tbuckley/cabot-search huggingface dataset:
Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC).
Authors: Enriqueta Felip, Filippo G. De Braud, Michela Maur, Herbert H. F. Loong, Alice Tsang Shaw, Johan F. Vansteenkiste, Tom John, Geoffrey Liu, Martijn P. Lolkema, Jeffrey W. Scott, Richard Yu, Giovanni Selvaggi, Kaushal Mishra, Yi-Yang Yvonne Lau, Daniel Shao-Weng Tan
Journal: Journal of Clinical Oncology (2017)

2502 Background: Induction of PD-L1 expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring EML4–ALK rearrangements. Here we explore whether the combination of ALKi (ceritinib) and PD1-inhibitor (NIVO) will provide sustained clinical benefit to pts with ALK+ NSCLC. Methods: This phase 1 dose escalation study enrolled previously treated (ALK inhibitor [ALKi] or chemotherapy) or tx-naive pts with stage IIIB/IV ALK+ NSCLC; who received NIVO 3 mg/kg IV Q2W + ceritinib with low-fat meal, at 450 mg/day (group 1) or 300 mg/day (group 2) until progression/unacceptable toxicity. Primary objective: MTD/recommended dose for expansion. Dose escalation was guided by Bayesian logistic regression model with overdose control. Results: Median follow-up: group 1 (n = 14) 13 mos (10-15); group 2 (n = 22) 6 mos (2-10). As of 9 Sep 2016, 16/36 (44%) pts discontinued tx: disease progression (11 [31%] pts), AE’s (3 [8%] pts), and death (2 [6%] pts). In group 1, 4 pts experienced DLT: pancreatitis (n = 2), lipase and transaminase increase (n = 1), and autoimmune hepatitis (n = 1). In group 2, 2 pts experienced DLT: G3 ALT increase. Both dose levels met Bayesian criteria for dose expansion. Overall most frequent (≥40%) AEs (n = 36), were diarrhea (64%), ALT increase (56%), AST increase (44%) and vomiting (42%). Most frequent ( &gt; 10%) grade ≥3 AEs were increases in ALT (22%), GGT (17%), amylase (11%), and lipase (11%), and maculopapular rash (11%). Incidence of rash (grouped term) was 61%; similar in both groups. Grade 3 rash was reported in 29% pts in group 1 and 14% pts in group 2. Preliminary ceritinib steady state PK (AUC 0-24 and C max ) suggested that 300 mg/day exposure was ~ 70-75% of 450 mg/day. Confirmed (c)/unconfirmed (u) ORR: ALKi-pretreated pts (group 1 [n = 8], group 2 [n = 12]) was 63% (4 cPR,1 uPR; 95% CI: 25%, 92%), and 33% (4 uPR) 95% CI: 10%, 65%) respectively; ALKi-naïve pts, (group 1 [n = 6], group 2 [n = 10]) was 83% (5 cPR; 95% CI: 36%, 100%), and 70% (1 cCR, 3 cPR 3uPR; 95% CI: 35%, 93%) respectively. Conclusions: Ceritinib + NIVO is an active combination in ALK+ NSCLC. However, the protocol will be amended to address observed toxicities. Data will be updated for presentation. Clinical trial information: NCT02393625.
Surveillance of congenital rubella in Great Britain
Authors: A J L Turner, P. A Tookey, C. S Peckham
Journal: BMJ (1999)

Children born after intracytoplasmic sperm injection What do authors mean by control infants?Editor-Sutcliffe et al compare babies born through intracytoplasmic sperm injection with control babies (matched for social class, maternal education, region, and sex) born after unassisted conception. 1 In their table they give means, standard deviations, and 95% confidence intervals for the two groups separately.These confidence intervals tell us about the estimation of the mean in the population of which the babies are a random sample, which they are not.They tell us nothing about the comparison between the cases and controls.These controls have been chosen to be similar to the study babies in many ways; they are not a representative sample of babies.It is the difference between the study babies and the control babies that is of interest, and the confidence interval we should have is that for this difference in mean.We cannot work this out from the data given, because this is a paired study and we have unpaired standard deviations.All we have for the comparison is the implication, not actually stated, that the differences are not significant.What we should be given are confidence intervals that tell us how different the cases and controls are.
Epidemiology and outcomes of bloodstream infections in patients with solid tumors in a Latin American population at Mexico Hospital, San Jose, Costa Rica.
Authors: Jorge Calvo, Juan Villalobos, Allan Ramos-Esquivel, Denis Ulises Landaverde
Journal: Journal of Clinical Oncology (2017)

