sequist
Journal: Journal of Clinical Oncology (2010)

7554 Background: NSCLCs harboring activating EGFR mutations often respond to EGFR TKIs, but drug resistance invariably occurs, usually after 9-12 months. Although two validated resistance mechanisms include T790M (50%) and MET amplification (10-15%), the mechanisms of drug resistance (MODR) in the remaining 35-40% of pts remain unknown. We recently implemented an innovative multiplexed PCR-based assay (SNaPshot) to genotype cancer pts more comprehensively. SNaPshot is performed in a CLIA-certified lab with tumor DNA from paraffin-embedded samples; it tests for common mutations in 13 key oncogenes such as EGFR, KRAS, PIK3CA, BRAF, and TP53. We examined SNaPshot results in EGFR mutant cancers with acquired TKI-resistance. Methods: We reviewed all NSCLC samples sent for prospective SNaPshot analysis from 03/09 to determine the range of tumor genotypes. A simultaneous chart review identified EGFR mutant pts undergoing repeat biopsy after the development of TKI-resistance in which a corresponding pre-treatment tumor sample was available for SNaPshot analysis and MET FISH testing. Results: A total of 271 patients with NSCLC underwent SNaPshot testing between 03/09 and 11/09; 164 (61%) were found to have at least one mutation. We identified 27 EGFR mutant pts who developed TKI-resistance and had paired samples available. SNaPshot results are summarized in the Table. Interestingly, 3 pts demonstrated a major histological change from NSCLC to SCLC in the TKI-resistant biopsy (confirmed by IHC), while maintaining the original EGFR mutation. Conclusions: Here we introduce SNaPshot as a comprehensive tumor genotyping assay that is valuable for examining MODR in the clinic. Among 27 EGFR mutant pts with TKI-resistance, T790M was found in 48% and MET amplification in 4%. Notably, 1 pt acquired a PIK3CA mutation, which has been described as a MODR in vitro. Three pts experienced a fundamental transformation from NSCLC to SCLC harboring the same EGFR mutation. Investigation into the significance of the SCLC evolution and the remaining pts without identified MODR is ongoing. Observed resistance mechanisms Number Total pts 27 T790M (2 T790M + TP53) 13 MET amplification 1 PIK3CA 1 No identified mutations 12 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Gatekeeper Biogen Idec, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, MedImmune, Millennium, Pfizer, Roche, Schering-Plough, Telik Novartis I participated in the development of the SNaPshot assay, which is the subject of a patent application and licensing discussions.
Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens.
Authors: M Markman, P G Rose, E Jones, I R Horowitz, A Kennedy, K Webster, J Belinson, N Fusco, L Fluellen, B Kulp, G Peterson, W P McGuire
Journal: Journal of Clinical Oncology (1998)

PURPOSE To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.