tbuckley/cabot-search huggingface dataset:
Feasibility pilot implementation of a low-dose CT screening program.
Authors: Joo Hyung Yoon, Aisha Lofters, Geoffrey Liu
Journal: Journal of Clinical Oncology (2018)

109 Background: The National Lung Cancer Screening Trial showed 20% reduction in lung cancer mortality with low dose CT (LDCT) screening. The highest risk populations for developing lung cancer are commonly found among lower socioeconomic groups. 30% of patients enrolled with St. Michael’s Hospital Academic Family Health Team (SMHAFHT) are below the low-income cut-off. This study aims to implement LDCT screening at SMHAFHT using the Knowledge-to-Action framework. Methods: Stakeholders were engaged to adapt an existing Princess Margaret Cancer Centre (PMCC) LDCT program with focus groups, interviews, and patient post-LDCT interviews to assess barriers and facilitators. Patients were referred from SMHAFHT to PMCC for LDCT. PLCO 2012 scores stratified patient risk, and those at highest risk were chosen. Results: 12 patients were assessed for eligibility; 7 (56%) qualified and 5 (42%) completed LDCT at PMCC. 11 (92%) patients assessed were from two Smoking Cessation Clinics (SCC) within SMHAFHT. Those at SCC (vs LDCT) group were younger (51±12 vs 69±7, p = 0.001), had lower Charlson comorbidity index scores (2.1±1.8 vs 3.4±1.7, p = 0.15) and had fewer pack years (37±24 vs 56±16, p = 0.06). The SCC (vs LDCT) group had comparable prevalence of males (64% vs 66%), COPD (30% vs 33%), personal cancer history (5% vs 0%), family history of lung cancer (17% vs 20%), and proportion of patients reporting the lowest quartile of household income (95% vs 80%), all p &gt; 0.05. Thematic analysis yielded the following barriers among practitioners: limited study awareness, difficulty providing consent forms and lack of time. Top patient reported barriers included fear: of positive results, LDCT and follow up procedures. Practitioner facilitating factors included greater research coordinator involvement, while patients reported clear communication of LDCT risks and benefits and accessibility of PMCC. Conclusions: Implementation predominantly took place within SMHAFHT SCCs. Barriers for future intervention were identified. Differences between participants of SCC and LDCT screening can be attributed to selection of the highest-risk group with PLCO 2012 scores. Implementing LDCT screening at SCCs allowed for the recruitment of those below the low-income cut-off.
A Functional Homologous Recombination Assay Predicts Primary Chemotherapy Response and Long-Term Survival in Ovarian Cancer Patients
Authors: Manuela Tumiati, Sakari Hietanen, Johanna Hynninen, Elina Pietilä, Anniina Färkkilä, Katja Kaipio, Pia Roering, Kaisa Huhtinen, Amjad Alkodsi, Yilin Li, Rainer Lehtonen, Erdogan Pekcan Erkan, Minna M. Tuominen, Kaisa Lehti, Sampsa K. Hautaniemi, Anna Vähärautio, Seija Grénman, Olli Carpén, Liisa Kauppi
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Homologous recombination deficiency (HRD) correlates with platinum sensitivity in patients with ovarian cancer, which clinically is the most useful predictor of sensitivity to PARPi. To date, there are no reliable diagnostic tools to anticipate response to platinum-based chemotherapy, thus we aimed to develop an ex vivo functional HRD detection test that could predict both platinum-sensitivity and patient eligibility to targeted drug treatments. Experimental Design: We obtained a functional HR score by quantifying homologous recombination (HR) repair after ionizing radiation-induced DNA damage in primary ovarian cancer samples (n = 32). Samples clustered in 3 categories: HR-deficient, HR-low, and HR-proficient. We analyzed the HR score association with platinum sensitivity and treatment response, platinum-free interval (PFI) and overall survival (OS), and compared it with other clinical parameters. In parallel, we performed DNA-sequencing of HR genes to assess if functional HRD can be predicted by currently offered genetic screening. Results: Low HR scores predicted primary platinum sensitivity with high statistical significance (P = 0.0103), associated with longer PFI (HR-deficient vs. HR-proficient: 531 vs. 53 days), and significantly correlated with improved OS (HR score &amp;lt;35 vs. ≥35, hazard ratio = 0.08, P = 0.0116). At the genomic level, we identified a few unclear mutations in HR genes and the mutational signature associated with HRD, but, overall, genetic screening failed to predict functional HRD. Conclusions: We developed an ex vivo assay that detects tumor functional HRD and an HR score able to predict platinum sensitivity, which holds the clinically relevant potential to become the routine companion diagnostic in the management of patients with ovarian cancer. Clin Cancer Res; 24(18); 4482–93. ©2018 AACR.
Racial Disparities in Lung Cancer Survival: The Contribution of Stage, Treatment, and Ancestry
Authors: Carissa C. Jones, Sarah Fletcher Mercaldo, Jeffrey D. Blume, Angela S. Wenzlaff, Ann G. Schwartz, Heidi Chen, Stephen A. Deppen, William S. Bush, Dana C. Crawford, Stephen J. Chanock, William J. Blot, Eric L. Grogan, Melinda C. Aldrich
Journal: Journal of Thoracic Oncology (2018)
Fight for abortion rights moves to Northern Ireland
Authors: Alison Shepherd
Journal: BMJ (2018)