e13057 Background: Bloodstream infections (BSI) are an important cause of mortality in patients with solid tumors. We decided to conduct a retrospective study to evaluate the epidemiological profile and mortality of BSI in admitted patients with solid tumors at Mexico Hospital, being the first study in Costa Rica and also Central America describing our current epidemiological situation. Methods: We analyzed the infectious disease database for BSI in patients with solid tumors admitted in our Institution from January 2012 to December 2014. Epidemiology and mortality was obtained according to microorganism, antibiotic sensitivity, tumor type and presence of central venous catheter (CVC). Descriptive statistics were used. Results: A total of 164 BSI were recorded, the median age was 58 years, 103 cases (63%) were males, 128 cases (78%) were due to gram-negative bacilli (GNB), K. pneumoniae (21%), E. coli (21%) and P. aeruginosa (15%) were the most common microorganisms isolated. Gram-positive cocci (GPC) were found in 36 cases, being the most frequent S. aureus (10%) and S. epidermidis (6%). In respect to tumor type, BSI were more frequent in the gastrointestinal tract, as follow: gastric 43 (27%), colorectal 23 (14%), pancreatic 9 (6%), but also 7 cases (4%) in breast cancer and lung cancer 6 (4%). In terms of antibiotic sensitivity only 17% (GNB) expressed extended spectrum beta-lactamase (ESBL) and 12% (GPC) had methicillin-resistance. Patients with CVC inserted (59 cases) were colonized by GNB (78%). In overall the mortality rate at 30 days was 30%. Conclusions: GNB are the most frequent cause of BSI in solid tumors, and in patients with CVC inserted. Gastrointestinal cancers reported more BSI than other sites. Mortality as well as antibiotic sensitivity remain stable and acceptable during the observational time, in this Latin American population.
Cancer characteristics of male <i>BRCA</i> mutation carriers in a Cancer Genetics Clinic database: The Beaumont Health System experience.
Authors: Mohammed Ibrahim, Foluso Nelson Ogunleye, Siddhartha Yadav, Ishmael A. Jaiyesimi, Dana Zakalik
Journal: Journal of Clinical Oncology (2016)

e13007 Background: BRCA mutations are associated with an increased risk of breast and ovarian cancers in women. The cancer characteristics of men with BRCA 1 and 2 mutations are less well studied. We reviewed data on male patients diagnosed with BRCA 1 or 2 mutations in our clinical database and described their unique cancer characteristics. Methods: After IRB approval, we performed a retrospective chart review on male patients seen at the Nancy and James Grosfeld Cancer Genetics Center from January 2004 to December 2014, who tested positive for a BRCA 1 or 2 mutation. Results: A total of 103 male patients were identified who tested positive for a BRCA1 or 2 deleterious mutation. Of these 103 patients, 32 (31%) had a diagnosis of cancer either prior to testing (12 pts) or after genetic testing was performed (20 pts). Of these 32 patients with cancer, the majority (18 pts) were found to carry a BRCA 2 mutation. Median age of cancer diagnosis was 65 years (range 35-75 years). Of the 32 patients diagnosed with cancer, 7 had two or more cancers, including 1 patient who had 4 cancers (breast cancer, DCIS, prostate and small cell neuroendocrine cancer). These 7 patients with multiple cancers were all BRCA 2 mutation positive. Prostate cancer was the most commonly diagnosed cancer seen in 10 patients, 9 of whom were BRCA 2 positive. Male breast cancer was the second most common cancer seen in 9 patients, 8 of whom were BRCA 2 positive. Other cancers diagnosed included pancreatic cancer, melanoma, skin cancer and others. Conclusions: This study describes the unique cancer characteristics of male BRCA mutation carriers. A third of male BRCA mutation carriers were diagnosed with cancer. A significant number of patients (all BRCA 2 mutation positive) developed multiple cancers, including 1 patient with 4 separate cancers.These findings have important implications for cancer screening and prevention in this population.
Electrochemotherapy: A treatment with specific intent in specific skin tumors—Experience from the European Institute of Oncology, Milan.
Authors: Alessandro Testori, Elisabetta Pennacchioli, Pier Francesco Ferrucci, Giulio Tosti, Francesco Verrecchia, Emilia Cocorocchio, Antonio Intelisano, Francesco Cataldo, Massimo Barberis, Franco Nole
Journal: Journal of Clinical Oncology (2014)

