tbuckley/cabot-search huggingface dataset:
Clinical application of comprehensive next generation sequencing in the management of metastatic cancer in adults.
Authors: Erin Frances Cobain, Dan R. Robinson, Yi-Mi Wu, Jessica Everett, Erica Rabban, Chandan Kumar, Scott Schuetze, Ajjai Shivaram Alva, Rashmi Chugh, Francis P. Worden, Mark Zalupski, Scott A. Tomlins, Nithya Ramnath, Anne F. Schott, Elena Martinez Stoffel, David C. Smith, Lakshmi Priya Kunju, Daniel F. Hayes, Moshe Talpaz, Arul M. Chinnaiyan
Journal: Journal of Clinical Oncology (2017)

101 Background: Next generation sequencing (NGS) platforms are frequently utilized in the care of patients (pts) with metastatic cancer to identify tumor genomic alterations that may serve as therapeutic targets. Biomarker driven clinical trials, such as NCI-Molecular Analysis for Therapy Choice (MATCH) and Targeted Agent and Profiling Utilization Registry (TAPUR) have augmented clinicians’ ability use this strategy in clinical practice. Methods: From 2011-2015 over 500 adult pts with metastatic solid tumors of diverse lineage underwent biopsy for whole exome and transcriptome sequencing of tumor and matched normal sample through the Michigan Oncology Sequencing Center (Mi-Oncoseq). Genomic alterations identified were reviewed at Precision Medicine Tumor Board and tiered according to their clinical relevance. Alterations were also classified as being identifiable or not identifiable by a commercially available NGS assay such as Oncomine Focus or FoundationOne. Results: Genomic alterations identified by Mi-Oncoseq provided rationale for enrollment in a clinical trial in 72% (n = 360) of cases. The percentage of pts who did receive therapy informed by NGS results increased over time (5% in 2012 versus 11% in 2015). 11% of pts (n = 55) had a pathogenic germline variant (PGV) conferring increased cancer risk identified, none of which were known prior to study entry. Numerous pts had clinically relevant molecular alterations identified by Mi-Oncoseq that would not have been identifiable utilizing targeted NGS assays, including PGVs and activating/deleterious gene fusions. Conclusions: Comprehensive NGS, including DNA and RNA sequencing, readily identifies potentially actionable alterations in the vast majority of pts beyond what is observed with use of targeted NGS platforms. Observed modest increase in utilization of NGS results to direct subsequent therapy over time is due to clinician employment of this strategy earlier in the therapeutic algorithm, increased availability of biomarker driven clinical trials and changes in physician referral patterns. Comprehensive NGS identified many unanticipated PGVs of clinical importance for pts and their families. Clinical trial information: HUM00067928.
A comparative analysis of clinicopathological characteristics and disease-free survival (DFS) outcomes in breast cancer patients: Mammograpghy vs symptomatic diagnosis.
Authors: Mustafa Karaca
Journal: Journal of Clinical Oncology (2017)

e12018 Background: Our goal was to compare clinicopathological characteristics and DFS time among breast cancer patients diagnosed with mammography or symptoms. Methods: This was retrospective analysis of 828 patient files. Diagnosis was done with mammography or symptom,considering the followings:age,menopause,hormone and HER2 receptor,grade,histologic subtype,lymphovascular(LVI) and perineuronal invasion(PNI),adjuvant chemotheraphy,adjuvant herceptin,adjuvant hormone and adjuvant radiotheraphy use.Recurrence dates,locations and last appointment dates were noted. Results: Breast cancer was detected by mammography in 324 patients vs by sysmptom in 504.The difference in most cases between these two methods were significant,and respectively:positive ALND 30% vs 53.7% p=0.0001,LVI 13.7% vs 31.6% p=0.0001,PNI 7.2% vs 18.1% p=0.0001,adjuvant chemo 67% vs 85% p=0.0001,adjuvant hormone use 87.3% vs 82% p=0.001.However, recurrence rates did not differ sigificantly among two groups 12% vs 12.6% p=0.4.The median follow-up and DFS time was 48 and 37 months,respectively.Prognostic parameters were also analyzed.Pathologic staging p=0.002,PNI p=0.027,LVI p=0.0001,hormone receptor status p=0.0001,triple negativity p=0.016,luminal A group p=0.048 were found statistically significant on DFS.Diagnosis with mammography was found to have no statistically significant effect on DFS. Conclusions: Although patients diagnosed with mammography had better prognostic parameters,recurrence rates were similar with symptomatic patients at the time of diagnosis.At survival analysis,recurrence rates were calculated to be similar to those of symptomatic patients’ group.
Expansion of the Lyme Disease Vector <i>Ixodes Scapularis</i> in Canada Inferred from CMIP5 Climate Projections
Authors: Michelle McPherson, Almudena García-García, Francisco José Cuesta-Valero, Hugo Beltrami, Patti Hansen-Ketchum, Donna MacDougall, Nicholas Hume Ogden
Journal: Environmental Health Perspectives (2017)

