tbuckley/cabot-search huggingface dataset:
Patient-derived induced pluripotent stem cells for modelling genetic retinal dystrophies
Authors: Leah P. Foltz, Dennis O. Clegg
Journal: Progress in Retinal and Eye Research (2018)

The human retina is a highly complex tissue that makes up an integral part of our central nervous system. It is astonishing that our retina works seamlessly to provide one of our most critical senses, and it is equally devastating when a disease destroys a portion of the retina and robs people of their vision. After decades of research, scientists are beginning to understand retinal cells in a way that can benefit the millions of individuals suffering from inherited blindness. This understanding has come about in part with the ability to culture human embryonic stem cells and the innovation of induced pluripotent stem cells, which can be cultured from patients and used to model their disease. In this review, we highlight the successes of specific disease modelling studies and resulting molecular discoveries. The greatest strides in cellular modelling have come from mutations in genes with established and well-understood cellular functions in the context of the retina. We believe that the future of cellular modelling depends on emphasising reproducible production of retinal cell types, demonstrating functional rescue using site-specific programmable nucleases, and shifting towards unbiased screening using next generation sequencing.
Impact of early trials in molecularly-characterized patients (pts) with head and neck cancer (HNC).
Authors: Neus Baste, Rodrigo Dienstmann, Irene Brana, Cristina Viaplana, Jose Jimenez, Fiorella Ruiz-Pace, Coro Bescos, Juan Lorente, Jordi Giralt, Margarita Alberola, Paolo Nuciforo, Ana Vivancos, Jose Maria Del Campo, Josep Tabernero, Enriqueta Felip, Jordi Rodon
Journal: Journal of Clinical Oncology (2017)

6031 Background: Multiple genomic alterations were described in HNC, including squamous cell carcinomas (SCC), salivary gland (SG) and nasopharyngeal (NF) tumors. Tumor molecular profiling (TMP) may increase therapeutic alternatives in early trials for pts with refractory metastatic (met) HNC. We evaluate the impact of matched/unmatched therapy (mT/uT) in HNC with potentially targetable alterations. Methods: From 2010-16, 47 met HNC pts were treated in 57 early trials after TMP. Clinical benefit was measured by: time to progression (TTP); clinical benefit rate (CBR: complete response [CR], partial response [PR] and stable disease [SD] &gt; 4months [m]); progression-free survival [PFS] ratio≥1.3 (PFS under molecular therapeutics/PFS upon last prior chemotherapy [pT]). Results: Median age was 51 years; median number of pT lines was 1 (0-5). In total, 26 SCC, 11 SG, 8 NF and 2 nasosinusal pts (mostly with lymph nodes and lung met) were treated with small kinases (SK) inhibitors (inh) (50%; main targets PI3K/HER/FGFR), immune-oncology (IO) drugs (40%, PD-1/PD-L1), angiogenesis inh (5%) or chaperone, cytidine analog, RNA polymerase (5%). 14/57 trials were mT including CDKinh (1 CDKN2A mutation [mut]), PI3Kinh (5 PIK3CA mut, 2 PTEN mut), PI3K/MEKinh (1 NRAS mut), HERinh (1 ERBB3mut), FGFRinh (2 FGFR1mRNA high, 1 FGF3/4/19 ligand amplified) and porcupine inh (1 ZNFR3mut). Distribution by tumor: IO (16 SCC/5 NF), SKmT (8SG/4SCC/2NF) and SKuT (9SCC/4SG). Responses: 1CR in SCC (IO), 5 PR in SCC (4 IO, 1 FGFRinh), 3 PR in NF (1 cytidin analog, 1 IO, 1 PI3K/MEKinh). Benefit: median TTP 9.33m (CI95% 7-20) with upward trend in NF and SG vs SCC (HR 0.6;p = 0.28), without differences according to target therapies (HR 0.8; p = 0.9); CBR of 58%, without differences by tumor type (p = 0.42) or therapy (SKmT, SKuT, IO; p = 0.5); 60% with PFS ratio≥1.3, significantly higher in SCC and SG (p = 0.016), particularly with IO drug and SKmT, respectively. Conclusions: Considering our preselected fit population as bias selection, individualized treatment selection with novel therapeutics based on TMP, especially in NF and SG irrespective of targets (SKmT, SKuT, IO), and in SCC with IO drugs, seems to confer substantial clinical benefit.
Measuring cancer care experiences: Introducing SEER-CAHPS.
Authors: Maria Andrea Rincon, Erin Kent, Lisa M Lines, Sarah Gaillot, Nicola C. Schussler, Michael T. Halpern, Michelle Mollica, Ashley Wilder Smith
Journal: Journal of Clinical Oncology (2017)

