tbuckley/cabot-search huggingface dataset:
Loss of heterozygosity in multiple myeloma: A role for PARP inhibition?
Authors: Charlotte Pawlyn, Andrea Loehr, Ruslana Tytarenko, Shayu Deshpande, James Sun, Kyle Fedorchak, Tariq I. Mughal, Faith Davies, Brian Walker, Mitch Raponi, Gareth John Morgan
Journal: Journal of Clinical Oncology (2017)

8026 Background: PARP inhibitors can induce synthetic lethality in tumors characterized by homologous recombination deficiency (HRD). Two PARP inhibitors are approved for the treatment of BRCA mutated ovarian cancer. HRD can be detected by evaluating genome-wide loss of heterozygosity (LOH), which is associated with response to PARP inhibition. Myeloma (MM) is a genetically unstable tumor and we hypothesized that LOH could be detected in patient samples, supporting a potential role for PARP inhibition in MM. Methods: We analyzed 406 cases at all disease stages: MGUS (n = 7), smoldering MM (SMM, n = 30) newly diagnosed MM (NDMM, n = 71), treated MM (TRMM, n = 64) and relapsed MM (RLMM, n = 234). CD138+ plasma cell DNA underwent targeted next generation sequencing (FoundationOne Heme) interrogating 405 cancer related genes and 3543 single nucleotide polymorphisms (SNPs) across the genome. An algorithm using the minor allele frequencies of the examined SNPs and copy number profile across the 22 autosomal chromosomes identified LOH segments. Events unlikely to be caused by HRD, e.g. whole chromosome or chromosome-arm loss, were excluded. The percentage of genomic LOH for each sample was calculated as the sum of the lengths of included LOH segments divided by the length of the interrogated genome. Results: We found evidence of HRD detected by LOH with higher LOH selecting for patients with poor outcome. LOH increases with advancing disease stage from a median of 0.3% in MGUS to 3.1% in RLMM. LOH was highest in the PR and MMSET molecular subgroups and correlated significantly with the gene expression defined risk score GEP70 (R = 0.4, p &lt; 0.001) and proliferation index (R = 0.4, p &lt; 0.001). Outcome of RLMM patients, the biggest clinical group, was analyzed and patients with LOH above the 3 rd quartile (≥5%LOH) had significantly worse overall survival than those with lower levels (p &lt; 0.001). LOH correlates and overlaps with other metrics of poor prognosis, suggesting it may be a prognostic marker itself. Conclusions: We demonstrated LOH in MM samples, increasing as disease progresses and associated with poor prognosis. These data support the further evaluation of PARP inhibitors in MM patients, particularly in the relapsed setting with a high unmet need for new treatments.
Comprehensive genomic profiling (CGP) of advanced papillary renal cell carcinoma (PRCC) to reveal distinctions from TCGA dataset.
Authors: Sumanta K. Pal, Daniel M. Geynisman, Siraj Mahamed Ali, Evgeny Yakirevich, Phil Stephens, Jeffrey S. Ross, Vincent A. Miller, Jon Chung, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