Background: A number of studies have assessed possible climate change impacts on the Lyme disease vector, Ixodes scapularis. However, most have used surface air temperature from only one climate model simulation and/or one emission scenario, representing only one possible climate future. Objectives: We quantified effects of different Representative Concentration Pathway (RCP) and climate model outputs on the projected future changes in the basic reproduction number (R0) of I. scapularis to explore uncertainties in future R0 estimates. Methods: We used surface air temperature generated by a complete set of General Circulation Models from the Coupled Model Intercomparison Project Phase 5 (CMIP5) to hindcast historical (1971–2000), and to forecast future effects of climate change on the R0 of I. scapularis for the periods 2011–2040 and 2041–2070. Results: Increases in the multimodel mean R0 values estimated for both future periods, relative to 1971–2000, were statistically significant under all RCP scenarios for all of Nova Scotia, areas of New Brunswick and Quebec, Ontario south of 47°N, and Manitoba south of 52°N. When comparing RCP scenarios, only the estimated R0 mean values between RCP6.0 and RCP8.5 showed statistically significant differences for any future time period. Conclusion: Our results highlight the potential for climate change to have an effect on future Lyme disease risk in Canada even if the Paris Agreement's goal to keep global warming below 2°C is achieved, although mitigation reducing emissions from RCP8.5 levels to those of RCP6.0 or less would be expected to slow tick invasion after the 2030s. https://doi.org/10.1289/EHP57
Chemotherapy induced-hair loss: A digni-life with DigniCap— Our experience and patient’s satisfaction.
Authors: Dario Loparco, Stefania Eufemia Lutrino, Laura Orlando, Paola Schiavone, Chiara Caliolo, Annamaria Quaranta, Palma Fedele, Antonella Marino, Nicola Calvani, Maria D'amico, Maria Concetta Chetrì, Manuela Caloro, Pietro Rizzo, Angelo Nacci, Francesco Sponziello, Enrica Mazzoni, Margherita Cinefra, Pasqualinda Ferrara, Saverio Cinieri
Journal: Journal of Clinical Oncology (2017)

e12016 Background: Alopecia (A) is one of the most emotionally distressing side effects of chemotherapy (CT). CT-induced A may lead to a negative body image, contributing to worsen the quality of life (QoL). The cancer treatments, especially in breast cancer (BC) patients (pts), often bring with it body image challenges, causing low self-esteem and having a detrimental effect on intimate relationships. DigniCap System (DCS), using the scalp cooling system, has been shown to reduce CT-induced A. The aim of this observational prospective study was to describe our experience. Methods: From February to December 2016, 31 consecutive pts with early stage BC who received anthracycline and/or taxane-based neoadjuvant or adjuvant treatment were enrolled. A nurse and a psychologist were dedicated. All pts received a psychological evaluation (EORTC QLQ-BR23; EORTC QLQ-C30; TAM; VAS). A has been graduated according to the Dean’s scale: G0 = no A; G1 &lt; 25% A; G2 = 25–50% A; G3 = 50–75% A; G4 &gt; 75% A. Results: A total of 31 pts were enrolled; 2 pts were not included because too early. Median age was 48 years (range 33-66). The majority of pts (96.5%) received adjuvant CT; only one patients received preoperative CT. Fifteen pts (51.7%) received 4 courses of EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 iv on day 1, every 21 days) followed by 12 courses of paclitaxel (P) (80 mg/m2 iv weekly); the remaining pts received 4 courses of EC (n = 13; 44.8%) or P and concurrent trastuzumab (2 mg/Kg iv; loading dose 4 mg/kg) for 12 consecutive doses (n = 1; 3.4%). All grade of A was observed in 96.5% (n = 28): G1 in 15 pts (51.7%), G2 in 5 pts (17%), G3 in 7 pts (24.1%) and G4 in 1 pt (3.4%). Among G1/2 DCS-related side effects, sore scalp and coldness were the main toxicity (52%). The other adverse events (AEs) were: headache G1/2 (44.8%); neck pain (34.5%) and heavy head (41.4%). No serious AEs were reported. Overall, 7% (n = 2) of pts discontinued DCS because of unsatisfactory hair preservation (n = 1) and headache (n = 1). Conclusions: Our results confirm previous evidences, showing that DCS is a good chance to keep hair during CT. In particular, it is interesting that 26 pts (89.6%) did not use wig or head cover.
Fulvestrant as maintenance therapy after first-line chemotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer (FANCY), a prospective, multicenter, single arm phase 2 study.
Authors: Shusen Wang, Qiufan Zheng, Fei Xu, Wen Xia, Quchang Ouyang, Danmei Pang, Huimin Yuan, Yanxia Shi, Roujun Peng, Zhongyu Yuan
Journal: Journal of Clinical Oncology (2017)