Niall Carson/PA

As Irish crowds filled public spaces, such as Dublin Castle (pictured), to celebrate the referendum result last weekend to repeal the eighth amendment that will lead to the decriminalisation of abortion, the spotlight fell on their Northern Irish neighbours, still living under the harshest termination laws in Europe.

The UK’s 1967 Abortion Act does not apply to Northern Ireland, and abortions there remain illegal in …
Integrative analysis reveals functional and regulatory roles of H3K79me2 in mediating alternative splicing
Authors: Tianbao Li, Qi Liu, Nick Garza, Steven Kornblau, Victor X. Jin
Journal: Genome Medicine (2018)

Accumulating evidence suggests alternative splicing (AS) is a co-transcriptional splicing process not only controlled by RNA-binding splicing factors, but also mediated by epigenetic regulators, such as chromatin structure, nucleosome density, and histone modification. Aberrant AS plays an important role in regulating various diseases, including cancers. In this study, we integrated AS events derived from RNA-seq with H3K79me2 ChIP-seq data across 34 different normal and cancer cell types and found the higher enrichment of H3K79me2 in two AS types, skipping exon (SE) and alternative 3′ splice site (A3SS). Interestingly, by applying self-organizing map (SOM) clustering, we unveiled two clusters mainly comprised of blood cancer cell types with a strong correlation between H3K79me2 and SE. Remarkably, the expression of transcripts associated with SE was not significantly different from that of those not associated with SE, indicating the involvement of H3K79me2 in splicing has little impact on full mRNA transcription. We further showed that the deletion of DOT1L1, the sole H3K79 methyltransferase, impeded leukemia cell proliferation as well as switched exon skipping to the inclusion isoform in two MLL-rearranged acute myeloid leukemia cell lines. Our data demonstrate H3K79me2 was involved in mediating SE processing, which might in turn influence transformation and disease progression in leukemias. Collectively, our work for the first time reveals that H3K79me2 plays functional and regulatory roles through a co-transcriptional splicing mechanism.
Shifting landscape of hemophilia therapy: Implications for current clinical laboratory coagulation assays
Authors: Hanny Al‐Samkari, Stacy E. Croteau
Journal: American Journal of Hematology (2018)

Clinical coagulation assays are an integral part of diagnosing and managing patients with hemophilia; however, in this new era of bioengineered factor products and nonfactor therapeutics, problems have arisen with use of traditional coagulation tests for the quantification of several of these new products. Discussion over the use of one‐stage clotting assays versus chromogenic substrate assays for clinical decision making and potency labeling has been ongoing for many years. Emerging factor concentrates have heightened concern over assay selection and availability. Emicizumab interferes with all aPTT based assays, rendering them unreliable and potentially falsely reassuring to the unaware provider. This review explores considerations for coagulation assays in the clinical setting and highlights how awareness of institutional coagulation assays and potential limitations have never been more critical for providers caring for patients with bleeding disorders.
Hearing Aids and Health-Related Quality of Life in Adults With Hearing Loss
Authors: Pádraig T. Kitterick, Melanie A. Ferguson
Journal: JAMA (2018)

<h3>Clinical Question</h3> Are hearing aids associated with improved health-related quality of life in adults with mild to moderate hearing loss? <h3>Bottom Line</h3> Compared with no hearing aids, the provision of hearing aids was associated with improvements in hearing-specific and general health-related quality of life.
A phase I study of palbociclib (PALBO) plus everolimus (EVE) and exemestane (EXE) in hormone-receptor positive (HR+)/HER2- metastatic breast cancer (MBC) after progression on a CDK4/6 inhibitor (CDK4/6i): safety, tolerability and pharmacokinetic (PK) analysis.
Authors: Romualdo Barroso-Sousa, Hao Guo, William Thomas Barry, Arlindo R. Ferreira, Rebecca Rees, Eric P. Winer, Nikhil Wagle, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2018)