6595 Background: Care experience ratings are recognized as measures of healthcare quality. Here we introduce a new, public data resource, SEER-CAHPS, which links cancer registry data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program with Medicare claims and the Medicare Consumer Assessment of Healthcare Providers and Systems (MCAHPS) survey. Methods: The SEER-CAHPS resource includes cancer registry data from 1973-2011 (diagnosis, incidence, mortality, and sociodemographic data), Medicare CAHPS survey data from 1998-2013 (sociodemographic, health status, and care experience ratings), and Medicare fee-for-service (FFS) claims data from 2002-2013. The survey includes global ratings of overall care, personal doctor, specialist, health plan, and prescription drug plans, and composite ratings of doctor communication, care coordination, getting needed care, and getting care quickly. Data also contain survey weights to account for the Medicare CAHPS sampling design. Cross-sectional and longitudinal analyses are possible. Results: Currently, SEER-CAHPS includes 205,339 individuals with a history of cancer documented in SEER (FFS: 26,802 with a survey before cancer diagnosis, and 55,231 with a survey after cancer diagnosis; Medicare Advantage [MA]: 57,227 with a survey before cancer diagnosis and 71,436 with a survey after cancer diagnosis). The data resource also includes 724,965 MCAHPS respondents without cancer in SEER regions (FFS: 282,592; MA: 447,358). The data provide insights on topics including experiences of cancer patients in their last year of life; experiences of cancer survivors; and the associations of guideline-concordant follow-up care with patient experiences among cancer survivors. We will demonstrate project sample-size estimation and present instructions for submitting data access applications. Conclusions: SEER-CAHPS, a new, publicly available resource, provides population-based, cancer-specific data on patient experiences, health outcomes and healthcare utilization.
Real-world study of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide (ENZA) or abiraterone acetate plus prednisone (AA+P): Patient characteristics and treatment persistence.
Authors: Kelvin A. Moses, David F. Penson, Neil M. Schultz, Fei Shi, Samuel Wilson, Bruce A. Brown, Arie Barlev, Scott Flanders
Journal: Journal of Clinical Oncology (2017)

e16542 Background: As the use of oral therapies in mCRPC increases, it is crucial to understand treatment persistence as it may be used as an effectiveness outcome. This study evaluated treatment persistence in chemotherapy-naïve and post-chemotherapy patients with mCRPC treated with ENZA and AA+P in the United States. Methods: A retrospective claims database analysis identified mCRPC patients treated with ENZA or AA+P from January 1, 2010, to November 30, 2015 . The Clinformatics Data Mart database (OptumInsight, Eden Prairie, MN) included Medicare and commercially insured patients. Treatment persistence (time from first dose to discontinuation [gap &gt; 30 days without index drug]) was assessed in subpopulations of chemotherapy-naïve and post-chemotherapy patients using Kaplan Meier plots with log-rank test. Hazard ratios (HR) [ENZA only/AA+P only] with 95% confidence intervals (CIs) were calculated using a Cox proportional hazards model. Results: In total, 2792 patients with mCRPC received ENZA (n = 827) or AA+P (n = 1965) after September 1, 2012, including subsets of ENZA-only (n = 689) and AA+P-only (n = 1329) patients. Mean age was 74 years and 75% were enrolled in a Medicare plan; 1689 patients with mCRPC were chemotherapy-naïve and 329 were post-chemotherapy. Overall, baseline characteristics were similar between the cohorts except for a higher comorbidity burden in the ENZA-only cohort. Median persistence in chemotherapy-naïve patients was longer with ENZA (ENZA only: 240 days [95% CI 197, 272] versus AA+P only: 186 days [95% CI 180, 212]) (HR 0.86; p = 0.02). In the post-chemotherapy cohort, median persistence was similar (ENZA only: 131 days [95% CI 107, 180] versus AA+P only: 127 days [95% CI 97, 172]) (HR 1.06; p = 0.64). Conclusions: In this real-world mCRPC analysis, treatment persistence was significantly longer in chemotherapy-naïve patients treated with ENZA only versus AA+P only; in post-chemotherapy patients, persistence was not statistically different. Treatment persistence may be utilized an as indicator of treatment effectiveness in clinical practice.
Analysis of TERT promoter mutations, polymorphisms, clinicopathologic features and recurrence-free survival in primary melanoma.
Authors: Gregory Chang, Eric Michael Robinson, Jyothirmayee S. Tadepalli, Christine Salvaggio, Yilong Zhang, Yongzhao Shao, Farbod Darvishian, Russell S. Berman, Richard L. Shapiro, Iman Osman, David Polsky
Journal: Journal of Clinical Oncology (2016)