e20042 Background: Elettrochemotherapy (ECT) is a consolidated treatment in Europe for the treatment of cutaneous and non-cutaneous cancers. The aim of this study was to analyse the effects of ECT in relation to different cancers histotypes, sites, and extent of disease. Methods: Between May 2006 and January 2013, 232 ECT treatments were carried out in 151 evaluable patients (pts) at the European Institute of Oncology, Milan, Italy. ECT treatment was proposed to pts with not operable local disease or to pts with systemic and local disease at risk for complications. The evaluation of response was evaluated on the treated lesions and on the whole local disease. Pts were followed up at one, three, six and twelve months; disease assessment was carried out at every visit. Treatment was performed in 67 pts with melanoma, 23 with basal cell carcinoma (BCC) and 30 with squamous cell carcinoma (SCC), 10 with breast cancer, 12 with Kaposi sarcoma, 3 with aggressive fibromatosis (AF), 6 with soft tissue sarcomas. Median age of pts was 70 years (range 27-88 years). Results: Objective Responses (OR) were significantly different among different histotypes (P=0.002 after the first month and P<0.001 after third, sixth and 12th months from treatment). OR in melanoma was 91%, 77%, 51% and 23%, in SCC was 70%, 39%, 36% and 30%, in BCC was 96%, 88%, 92%, 81%, in Kaposi sarcoma was 100%, 89%, 89%, 78% at the first, third, sixth and 12th month respectively. Mild side effects were observed at the site of electrodes application and consisted in transient erythema and slight edema around the treated lesions. Conclusions: ECT demonstrated a good safety profile. According to our data, ECT could be considered a palliative local treatment for melanoma and breast cancer and a definitive curative treatment for Kaposi sarcoma and BCC.
Quadruple negative tumors to demonstrate unique pairwise gene associations linked to recurrent and metastatic breast cancer.
Authors: Clayton Clopton Yates, Essynce Mothershed, Melissa Davis, Shweta Tripathi, Windy Marie Dean-Colomb
Journal: Journal of Clinical Oncology (2016)

e12565 Background: Despite current standard of care for treatment for Triple Negative Breast Cancer (TNBC), many patients still die from this disease. Quadruple negative tumors, which are TN tumors that lack androgen receptor (AR), represent a more aggressive subtype of TNBC, however the molecular features are not well understood. Methods: Immunohistochemical (IHC) analysis of estrogen receptor (ER), progesterone receptor (PR), HER2, and (AR) was determined in 205 primary and 145 cases of recurrent/metastatic patients. Expression was correlated with a panel of 25 cancer-related proteins using IHC. Results: We observed that 76% (63 of 83) of primary TNBC tumors and 76% (159 of 210) of recurrent/metastatic TNBC tumors are QNBC. Bivariate fit analysis demonstrated that QNBC significantly (p < .03) correlated with younger aged patients at initial biopsy compared to AR positive TNBC patients. Intra-individual analysis of recurrent/metastatic QN tumors demonstrated a significant difference (p < 0.05) between ER and AR statuses in both locally recurrent/metastatic tumors. Multivariate analysis of all biopsies with a panel of additional cancer- related genes, demonstrated that pairwise gene correlations differ by molecular profile: Luminal (ER+/AR+), TN (ER-), TN AR-positive (ER-/AR+), and QN (ER-/AR-). The Luminal BC subtype showed 13 highly significant positive gene correlations, with PTEN-EGFR (p < 0.0001) as the most significant pairs. AR-positive TN tumors expressed 9 significant correlations, with PIK3CA-TP53 (p < 0.0001) as the most significant pair. QN tumors displayed 15 significant pairwise gene correlations that differed from AR positive tumors, with EGFR- TOPO1 (p < .0001) as the most significant pair. Conclusions: Standard treatment of BC relies on reliable assessment by IHC analysis of ER, PR, and HER2. Our analysis suggest that the heterogeneity of TNBC is at least partially associated with the presence or absence of AR expression, suggesting that QNBC should be considered as a clinically relevant BC subtype. IHC analysis of AR appears to be a practical assay to determine the most aggressive TNBC subtypes and identifies tumors that could benefit from available targeted therapies.
Abstract 13046: Platelet Reactivity During Antiplatelet Therapy in Patients with CYP3A5 Polymorphism Depends on Chronic Kidney Disease (CKD)
Authors: Seiji Hokimoto, Tomonori Akasaka, Koichi Kaikita, Kazuko Nakagawa, Hisao Ogawa
Journal: Circulation (2013)