1066 Background: Fulvestrant is potent for treatment of hormone receptor (HR)-positive advanced breast cancer (ABC); however, few data exist for this regimen as maintenance endocrine treatment after chemotherapy (CT). In our phase 2 trial, we aimed to assess efficacy and tolerability of fulvestrant 500mg as maintenance therapy in patients with disease control after first-line CT. Methods: Simon’s two-stage design was used. We enrolled postmenopausal women with histologically confirmed HR-positive, HER2-negative ABC, who achieved disease control after four to eight cycles of first-line CT. Fulvestrant 500 mg was intramuscularly injected on day 1, 15, 29, then every 28 (±3) days subsequently, until disease progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR), secondary endpoint included progression-free survival (PFS) since maintenance treatment, PFS since first-line CT, objective response rate (ORR) and safety. Results: Between Dec 10, 2013, and Sept 30, 2015, 58 patients were enrolled. 25 (43%) patients were deemed as resistance to endocrine treatment, 36 (62%) patients had a visceral disease. Median follow-up was 21 months. After fulvestrant maintenance treatment, 36 patients remained disease stabilising for at least six months, and eight (14%, 95% CI 6-25) patients achieved a response, resulted in a CBR of 76% (95% CI 63-86), which met its primary endpoint. The median PFS since fulvestrant treatment was 16·1 months (95% CI 10·3 to not reached), and median PFS since first-line CT was 19·5 months (95% CI, 15·6 to not reached). 39 (67%) of 58 patients reported at least one adverse event (AE), of which predominantly were grade 1 or 2. The most common grade 3 AEs were increased alanine aminotransferase in two (3%) patients, increased aspartate aminotransferase in one (2%) patient, and arthralgia in one (2%) patient. No patient discontinued treatment due to AE. Conclusions: Fulvestrant 500mg is active in maintenance therapy in non-progrssion patients with HR-positive ABC after first-line CT. Further study is needed to assess long-term outcome of maintenance therapy. Clinical trial information: NCT02000193.
Abstract 193: RNA-sequencing of Disease-specific iPSC as a New Filter to Identify Genes Associated With Hypoplastic Left Heart Syndrome
Authors: Almudena Martinez Fernandez, Xing Li, Jeanne L Theis, Andre Terzic, Timothy M Olson, Timothy J Nelson
Journal: Circulation Research (2015)