e21065 Background: Somatic mutations in the promoter of the telomerase reverse transcriptase gene (TERT) appear to confer a worse prognosis in several cancers, an effect which may be modulated by inheritance of nearby germline polymorphism. Methods: We analyzed primary tumors from a cohort of prospectively accrued melanoma patients for sequence variants in the TERT promoter (somatic and germline). We tested the associations between these variants and several other variables including BRAF and NRAS mutations, and clinicopathologic factors including survival outcomes using Chi-Square test and log rank test for Kaplan Meier analysis. We used SNaPshot assays and Sanger sequencing to detect BRAF V600; NRAS Q61; and TERT -124 (C > T) and -146 (C > T) mutations, and the rs2853669 germline polymorphism. Results: Among 367 patients 212 (58%) were male; 188 (51%) were over 60 years old; and 227 (62%), 96 (26%), and 44 (12%) had stages I, II, and III disease respectively. Fifty patients recurred; median follow up was 3.6 years. We found TERT -124 (C > T) mutations in 77/367 (21%) patients and -146 (C > T) mutations in 113/367 (31%) patients. TERT promoter mutations were significantly associated with age > 60 years (p= 0.022), nodular histotype (p= 0.006), higher stage (p= 0.009), thicker tumors (p= 0.021), and ulceration (p= 0.013). TERT promoter mutations were significantly associated with shorter recurrence-free survival (RFS) (p= 0.010). While neither BRAF nor NRAS mutations alone were significantly associated with survival outcomes, they were associated with shorter survivals when co-occurring with TERT mutations (p= 0.015). Patients with the TERT rs2853669 variant whose tumors had the -124 promoter mutation had shorter RFS than those with the -124 mutation alone (p= 0.029). Conclusions: TERT promoter mutations have a significantly deleterious impact on RFS in patients with primary melanoma regardless of mutations in BRAF and NRAS. Importantly, the presence of the inherited rs2853669 variant may further accentuate the impact of TERT mutations on survival. TERT sequence variants may be useful biomarkers to identify early/intermediate stage patients at high risk of recurrence.
Survival outcomes from a cumulative analysis from worldwide observational studies on sequential use of new agents (NAs) in metastatic castration-resistant prostate cancer (mCRPC) (CASTOR study).
Authors: Orazio Caffo, Michel Wissing, Diletta Bianchini, Andre M. Bergman, Frederik BirkebÃ¦k Thomsen, Sebastian Schmid, Evan Y. Yu, Evangelos Bournakis, Avishay Sella, Umberto Basso, Ugo De Giorgi, Marcello Tucci, Hans Gelderblom, Luca Galli, Isabella Sperduti, Stephane Oudard
Journal: Journal of Clinical Oncology (2018)