4517 Background: Biologic characterization of PRCC by TCGA reveals alterations in MET in type 1 disease, and CDKN2Asilencing, SETD2 mutations and TFE3 fusions in type 2 disease. A limitation of TCGA data is that of 161 pts analyzed, 73% and 3% had M0 and M1 disease, respectively. We present the gene alterations (GA) identified in pts with advanced PRCC.Methods: FFPE tissue was obtained from 169 patients with PRCC. Diagnosis and PRCC subtyping was centrally confirmed by 2 board-certified pathologists. DNA was extracted and comprehensive genomic profiling (CGP) was performed (median coverage, 648X) in a CLIA-certified central laboratory. Results: Of 169 pts with advanced PRCC, 39 (23%) were type 1, 108 (64%) were type 2 and 22 (13%) were unclassified. 66 samples (39%) were from a metastatic site biopsy, and 103 were from the kidney (61%). An average of 2.4 GA/tumor were detected. In type 1 pts, commonly altered genes were MET (33%: 8 activating mutations, 5 amplifications), TERT (30%), CDKN2A/B (13%), and EGFR (8%). In type 2 pts, commonly altered genes were CDKN2A/B (18%), TERT (18%), NF2 (13%) and FH (13%); METGAs (5 mutations, 3 amplifications) were observed in 7.4% of type 2 pts. MET GA was significantly associated with type 1 PRCC (p = 0.0002) and NF2 GA and alterations in SWI/SNF complex genes were both significantly associated with type2 PRCC (p = 0.02 and p = 0.007, respectively). Overall, frequent alterations were found in genes involved in SWI/SNF complexes (25%), chromatin modification (23%) and cell cycle regulation (22%). RAS/RAF pathway (9%) and PI3K/mTOR pathway (8%). Notable differences with TCGA include higher frequencies of MET and NF2 GAs, association of GAs in the SWI/SNF with type 2 PRCC, and frequent CDKN2A/B alteration in both type 1 and type 2 disease. MET alteration was lower in metastases vs primary (type 1: 15% vs 38%; type 2: 4% vs 10%). Conclusions: In a cohort of PRCC patients slightly larger than the TCGA experience, key differences in CRGA frequency were observed. These likely underscore the marked difference in stage distribution between datasets. Results of this study may inform trials of relevant targeted therapy in metastatic PRCC.
Impact of insurance status on treatment for stage 0-IV breast cancer.
Authors: Rachel Adams Greenup, Samantha Marie Thomas, Oluwadamilola Motunrayo Fayanju, Terry Hyslop, Eun-Sil Shelley Hwang
Journal: Journal of Clinical Oncology (2017)

6532 Background: Health insurance can influence utilization of cancer care. We sought to determine whether insurance status impacts treatment patterns and survival in women with stage 0-IV breast cancer. Methods: Women ages 18-69 years old, diagnosed with unilateral stage 0-IV breast cancer between 2004 and 2014 were selected from the National Cancer Data Base. Insurance status was categorized as Private, Medicare (65+ yo), Medicare (18-64 yo), Medicaid, or Uninsured. After adjustment for known covariates, generalized and binary logistic regression were used to estimate the association of insurance type with receipt of treatment. A multivariate Cox proportional hazards model was used to estimate the association of insurance status with overall survival. Results: A total of 610,450 women met inclusion criteria. Median age was 56 (48-63). Insurance status included: 72.1% Privately insured, 13.9% Medicare 65+, 4.8% Medicare 18-64, 7.1% Medicaid, and 2.1% Uninsured. Women with private insurance were more likely to present with stage 1 breast cancer, and less likely to present with stage 4 disease when compared to Medicaid or Uninsured patients (stage 1: 63.4%, 49.4%, 48.2%, p &lt; 0.01; stage IV: 0.8%, 1.8%, 2.1%, p &lt; 0.01). Risk of death was higher in uninsured or Medicaid patients when compared to those with private insurance (HR 1.52, 95% CI 1.41-1.64; HR 1.6, 95% CI 1.52-1.68). Receipt of chemotherapy and radiation did not differ between Medicaid, Uninsured, or Privately insured patients, but women without private insurance were more likely to receive neoadjuvant chemotherapy (OR 1.14, 95% CI 1.09-1.19; OR 1.16, 95% CI 1.07-1.25, respectively, p &lt; 0.01). Uninsured women were more likely to undergo mastectomy without reconstruction (OR 1.57, 95% CI 1.49-1.65), and less likely to undergo unilateral or bilateral mastectomy with reconstruction than lumpectomy and radiation (OR 0.57, 95% CI 0.53-0.61; OR 0.35, 95% CI 0.32-0.39). Conclusions: Stage at diagnosis and risk of death were higher in Medicaid and uninsured breast cancer patients when compared to those with private insurance. Insurance status did not predict differences in receipt of surgery, chemotherapy, or radiation but did affect oncologic outcomes.
Counterpoint: Successes in the Pursuit of Precision Medicine: Biomarkers Take Credit
Authors: Shumei Kato, Vivek Subbiah, Razelle Kurzrock
Journal: Journal of the National Comprehensive Cancer Network (2017)