1068 Background: Although adding a CDK4/6i to endocrine therapy (ET) has proved to prolong progression-free survival in patients (pts) with HR+/HER2- MBC, it is unclear if continuing a CDK4/6i, together with subsequent lines of ET, is beneficial. Preclinical data showed that the combination of PI3K inhibitors and CDK4/6i are synergistic, and could restore sensitivity to both CDK4/6i and ET. We present phase Ib data of PALBO + EVE + EXE in pts with HR+/HER2- MBC. Methods: In this phase Ib/II study (NCT02871791), pts received escalating doses of PALBO (once daily, days 1–21 of 28-day cycle) + EVE (5 mg/d) + EXE (25 mg/d). Eligible pts had HR+/HER2- MBC, with measurable disease, and prior progression on any CDK4/6i and a non-steroidal aromatase inhibitor. Pts may have received any number of prior lines of ET, and 0-1 prior line of chemotherapy. Exclusion criteria included prior intolerance to 125mg of PALBO and prior use of mTORi or EXE. The primary objective of the phase Ib was to evaluate the safety, tolerability, and to define the maximal tolerated dose (MTD)/recommended Phase II dose (RP2D) of the triplet. Secondary objectives included PK analyses and characterization of genomic alterations by circulating tumor DNA (ctDNA). Results: 9 pts were treated on the phase 1 portion of the trial. In the first dose level of PALBO (100mg), 1 out of 3 pts experienced a DLT (G3 neutropenia and G2 mucositis). None of the 3 pts subsequently enrolled had a DLT. PALBO dose was escalated 125mg, and all the 3pts had a DLT (all had G3 neutropenia). PALBO 100mg/d (21 of 28 days) was declared the MTD. Most common G3/4 treatment-related adverse events were neutropenia (77%), and thrombocytopenia (22%). Five pts developed G2 oral mucositis; prophylactic oral dexamethasone rinse was not mandatory. The RP2D was PALBO 100mg/d (21 of 28 days), EVE 5mg/d, and EXE 25mg/d. PK analysis and genomic alterations seen in ctDNA will be presented. Conclusions: The triplet combination of PALBO 100mg/d (21 of 28 days) + EVE 5mg/d + EXE 25mg/d is safe in pts with HR+/HER2- MBC. The phase II portion of this trial is ongoing. Clinical trial information: 02871791.
Genomic stratification with BCI of ER+ early breast cancer patients with limited long-term risk of breast cancer death.
Authors: Virginia G. Kaklamani, Graham M. Poage, Tommy Fornander, Bo Nordenskjold, Olle Stål, Yi Zhang, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2018)

516 Background: An increasing body of evidence from extended endocrine therapy trials underscores the unmet need to manage risk-benefit at the individual patient (pt) level. Breast Cancer Index (BCI) is a multigene assay that identified women with a 4.8%-6.6% low risk of cumulative recurrence (0-10y) and a low risk of late recurrence of 2.5%-3.5% in validation studies. In this post-hoc analysis, an optimized assay threshold to identify patients with favorable long-term breast cancer–specific survival was developed and characterized. Methods: An adjusted BCI cut point for indolent disease was trained using a cohort of node-negative, post-menopausal women with HR+ breast cancer from the Stockholm trial treated with surgery alone (UNT, n = 283). Initial performance of the optimized model was evaluated in tamoxifen-treated HR+ patients (TAM, n = 317). Breast cancer–specific survival (BCSS) was the primary analysis using Kaplan-Meier estimates over 0-20y and 5-20y. Subsets based on tumor size and tumor grade were also analyzed for BCSS. Median follow-up was 17 years. Results: Long-term survival analysis demonstrated that BCI optimized for minimal risk classified pts into 4 distinct risk groups for years 0-20 (p < 0.0001) and 5-20 (p = 0.032), with an 8% risk of breast cancer–specific death for the minimal risk group in the UNT arm. BCI classified 27% of pts treated with adjuvant TAM into a BCI minimal risk group with 98% and 99% BCSS for years 0-20 and 5-20, respectively. Among clinically high-risk grade 2 and 3 tumors (n = 250), BCI classified 20% of pts as BCI minimal risk with 98% BCCS for years 0-20 and 5-20. Conclusions: In this analysis, a BCI minimal risk group identified more than 1/4 of pts as having favorable long-term outcome (2% risk of breast cancer death) over 20 years after 2-5 years of tamoxifen therapy. Results suggest that the specific gene characteristics of BCI, which combine measures of cell proliferation and estrogen signaling, are an effective prognostic marker of indolent disease. BCI stratification of a genomic subset with favorable long-term outcome may identify node-negative pts with early-stage breast cancer in which more than 5 years of endocrine therapy is unlikely to be of benefit.
Sperm associated antigen 5 (SPAG5) as a predictor and monitor for response and distant relapse risk (DRR) to endocrine (ET) and chemo-therapies (CT) in oestrogen receptor positive (ER+) breast cancer (BC).
Authors: Tarek Mohamed Ahmed Abdel-Fatah, Graham Ball, Amy McCart Reid, Peter Simpson, Sunil R. Lakhani, Lorinc Pongor, Balazs Gyorffy, Paul M Moseley, Andrew R. Green, A. Graham Pockley, Carlos Caldas, Ian O. Ellis, Stephen Chan
Journal: Journal of Clinical Oncology (2018)

1066 Background: SPAG5 is an ultimate proliferation marker and important driver that is commonly amplified in “luminal B” BC. Methods: SPAG5 copy number aberrations (CNAs), mRNA and protein expression and their association with BC specific survival (BCSS) were determined in 4998 cases of ER+ BC. The association between the pathological complete response (pCR) to neoadjuvant anthracycline based CT (NACT) and SPAG5 expression was evaluated in 1073 (mRNA) and 332 (protein) patients with ER+ BC . The association between the dynamic response to the neoadjuvant ET (NAET) and SPAG5 mRNA expression was evaluated in 101 cases of ER+ BC. The association between distant relapse risk (DRR) and SPAG5 expression were tested in ER+/HER2- patients who received (if eligible) NACT or adjuvant CT in addition to 5-year tamoxifen (mRNA: n = 2819; protein: n = 2501). Results: SPAG5 amplification (CNA) and overexpression (SPAG5+, mRNA, protein) were all associated with shorter BCSS (HR: 1.55, 1.31, and 1.90, ps < 0.001); respectively). After receiving NACT, multivariable logistic regression analyses confirmed that SPAG5+ mRNA and protein expression were independently associated with higher pCR (OR: 1.90; p = 0.041 and 23.03; p < 0·0001; respectively). Downregulation of SPAG5 has been observed after 2-weeks on NECT and this predicted the dynamic clinical response (p < 0.01). In patients received Tamoxifen alone with either lymph node positive (LN+) or LN negative disease, SPAG5+ BC (mRNA, protein) exhibited a two-fold increase in DRR compared to patients with SPAG5- disease (ps < 0·0001). In contrast, in patients received CT+Tamoxifen with LN+ or LN-disease, SPAG5+ (mRNA, protein) exhibited a similar DRR to that with SPAG5- disease. ER+ patients with SPAG5+ mRNA tumours receiving CT+Tamoxifen has improved 5-year-DRFS by 28% for those with LN- disease (89% vs., 67%; p < 0·001) and 22% for those with LN+ disease (76% vs., 54%; p < 0·001), as compared to receiving Tamoxifen alone. Conclusions: SPAG5 could be used as a prognostic and predictive tool for selecting systemic therapies and monitoring response to the selected therapy in patients with ER+ BC.
Bootstrap and Rogue Identification Tests for Phylogenetic Analyses
Authors: Claudia Augusta de Moraes Russo, Alexandre Pedro Selvatti
Journal: Molecular Biology and Evolution (2018)

Most phylogenetic tree-generating programs produce a fully dichotomous phylogenetic tree. However, as different markers may produce distinct topologies for the same set of organisms, topological tests are used to estimate the statistical reliability of the clades. In this protocol, we provide step-by-step instructions on how to perform the widely used bootstrap test using MEGA. However, a single unstable lineage, also known as a rogue lineage, may decrease the bootstrap proportions in many branches of the tree. This occurs because rogue taxa tend to bounce between clades from one pseudo-replicate to the next, lowering bootstrap proportions for many correct clades. Thus, it is important to identify and exclude rogue taxa before initiating a final phylogenetic analysis; here, we provide this protocol using the RogueNaRok platform.
Analysis of germline <i>BRCA1/2 m</i>utated (g<i>BRCA<sup>mut</sup></i>) hormone receptor-positive (HR+) and triple negative breast cancer (TNBC) treated with talazoparib (TALA).
Authors: Wolfgang Eiermann, Hope S. Rugo, Sami Diab, Johannes Ettl, Sara A. Hurvitz, Anthony Goncalves, Kyung-Hun Lee, Louis Fehrenbacher, Rinat Yerushalmi, Lida A. Mina, Miguel Martin, Henri Hubert Roche, Young-Hyuck Im, Denka Markova, Iulia Cristina Tudor, Joanne Lorraine Blum, Alison L. Hannah, Jennifer Keating Litton
Journal: Journal of Clinical Oncology (2018)

1070 Background: TALA is a dual-mechanism PARP inhibitor that traps PARP on DNA in BRCA1/2-mutated cells, preventing DNA damage repair and causing cell death. Methods: EMBRACA (NCT01945775) is a randomized phase 3 trial comparing TALA (1 mg/day) with physician’s choice of therapy (PCT) (capecitabine, eribulin, gemcitabine, vinorelbine) in patients (pts) with gBRCAmut advanced breast cancer (aBC). Pts had HR+ BC or TNBC (HER2+ BC pts were excluded). An analysis was conducted to determine if TALA had different efficacy and safety based on receptor expression. Results: Of 431 pts randomized, 241 had HR+ BC and 190 had TNBC. TNBC pts had a lower median age compared to HR+ pts (43 vs 50 years); only HR+ pts included males (n = 7). More TNBC pts had received prior platinum therapy (26% vs 11% HR+); both groups had received a median of 1 prior cytotoxic regimen for aBC. Duration of TALA therapy was longer for pts with HR+ compared to TNBC (7.3 vs 5.4 months); 19% of both TNBC and HR+ pts received 12+ months of TALA. The hazard ratio for PFS was similar between the 2 groups, but the median estimates for TALA were different: 0.596 (0.406, 0.874) for TNBC pts, with mPFS of 5.8 months; 0.474 (0.318, 0.708) for HR+ pts, with mPFS of 9.4 months. ORR for TALA was similar for the 2 groups: 61.8% for TNBC vs 63.2% for HR+. Duration of response median for TALA was longer for HR+ (6.8 months) compared to TNBC (4.3 months); both groups included a subset with a prolonged response to TALA (28% HR+ and 17% TNBC had a continued response at 12 months; no PCT patient had a continued response at 12 months). The majority of both HR+ and TNBC TALA pts achieved a CBR24 (74.5% vs 61.5%). The primary toxicity for both groups was hematologic: for HR+ and TNBC, grade 3+ anemia (38.5% vs 40.0%), neutropenia (16.7% vs 26.2%), and thrombocytopenia (12.8% vs 16.9%). Drug-related grade 3+ nonhematologic toxicities were rare in both groups. Serious AEs were similar (30.8% HR+ vs 33.1% TNBC). Few pts experienced an AE that resulted in permanent discontinuation (5.8% HR+ vs 6.2% TNBC). Conclusions: Talazoparib demonstrated improved PFS and ORR in pts both with gBRCAmut HR+ BC and TNBC. The safety profile in these 2 groups was similar. Clinical trial information: NCT01945775.
Immune oncology, immune responsiveness and the theory of everything
Authors: Tolga Turan, Deepti Kannan, Maulik Patel, J. Matthew Barnes, Sonia G. Tanlimco, Rongze Lu, Kyle Halliwill, Sarah Kongpachith, Douglas E. Kline, Wouter Hendrickx, Alessandra Cesano, Lisa H. Butterfield, Howard L. Kaufman, Thomas J. Hudson, Davide Bedognetti, Francesco Marincola, Josue Samayoa
Journal: Journal for ImmunoTherapy of Cancer (2018)

Anti-cancer immunotherapy is encountering its own checkpoint. Responses are dramatic and long lasting but occur in a subset of tumors and are largely dependent upon the pre-existing immune contexture of individual cancers. Available data suggest that three landscapes best define the cancer microenvironment: <b><i>immune-active</i></b>, <b><i>immune-deserted and immune-excluded</i></b>. This trichotomy is observable across most solid tumors (although the frequency of each landscape varies depending on tumor tissue of origin) and is associated with cancer prognosis and response to checkpoint inhibitor therapy (<b>CIT</b>). Various gene signatures (e.g. Immunological Constant of Rejection - <b>ICR</b> and Tumor Inflammation Signature <b>- TIS</b>) that delineate these landscapes have been described by different groups. In an effort to explain the mechanisms of cancer immune responsiveness or resistance to CIT, several models have been proposed that are loosely associated with the three landscapes. Here, we propose a strategy to integrate compelling data from various paradigms into a "<i>Theory of Everything</i>". Founded upon this unified theory, we also propose the creation of a task force led by the Society for Immunotherapy of Cancer (<b><i>SITC</i></b>) aimed at systematically addressing salient questions relevant to cancer immune responsiveness and immune evasion. This multidisciplinary effort will encompass aspects of genetics, tumor cell biology, and immunology that are pertinent to the understanding of this multifaceted problem.