Background:  Several studies report that the platelet reactivity (PR) varies widely according to CYP3A5 polymorphism during dual antiplatelet therapy. Antiplatelet efficacy of clopidogrel is reduced in patients with chronic kidney disease (CKD). The aim of this study was to examine whether PR is associated with CKD according to CYP3A5 genotypes.   Methods:  We examined the PR by light transmittance aggregometer in patients who underwent coronary stent implantation (n=103, 69ys, male; 70%) with dual antiplatelet therapy including 100mg/day aspirin and 75mg/day clopidogrel. The residual PR was measured two times at the time of stent implantation and the chronic phase (9 months after stent implantation), respectively. CYP3A5 polymorphism was examined, and classified into two phenotypes: (1) patients with CYP3A5 expressor genotype (at least one normal function allele, *1/*1, *1/*3), (2) patients with CYP3A5 non-expressor genotype (two loss-of-function (LOF) alleles, *3/*3). CKD was defined as estimated glomerular filtration rate (eGFR) ≤60ml/min/1.73m*m.   Results:  The ratio of CYP3A5 expressor and non-expressor genotypes was 40 versus 60%. In patients with CYP3A5 expressor genotype, PR was significantly decreased in the late phase compared with the early phase regardless of CKD (early vs. late: non-CKD, 4792 vs. 3379, n=25, P=0.0007; CKD, 5117 vs. 3604, n=9, P=0.007). In patients with CYP3A5 non-expressor genotype, in cases of non-CKD, PR in the early phase was significantly decreased in the late phase (early vs. late; 4416 vs. 3522, n=39, p=0.014), however, in cases of CKD patients with CYP3A5 non-expressor genotype, there was no significant difference in PR between in the early and late phase (early vs. late; 4545 vs. 3647, n=28, NS). In short, antiplatelet efficacy of clopidogrel was not sufficient in CKD patients with CYP3A5 non-expressor genotype even in the late phase.   Conclusions:  These results indicate that the PR during dual antiplatelet therapy may depend on renal function in patients with CYP3A5 non-expressor genotype. Thus, there is a possibility that the impact of CKD on PR during antiplatelet therapy is more powerful in patients with CYP3A5 non-expressor genotype compared with CYP3A5 expressor genotype.
Pathogenicity of mutation analyzer (PathoMAN): A fast automation of germline genomic variant curation in clinical sequencing.
Authors: Vijai Joseph, Vignesh Ravichandran, Kenneth Offit
Journal: Journal of Clinical Oncology (2017)

1529 Background: A challenge in clinical oncology is interpretation of multiplexed gene sequencing of patients at risk. The plethora of variants to be curated for pathogenicity or actionability poses a growing burden for cancer care professionals. Current guidelines by the ACMG requires the aggregation of multiple lines of genomic data evidences from diverse resources. A computational tool that automates, provide uniformity and significantly speed the interpretive process is thus necessary. Methods: The Pathogenicity of Mutation Analyzer (PathoMAN), is a tool that automates germline genomic variant curation from clinical sequencing based on ACMG guidelines. PathoMAN aggregates multiple tracks of genomic, protein and disease specific information from public sources such as ClinVar, ExAC, UniProt, 1000 genomes, dbNSFP and locus specific databases. Variant specific and gene specific annotations are used to classify variants to model the ACMG rubric. We analyzed 2500 manually curated and classified, high quality variants in 180 genes from 3 large, published studies to quantify the performance of PathoMAN; analyzing 242 pathogenic/likely pathogenic (P/LP), 1272 benign/likely benign (B/LB) and 1261 variants of uncertain significance (VUS). We report the summary of PathoMAN classifications in four categories contrasted against the manual curation. Results: PathoMan achieves an average of 75% concordance and 1.5% discordance for P/LP mutations and 60% and 0.1% for B/LB variants. PathoMAN is able to resolve 12% of reported VUS as either P/LP or B/LB. It loses resolution to classify 25% of P/LP and B/LB variants due to lack of information and due to inconsistencies in available data from public resources. Conclusions: PathoMAN provides a breakthrough in rapid classification of genetic variants by generation of robust models using a knowledgebase of diverse genetic data. It is easily accessible, web-based resource that allows the community to rapidly test a large number of variants for pathogenicity. Such bioinformatic tools are essential to reduce manual workload of a domain level experts. We propose, a new nosology for the 5 ACMG classes to facilitate better reporting to ClinVar.
Durable disease control in patients with metastatic breast cancer treated with single agent capecitabine.
Authors: Zoran Tomasevic, Zorica Tomasevic, Ivana Bozovic- Spasojevic, Kristina Serovic, Aleksandar Stojanovic, Zdravko Zdrale
Journal: Journal of Clinical Oncology (2016)

e12522 Background: Capecitabine is effective chemotherapy in metastatic breast cancer (MBC) and is usually given as a third line chemotherapy. Since there is no cumulative dose, if tolerability is good treatment can be given for long time until disease progression. However there are limited data of treatment duration in patients with MBC treated with single agent capecitabine. Methods: At the Institute for Oncology and Radiology of Serbia, a cohort of 24 MBC patients treated with single agent capecitabine and durable disease control have been analyzed. Durable disease control is defined as absence of disease progression during at least 24 months of continuous capecitabine treatment. All patients had progression during or after antracycline and taxane based chemotherapy +/-hormonal therapy +/-trastuzumab therapy. Lapatinib was not available at the time of treatment initiation in 3 patients with HER2 3+ MBC Dose of capecitabine ranged from 1500-2000 mg/m2 bd, days 1-14, q3w; tolerability and clinical evaluation were assessed before each cycle; imaging was performed at 3-4 months intervals. Results: Median age at capecitabine initiation was 62 years (range 28-78); majority were ECOG PS 0/1 (92%) Median time from BC diagnosis to capecitabine initiation was 74 months (range 12-204). Metastatic sites were: liver (8); lungs (8); bones (8); soft tissue (3); CNS (2); while 13/24 (54.2%) patients have multiple metastases sites. 7/24 patients (29.2%) had MBC at the time of initial BC diagnosis; 20/24 (83.3%) had hormone receptor +BC, and 3/24 (12.5%) patients had HER2 3+BC. Median number of capecitabine cycles was 36 (range 27-69+). Responses were: 1(4%) CR; 5 (20.8%) PR; 18/24 (75%) SD. CR was achieved in patient with lung metastases. Median time to progression is 62+ months. At the time of this analysis 18/24 (75%) are still without progression, receiving unchanged capecitabine dose and schedule. Conclusions: Capecitabine can induce durable disease control in a subset of MBC patients who experienced progression during previous antracycline/taxane based chemo +/-hormonal +/-trastuzumab treatment. It seems that treatment benefit might be achieved irrespective of molecular characteristics of MBC.
The association between the anti-inflammatory protein CC10 and smoking status among participants in a chemoprevention trial.
Authors: Jiping Chen, Stephen Lam, Aprile Pilon, Eva Szabo
Journal: Cancer Research (2006)

5738   CC10 is a 10-kDa protein secreted by nonciliated Clara cells which are progenitor cells in the bronchiolar epithelium. CC10 is infrequently expressed in non-small cell lung cancer (NSCLC) and overexpression of CC10 in NSCLC cell lines results in a less malignant phenotype. CC10 levels in bronchoalveolar lavage fluid (BAL) and serum are significantly lower in current smokers compared with healthy non-smokers, but it is not known whether long term smoking cessation results in restoration of CC10 expression. To determine whether smoking cessation plays a role in up-regulating the BAL and plasma CC10 levels, we used specimens collected during a chemoprevention trial assessing the efficacy of budesonide vs. placebo to regress bronchial dysplasia in current (n=80) and former (n=22) smokers. CC10 was measured by a competitive ELISA in baseline BAL and plasma specimens. Interestingly, current smokers appeared to have significantly lower baseline plasma CC10 levels compared to former smokers [mean 36.7 (95% CI: 29.4∼44.1); range (5.0∼171.0) ng/ml for current smokers, and mean 58.1 (95%CI: 39.9∼76.2); range (23.0∼175.0) ng/ml for former smokers, p