Recent years have ushered in technologies that have transformed our ability to interrogate the underlying abnormalities in individual tumors, including next-generation genomic sequencing, transcriptomics, and proteomics.As a result, numerous actionable molecular targets have emerged.There are currently >70 targeted agents FDA approved for the treatment of solid and hematologic malignancies, and the numbers continue to increase (http://www.mycancergenome.org/content/molecular-medicine/overviewof-targeted-therapies-for-cancer/).Further, immunotherapy has arisen as a new type of targeted therapeutic that specifically reactivates the immune system based on knowledge of checkpoints.Once reactivated, the immune system differentiates tumor cells from normal elements based on the neoantigens presented by the cancer cells as a result of the mutanome.Hence, the fields of genomics and immunotherapy, considered the pillars of precision medicine, are wedded to each other.In his commentary elsewhere in this issue (page 859), Gyawali asks why an approach as attractive as precision medicine has failed to improve outcomes.He then proceeds to postulate the following explanations for this presumed failing: (1) the concept of precision medicine may be fallacious, and (2) the biomarkers used are inadequately validated.For the latter, he uses the examples of ERCC1 as a predictor of response to platinum agents and PD-L1 as a predictor of response to anti-PD-1/ PD-L1 checkpoint inhibitors.Herein, we will show that precision medicine has already made substantial advances and has dramatically improved outcomes in several lethal cancers.Further, there are many remarkably useful biomarkers for response. Defining Precision MedicineGyawali defined precision medicine as the concept of "tailoring treatment to individual patients based on the presence or absence of…biomarkers."We agree with this definition.There is now abundant evidence that metastatic tumors have complex genomic alterations that differ from patient to patient.Hence, in order to be precise in prosecuting them, one would need to personalize/individualize therapy.These concepts are the cornerstones of precision medicine.
Heredity in Uterine Cancer
Journal: JAMA (1952)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Survival among elderly breast cancer patients by receipt of human epidermal growth factor receptor 2-targeted therapy: A matched analysis of national registry data.
Authors: Jaqueline Willemann Rogerio, Yanni Hao, Huan Huang, Iris Lin, Joseph Menzin
Journal: Journal of Clinical Oncology (2014)

607 Background: Few studies have examined survival among elderly breast cancer (BC) patients by receipt of human epidermal growth factor receptor 2 (HER2)-targeted therapy. Methods: Women aged 65+ with an incident diagnosis of BC (index) and no history of other cancer were identified from 2006-2010 linked Surveillance, Epidemiology, and End Results (SEER) and Medicare data. Women with BC were classified by receipt of HER2-targeted therapy (trastuzumab or lapatinib) or not, each matched 1:1 to a non-cancer comparison cohort by demographics. Patients had one year of continuous enrollment prior to index and were followed through the earliest of disenrollment, death, or the end of the data. Mortality and time to death were evaluated for all cohorts, by stage, age and race. One Cox model for each disease stage (I-IV) was constructed, with indicators for BC with HER2-targeted therapy and BC without such therapy, using the pooled non-BC comparison cohorts as the reference group. Results: We identified 1,746 BC patients with and 35,114 without HER2-targeted therapy. Patients with and without HER2-targeted therapy had similar mortality (13.0% versus 14.2%; P = 0.18) during follow-up (mean 28 versus 27 months; P = 0.03). Among patients who died, patients with HER2-targeted therapy experienced longer time to death (median 17 versus 13 months; P < 0.01). Among patients with HER2-targeted therapy, increased age (P<0.01) and later stage (P<0.01) were associated with higher mortality. In the Stage IV Cox model, both BC with HER2-targeted therapy and BC without HER2-targeted therapy (vs. no BC) were associated with significantly higher mortality (hazard ratio [HR] = 2.46 and 5.24, respectively; both P < 0.01). BC without HER2-targeted therapy was also a significant predictor of increased mortality in the Stage III model (HR = 1.37; P < 0.01). Significant predictors of increased mortality across the four models included older age (75+) and baseline Charlson comorbidity score >2. Conclusions: BC patients with and without HER2-targeted therapy had similar mortality, with longer time to death among the former. Mortality and time to death also varied by stage, age, and race.
Molecular landscape of BRAF mutations in large cell neuroendocrine carcinoma of lung: An analysis of BRAF mutations and a case report of a BRAF non-V600E mutated tumor responding to targeted therapy.
Authors: Keerthi Tamragouri, Young Kwang Chae, Jon Chung, Vincent A. Miller, Siraj Mahamed Ali, Francis J. Giles
Journal: Journal of Clinical Oncology (2017)