Hypoplastic Left Heart Syndrome (HLHS) is a complex multifactorial disease for which no definitive genetic causes have been found. Current genetic filtering strategies render lists of genes with unknown relevance in terms of pathogenesis. A complementary filter based on biological evidence would create a new approach to prioritize relevant candidate genes and mutations. In our study, 5 members of a nuclear family including a child with HLHS were evaluated using echocardiography and their genetic information was obtained through whole genome sequencing (WGS). Data filtering including rarity, functional impact and mode of inheritance was implemented, resulting in identification of 34 genes with recessive or de novo variants potentially involved in the pathogenesis of HLHS. Additionally, iPSC were derived from proband and parents and subjected to RNA-sequencing at the undifferentiated state and following spontaneous differentiation. Comparative transcriptional analyses identified genes differentially expressed in proband samples at each stage. These gene sets were used as an additional filter for the previously generated WGS data. This strategy revealed that out of 34 mutated genes originally identified, 10 displayed transcriptional differences in undifferentiated iPSC from the HLHS-affected individual while 16 out of 34 mutated genes showed significantly different expression levels in differentiated cells from proband. Furthermore, expression dynamics were studied during guided cardiac differentiation for the 9 genes fulfilling all applied criteria. Two genes not previously linked to HLHS, ELF4 and HSPG2 were found to behave significantly different in HLHS-iPSC when compared to control counterparts. In summary, filtering WGS data according to a new layer of transcriptional information that leverages iPSC plasticity allows prioritization of genes associated with HLHS in an in vitro model of disease.
Diabetes increases mortality after myocardial infarction by oxidizing CaMKII
Authors: Min Luo, Xiaoqun Guan, Elizabeth D. Luczak, Di Lang, William Kutschke, Zhan Gao, Jinying Yang, Patric Glynn, Samuel Sossalla, Paari D. Swaminathan, Robert M. Weiss, Baoli Yang, Adam G. Rokita, Lars S. Maier, Igor R. Efimov, Thomas J. Hund, Mark E. Anderson
Journal: Journal of Clinical Investigation (2013)
IMGN632: A CD123-Targeting Antibody-Drug Conjugate (ADC) with a Novel DNA-Alkylating Payload, Is Highly Active and Prolongs Survival in Acute Myeloid Leukemia (AML) Xenograft Models
Authors: Sharlene Adams, Alan Wilhelm, Lauren Harvey, Chen Bai, Nicholas Yoder, Yelena Kovtun, Thomas Chittenden, Jan Pinkas
Journal: Blood (2016)
A feasibility study of neoadjuvant talazoparib for early-stage breast cancer patients with a germline <i>BRCA</i> pathogenic variant: NCT02282345.
Authors: Jennifer Keating Litton, Marion Scoggins, Gary J Whitman, Carlos Hernando Barcenas, Stacy L. Moulder, Rashmi Krishna Murthy, Sausan Abouharb, Beatriz Adrada, Thorunn Helgason, Jill Schwartz-Gomez, Elizabeth Ann Mittendorf, Alastair Mark Thompson, Banu Arun
Journal: Journal of Clinical Oncology (2017)

TPS595 Background: Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a family of enzymes responsible for DNA repair via base excision repair as well as maintenance of genetic stability. BRCA mutation carriers appear to have significant sensitivity to PARP inhibitors, not only from synthetic lethality but also potentially PARP trapping in the metastatic setting. A 2-month window study of talazoparib was reported at ESMO in 2016. In 13 patients treated, the median % tumor shrinkage by ultrasound was 88% (range 30-98%) and the study was halted early to allow for this expansion of neoadjuvant talzoparib as the only treatment prior to surgery to evaluate pathologic response. Primary Objective: Evaluate the rate of pathologic complete response (pCR)/RCB-0 + residual cancer burden (RCB)-I responses in patients with early stage breast cancer and a known BRCA pathogenic variant. Methods: 20 patients with stage I-III breast cancer and a known BRCA mutation will be accrued on this IRB-approved study. Patients will receive 4-6 months of neoadjuvant talazoparib and then proceed to surgery. Radiation, chemotherapy and endocrine therapy will be given when appropriate in teh adjuvant setting. Brief Eligibility Criteria: Patients with an identified BRCA pathogenic variant and diagnosed with a stage I-III breast cancer at least 1 cm in size are eligible. Tumors can have any ER or PR status but HER2 over-expressed cancers were excluded. Prior systemic or radiation therapy for previous breast cancer is excluded, but prior surgical treatment for contralateral DCIS is allowed. Correlative Science: Blood and biopsies prior to initiation of therapy will be collected to evaluate biomarkers of therapy efficacy as well as to initiate patient derived xenograft (PDX) models. Other studies will include: immunohistochemistry, targeted or whole exome sequencing for BRCA pathway mutations and other somatic and germline alterations; RNA sequencing; immune response; transcriptional profiles to assess TNBC subtype, reverse phase protein array (RPPA); generation of PDX models and mammosphere cultures. Clinical trial information: NCT02282345.
Induced Pluripotent Stem Cells 10 Years Later
Authors: Yoshinori Yoshida, Shinya Yamanaka
Journal: Circulation Research (2017)

Induced pluripotent stem cells (iPSCs) are reprogrammed cells that have features similar to embryonic stem cells, such as the capacity of self-renewal and differentiation into many types of cells, including cardiac myocytes. Although initially the reprogramming efficiency was low, several improvements in reprogramming methods have achieved robust and efficient generation of iPSCs without genomic insertion of transgenes. iPSCs display clonal variations in epigenetic and genomic profiles and cellular behavior in differentiation. iPSC-derived cardiac myocytes (iPSC cardiac myocytes) recapitulate phenotypic differences caused by genetic variations, making them attractive human disease models, and are useful for drug discovery and toxicology testing. In addition, iPSC cardiac myocytes can help with patient stratification in regard to drug responsiveness. Furthermore, they can be used as source cells for cardiac regeneration in animal models. Here, we review recent progress in iPSC technology and its applications to cardiac diseases.
Studies in the Epidemiology of Tinea Pedis: I.Tinea Pedis in School Children
Authors: M. P. English, M. D. Gibson
Journal: BMJ (1959)

Although there are numerous reports of the incidence and epidemiology of tinea pedis in skin clinics, closed communities, and industrial groups, the natural history of this disease in the general population has received very little study.The difficulty of examining a representative cross- section of adults is obvious, apart from the prohibitive amount of time which would be involved in visiting sufficient families in their own homes.Also, in adults, the past lives of individuals would be so varied that any results obtained would be very difficult to assess.Investigation of recruits for the Forces or of first-year university students has a number of limitations, the greatest being that the subjects are drawn from widely scattered geographic areas, so that results would show the incidence rather than the epidemiology of the disease.A cross-section of the children resident in any one district can, however, be obtained by carrying out surveys in comprehensive and bilateral schools and, to a less extent, in secondary modern schools.The study of day-school children has the further advantage that they have usually lived exclusively within their families and in the district in which the school is situated; also, the difference in the way of life of the sexes is far less marked than in adults.Examination of school children might therefore throw a useful light on the epidemiology of tinea pedis.We can find no record of any such survey in the United Kingdom.In Europe large-scale investigations have been carried out by Lomholt (1938) in Sweden, and by Wilde (1951) and Polemann (1955) in Germany, but their conclusions were based almost exclusively on clinical evidence.Amrein (1953), in Switzerland, examined 707 children and confirmed his clinical diagnosis by microscopical examination of scrapings, but he made no cultures and did not differentiate between the incidence in boys and girls.Bocobo and Garcia (1950), using laboratory diagnostic tests, examined 203 Philippine students between 11 and 22 years old, but did not correlate incidence with age.In America, Andrews and Birkman (1931) and Wallace and Moorman (1943) examined 520 and 60 children respectively, but in neither investigation were conditions comparable with those in schools in this country.The present investigation sets out to study aspects of the natural history of tinea pedis through the medium of Bristol's school children, to obtain some factual information on a number of epidemiological problems about which there is at present much guesswork, and to open up lines for more detailed work later.
Comparison of terminal duct lobular units in the nipple areolar complex by tumor subtypes-the implication for nipple sparing mastectomy.
Authors: Kenna Schnarr, Fang Fan, Amanda Leigh Amin, Christa Balanoff, Joshua Mammen, Jamie Lynn Wagner
Journal: Journal of Clinical Oncology (2017)

e12082 Background: Nipple-sparing mastectomy (NSM) has gained popularity for surgical treatment of breast cancer. Terminal duct lobular units (TDLU) have been shown to be present in 25% of nipple areolar complex (NAC). Pathologic tumor subtype influence on presence of TDLU in the NAC has not been assessed. In addition, criteria for technically performing the dissection below the NAC have not been established. We sought to evaluate TDLU characteristics by tumor subtype and determine NSM dissection criteria below the NAC. Methods: A retrospective review was performed of 120 total and skin sparing mastectomies, 30 of each breast cancer subtype, from 1/2013 to 1/2015. The NAC of each mastectomy was assessed for number of TDLU and distance from TDLU to the skin. Results: Thirty of the 120 mastectomies (25%) had TDLU present below the NAC. Of the 30 with TDLU, there was no statistically significant difference in number of TDLU present based on tumor grade (gd) (gd 1 vs 2, p = .67; gd 1 vs 3, p = .24). Compared to luminal A, luminal B showed statistical significance (p &lt; .05) for number of TDLU at the NAC whereas Her 2 and triple negative breast cancer (TNBC) were not statistically significant (p = .09 and .10). In mastectomies with TDLU present, gd 2 (p &lt; .05) and gd 3 (p = .05) had a closer skin distance than gd 1. When compared by tumor subtype, there was no difference in TDLU to skin distance (table). Conclusions: NSM has been adopted as a safe oncologic approach to breast cancer treatment. Although presence of TDLU in luminal B subtype was statistically significant, this may not be clinically significant, as there were only 2 of 30 cases with TDLU. Our study indicates that a careful dissection at the level of the dermis below the NAC is necessary, as 25% of women will have TDLU present. This will provide an appropriate oncologic outcome similar to total and skin sparing mastectomy. Tumor subtype does not appear to be exclusion criteria for NSM. However, more aggressive dissection may be necessary to clear all TDLU from below the NAC in higher gd cancers. [Table: see text]