5026 Background: After the introduction in the daily clinical practice of cabazitaxel (CABA) and new hormone agents (NHAs), abiraterone acetate (AA) and enzalutamide (ENZ), several small retrospective reports described their activity when sequentially used as second- and third-line after docetaxel (DOC) failure. Data from survival plots suggested that after DOC, CABA-based sequences led to a better overall survival (OS) than sequences based on NHAs only. The present work is based on individual-data analysis from some of the published reports on sequential use of at least two NAs after DOC. Methods: All authors of the published papers meeting the study criteria were prompted to provide individual data of the pts evaluated in their work. We calculated the overall survival (OS) from the second-line start by sequence strategy. For the OS analysis we considered three different types of NAs sequences after DOC: one new hormone agent (AA or ENZ) followed by CABA (NHA→CABA); CABA followed by AA or ENZ (CABA→NHA); one NHA followed by the other NHA (NHA→NHA). Results: We collected data from 1,099 pts. Cumulative OS did not differ significantly among the three different strategies (median cumulative OS ranging 21.0-22.1 mos, p = 0.957). Pts treated with NHA second-line had a statistically significant longer PFS although marginal in clinical terms (6.1 vs 5.6 mos, p < 0.0001), while in third-line CABA led to a statistically significant prolongation of OS (from the third-line start) compared to NHAs: 12.2 vs 9.1 mos (p = 0.039). These results were confirmed after adjustment by age and visceral mets presence. Interestingly, in the case of a NHA-based second-line pts with a longer PFS ( > 6 mos) were more frequently treated with a NHA in third-line: in this setting of pts the sequence NHA→ NHA led to a cumulative OS worse than NHA → CABA: 24.8 vs 30.0 (p = 0.022). Conclusions: Recognizing the limits of a retrospective analysis, this report is the largest on sequencing use of NAs after DOC and provides some useful suggestions for the therapeutic strategy in DOC pre-treated mCRPC pts.
Dismissal Policies for Vaccine Refusal—Reply
Authors: Michael J. Deem, Mark C. Navin, John D. Lantos
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Disparities in first treatment type in breast cancer patients.
Authors: Shivani Khanna, Muhammad M. Qureshi, Naomi Ko, Ankit Agarwal, Alexander Rand, Ariel Hirsch
Journal: Journal of Clinical Oncology (2016)

e18073 Background: Disparities in breast cancer treatment and outcomes are recognized in the literature. We analyzed the association of patient demographics and tumor characteristics on the type of first treatment received at a diverse safety net medical center. Methods: 1,130 patients were diagnosed and treated for breast cancer between 2004 and 2014 at our institution. We retrospectively collected data on patient race/ethnicity, primary language, marital status, insurance coverage, age at diagnosis (years), AJCC stage, type of treatment, and hormone receptor status. Chi-square or Fisher’s exact test was performed to test for differences in categorical variables. Results: The distribution of first treatment received was as follows: surgery 80.5% (n = 910), chemotherapy (CT) 14.3% (n = 162), hormone therapy (HT) 5.1% (n = 58). Black patients were more likely to receive CT as a first treatment (19.3%) compared to White (10.2%), Hispanic (13.0%), or Other race patients (13.1%), p = 0.008. Patients with advanced AJCC stage (III- IV) were more likely to receive CT as a first treatment, stage III (48.6%), stage IV (36.4%), compared to earlier AJCC stage patients, p < 0.0001. ER-/PR-/HER2- patients were more likely to receive CT as a first treatment (30.8%) compared to ER+/PR+/HER2- patients (6.9%), p < 0.0001. Single patients were more likely to receive CT as a first treatment (18.1%) compared to married or other patients, p < 0.008. Patients with Medicaid/Charity insurance were more likely to receive CT as a first treatment (21.9%) compared to patients with other insurance, p < 0.0001. Younger patients ( < 50 years) were more likely to receive CT as a first treatment (24.9%) compared to older patients ( > 50 years), p < 0.0001. Haitian Creole and Other language speaking patients were more likely to receive CT as a first treatment (17.8%, 18% respectively) compared to other language speaking patients, p = 0.03. Conclusions: In this large retrospective analysis, patients more likely to receive CT as a first treatment were Black, had advanced AJCC stage, were ER-/PR-/HER2-, younger, unmarried, or had Medicaid/Charity insurance. Further research is needed to understand causes of disparities in the type of first treatment received for breast cancer and their impact on outcomes.
Factors influencing the analgesic response over time of the oxycodone-naloxone association in painful cancer patients: GREAT study.
Authors: Oscar Corli, Lorenzo Legramandi, Mirko Marabese, Anna Roberto
Journal: Journal of Clinical Oncology (2017)

10089 Background: The prolonged use of opioids is usually associated with the appearance of adverse events as drowsiness, constipation, nausea/vomiting, and dizziness. Some effects are self-limiting over time for the onset of tolerance while others, as constipation, persist. Clinical studies demonstrated that the association oxycodone-naloxone (OXN), reduced the constipation in the presence of unchanged analgesic efficacy. Though, the variability of the analgesic response to OXN is not explained yet. The aim of this study was to evaluate the association between the clinical and genetics factors and analgesics response at OXN. Methods: In this study the cancer patients with moderate to severe pain received OXN and followed for 28 days. At each visit pain intensity modifications of therapy and adverse drug reactions (ADRs) were recorded. The primary efficacy endpoint was the proportion of responders, defined as patients with a decrease of the average pain intensity from baseline to last visit ≥30% and a final average pain score≤4, measured on 0-10 numerical rating scale. Genetic tests to identify SNPs related to opioid response were performed in each patient. Results: 14 centers participated in the study and recruited 206 patients. Among 176 patients analyzed for a primary endpoint the mean age was 68 (SD 10); 56% were male. Average and worst pain intensity decreased from baseline to last visit from 6.2 to 2.9 and from 8.3 to 4.6 respectively. 81% of patients were responders. Digestive system tumors (p = 0.05), concomitant thyroid endocrinopathy (p = 0.023), psychological irritability (p = 0.0029) and breakthrough pain at baseline were found to decrease the risk of positive response. None of the investigated polymorphisms influenced the analgesic response. Moderate to severe intensity ADRs were mainly constipation (26%), drowsiness (19%) and dry mouth (12%). Conclusions: In patients with moderate to severe cancer pain, OXN showed a strong analgesic effect (about 50% pain reduction). In comparison with other studies the induced constipation appears substantially lower. Some clinical factors influence the analgesic response while none genetic polymorphisms modulate the response. Clinical trial information: NCT02293785.
The novel detection of EGFR-T790M mutations in exhaled breath condensate.
Authors: Robert Smyth, Sinead Toomey, Alexander Sartori, Emer O. Hanrahan, Sinead Cuffe, Hazel Murray, Deirdre McDonnell, Oscar S. Breathnach, Stephen P. Finn, William Grogan, Patrick G. Morris, Ross Morgan, Bryan Hennessy
Journal: Journal of Clinical Oncology (2017)

9032 Background: The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in NSCLC. However patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is being actively investigated. Furthermore these 'liquid biopsies' may also overcome the problem of tumour genomic heterogeneity. Unfortunately the sensitivity of plasma for T790M detection has been disappointing with a significant chance of a false negative result. Exhaled breath condensate (EBC) is an easily collected sample and is known to harbour cfDNA, including lung cancer mutations. We explored the potential of EBC as a novel method of T790M detection. Methods: We recruited 26 patients who were either 1) known T790M positive pre/during Osimertinib therapy or 2) other mEGFR positive patients on 1st/2nd generation TKI. We collected matched plasma and EBC samples in the majority of cases. EBC samples were collected using the RTube device. Plasma was collected using standard EDTA tubes and extracted within 90 minutes. Using UltraSEEK chemistry, a targeted PCR for ultra-sensitive somatic mutation profiling on the MassARRAY system (Agena Bioscience), we compared the performance of EBC to plasma for the detection of T790M. Results: See Table. Conclusions: In this pilot study we describe the first ever report of the successful and consistent detection of T790M in the EBC of patients with EGFR mutated NSCLC, using a commercially available targeted assay. Our results suggest EBC is responsive to recognised dynamic molecular changes that occur on TKI treatment. We believe this makes EBC analysis an attractive avenue for future research, to optimise the detection of T790M mutations in liquid biopsies. [Table: see text]