11621 Background: In advanced stages, large cell neuroendocrine carcinoma of the lung (L-LCNEC) mimics small cell lung cancer (SCLC) despite its traditional classification as a non-small cell lung cancer (NSCLC). Here we present a focused analysis of BRAF mutations in this population. Methods: Comprehensive genomic profiling of tumor tissues was performed from a cohort of 300 patients with biopsy proven L-LCNEC. Specimens were either from a primary lung lesion or metastatic site. Results: 14 unique BRAF alterations (amplifications, mutations) were identified in 13 patients. The importance of biomarker driven therapy is subsequently highlighted with our case of a 69 year-old male diagnosed with metastatic L-LCNEC that did not respond to cisplatin/etoposide. He then demonstrated a significant durable response with therapy targeted toward a BRAF non-V600E mutation (G469R) associated with biomarker response identified through circulating cell free tumor DNA analysis. A change in clonal allele frequency from nearly 50% to non-detectable was observed. Conclusions: Though uncommon, L-LCNEC does appear to contain activating and therefore actionable alterations. We thus highlight the value of pursuing NGS for these patients. [Table: see text]
The Use of Tissue Microarrays for the Validation of Immunohistochemical Analysis of Hereditary Nonpolyposis Colorectal Cancers within a Diagnostic Setting
Authors: M Mullarkey, A O'Grady, EW Kay
Journal: Endoscopy (2006)

Aims: This study aimed to establish a validation study for immunohistochemical (IHC) analysis of microsatellite instability (MSI) in possible Hereditary NonPolyposis Colorectal Cancer (HNPCC) cases using tissue microarrays (TMAs) within our own and other laboratories.
Osteoporotic Fractures Associated With Dabigatran vs Warfarin
Authors: Toshihiro Sugiyama
Journal: JAMA (2017)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Superior GVHD-free, relapse-free survival for G-BM to G-PBSC grafts is associated with higher MDSCs content in allografting for patients with acute leukemia
Authors: Qian Fan, Hui Liu, Xinquan Liang, Ting Yang, Zhiping Fan, Fen Huang, Yiwen Ling, Xin Liao, Li Xuan, Na Xu, Xiaojun Xu, Jieyu Ye, Qifa Liu
Journal: Journal of Hematology & Oncology (2017)

Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (G-PBSC) has largely replaced unstimulated bone marrow (un-BM) for allografting because of accelerated engraftment, but with a higher morbidity and mortality of graft-versus-host-disease (GVHD). Recent studies suggested that G-CSF-primed BM (G-BM) had similar engraftment but lower morbidity and mortality of GVHD comparing to G-PBSC. A prospective, randomized, multicenter study was conducted to compare G-BM with G-PBSC as the grafts in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute leukemia in first complete remission (CR1). Totally 101 adult leukemia in CR1 undergoing HLA-identical sibling transplants were randomized into G-BM or G-PBSC group. The primary study endpoint was GVHD-free/relapse-free survival (GRFS). Both the engraftment of neutrophil and platelet were 2 days later in G-BM than in G-PBSC group (P = 0.412, P = 0.39). G-BM group showed significantly lower II–IV acute GVHD (aGVHD) and similar III–IV aGVHD compared with G-PBSC group (12.2% vs 28.8% for II–IV, P = 0.048; 4.1% vs 9.6% for III–IV aGVHD, P = 0.267, respectively). The overall cumulative incidence of chronic GVHD (cGVHD) at 3 years were 22.3% ± 6.3% and 44.8% ± 7.6% (P = 0.026), respectively, and extensive cGHVD were 4.5% ± 3.1% and 15% ± 5.3% (P = 0.08), respectively, in G-BM and G-PBSC groups. Two groups had similar 3-year relapse, transplant-related mortality (TRM), overall survival (OS), and disease-free survival (DFS) (all P > 0.05). G-BM group showed significantly higher probability of GRFS than G-PBSC group (73.5% ± 6.3% vs 55.8% ± 6.9% at 1 year, P = 0.049; 69.0% ± 6.7% vs 49.7% ± 7.0% at 2 and 3 years, P = 0.03, respectively). Graft content analysis revealed statistically higher frequency of myeloid-derived suppressor cells (MDSCs) in the G-BM than in G-PBSC grafts (P < 0.01), and recipients received statistically higher numbers of MDSCs in G-BM than in G-PBSC group (P = 0.045). Numbers of MDSCs infused to patients were negatively correlated with the severity of aGVHD (P = 0.032, r = −0.214). Multivariate analysis showed that MDSC cell dose below the median (HR = 3.49, P < 0.001), recipient age (HR = 2.02, P = 0.039), and high risk of disease (HR = 2.14, P = 0.018) were independent risk factors for GRFS. G-BM grafts lead a better GRFS and less GVHD associated with a higher MDSCs content compared with G-PBSC grafts.
Analysis of Primary Hemostasis Alterations Induced By Ibrutinib Assessed By Shutter Speed and Aggregometry Impedance
Authors: Raul Cordoba, Rosa Vidal, Aranzazu Garcia-Raso, Tamara Castaño, Carlos Plaza, Elham Askari, Maria-Angeles Perez, Valentin Garcia Gutierrez, Pilar Llamas
Journal: Blood (2016)
Proposal for a standardised treatment regimen to manage pre- and extensively drug-resistant tuberculosis cases
Authors: Jose A. Caminero, Alberto Piubello, Anna Scardigli, Giovanni Battista Migliori
Journal: European Respiratory Journal (2017)

Drug-resistant tuberculosis (TB) has become one of the main obstacles to controlling (and eventually eliminating) this disease [1–4]. The World Health Organization (WHO) reports that the number of patients suffering from TB with resistance to rifampicin (RR-TB) or multidrug-resistant TB (MDR-TB, resistance to at least isoniazid and rifampicin) is increasing alarmingly each year. Furthermore, the treatment success rates achieved globally are suboptimal, barely exceeding 50% [1, 2, 5]. The proportion decreases to 25% in patients with extensively drug-resistant tuberculosis (XDR-TB) (MDR-TB plus resistance to at least one fluoroquinolone (FQ) and a second-line injectable (SLI) drug) and to <20% when the drug resistance profile is beyond XDR [1, 2, 5]. A potential standardised regimen to manage extensively drug-resistant tuberculosis (XDR-TB) and pre-XDR cases <http://ow.ly/LucH30bUjjH> The authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions and policies of their institutions. The authors wish to thank Lia D'Ambrosio and Rosella Centis (Maugeri Care and Research Institute, Tradate, Italy) for their useful comments and the support in preparing the manuscript.
Highlights of the 31st annual meeting of the Society for Immunotherapy of Cancer (SITC), 2016
Authors: James L. Gulley, Elizabeth A. Repasky, Laura S. Wood, Lisa H. Butterfield
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Abstract</h3> Therapeutic efforts to engage the immune system against cancer have yielded exciting breakthroughs and a growing list of approved immune-based agents across a variety of disease states. Despite the early successes and durable responses associated with treatments such as immune checkpoint inhibition, there is still progress to be made in the field of cancer immunotherapy. The 31st annual meeting of the Society for Immunotherapy of Cancer (SITC 2016), which took place November 11–13, 2016 in National Harbor, Maryland, showcased the latest advancements in basic, translational, and clinical research focused on cancer immunology and immunotherapy. Novel therapeutic targets, insights into the dynamic tumor microenvironment, potential biomarkers, and novel combination approaches were some of the main themes covered at SITC 2016. This report summarizes key data and highlights from each session.
Hunt for an HIV Vaccine Intensifies
Authors: Jeff Lyon
Journal: JAMA (2017)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal