tbuckley/cabot-search huggingface dataset:
Activity and safety of crizotinib in patients with advanced, metastatic alveolar soft part sarcoma (ASPS) with rearrangement of <i>TFE3:</i> European Organization for Research and Treatment of Cancer (EORTC) phase 2 trial 90101 CREATE.
Authors: Patrick Schoffski, Agnieszka Wozniak, Bernd Kasper, Steinar Aamdal, Michael Gordon Leahy, Piotr Rutkowski, Sebastian Bauer, Hans Gelderblom, Antoine Italiano, Lars H Lindner, Ivo M. Hennig, Sandra J. Strauss, Branko Zakotnik, Alan Anthoney, Birgit Geoerger, Jean-Yves Blay, Peter Reichardt, Winette TA van der Graaf, Sandrine Marreaud, Silvia Stacchiotti
Journal: Journal of Clinical Oncology (2018)

11540 Background: ASPS is an orphan disease associated with rearrangement of transcription factor E3 (TFE3), leading to abnormal MET expression. We assessed crizotinib in pts with ASPS (NCT01524926). Methods: Eligible pts with reference pathology-confirmed ASPS received crizotinib 250 mg bid. By central FISH assessment of TFE3 rearrangement , pts were attributed to MET+ or MET- sub-cohorts. Primary endpoint was objective response rate (ORR; RECIST 1.1) according to local investigator. Secondary endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival rate (OSR), overall survival (OS) and safety. Results: Among 53 consenting pts with confirmed diagnosis of ASPS, 48 were treated and 45 were evaluable. Among 40 MET+ pts, 1 achieved a confirmed partial response (PR) lasting 215 d and 35 had stable disease (SD) (ORR: 2.5%, 95%CI: 0.6-80.6%). Further efficacy endpoints in MET+ cases were: DCR 90.0% (76.3-97.2%); 1-year PFR 37.5% (22.9-52.1%); 1-year OSR 97.4% (82.8-99.6%). Among 4 MET- pts, 1 achieved a PR lasting 801 d and 3 had SD (ORR: 25.0%, 0.6-80.6%) for a DCR of 100% (39.8-100.0%). The 1-year PFR in MET- cases was 50% (5.8-84.5%); 1-year OSR was 75% (12.8-96.1%). One pat with unknown MET status (technical failure) achieved SD but progressed after 17 cycles. Shrinkage of target lesions was seen in 17 pts, both in MET+ and - cases. The most common related AEs were nausea (34/48 [70.8%]), vomiting (22/48 [45.8%]), blurred vision (22/48 [45.8%]), diarrhea (20/48 [41.7%]) and fatigue (19/48 [39.6%]). Conclusions: According to EORTC efficacy criteria for sarcoma, our data suggest that crizotinib has activity in TFE3 rearranged ASPS. While objective responses were infrequent, we observed tumor shrinkage in a significant proportion of pts, excellent DCR and good survival. We present very mature and reliable prospective PFS and OS estimates as reference for future research in pts with ASPS. Clinical trial information: NCT01524926.
Genetic aberrations in the CDK4 pathway and association with innate resistance to PD-1 blockade in acral melanoma.
Authors: Jiayi Yu, Yan Kong, Zhihong Chi, Bixia Tang, Xinan Sheng, Lu Si, Chuanliang Cui, Li Li Mao, Siming Li, Bin Lian, Xuan Wang, Xue Bai, Jun Guo
Journal: Journal of Clinical Oncology (2018)

9588 Background: PD-1 checkpoint blockade immunotherapy induces long durable responses in patients with advanced melanoma. However, only a minor subset of acral melanoma patients could gain benefit from it. In this study, we aim to explore factors that may influence innate sensitivity or resistance to anti-PD-1 therapy and screen drugable targets with potential to be combined with anti-PD-1 antibody monotherapy in acral melanoma. Methods: Whole exome sequencing (WES) and RNAseq analyses were performed in 13 biopsies from baseline lesions of advanced melanoma patients who were treated with anti-PD-1 antibody (JS001, Shanghai Junshi Biosciences, China). The copy number variations (CNV) of candidate genes were identified by TaqMan Copy Number Assay in an independent cohort. The effect of CDK4/6 inhibitors combined with anti-PD-1 antibody monotherapy was evaluated by PD-1 humanized mouse (C57BL/6-hPD-1) and patient-derived xenograft (PDX) models. Results: WES revealed parallel CNV amplifications in both the CR+PR and PD cohorts, such as 4q22.1, 10q23.32, 15q26.3, 22q13.1. However, several significant CNV amplifications notably only occurred in the PD cohort, such as 1q23.1, 5p15.33, 7p22.3, 11q13.3, 12q14.1, which harbor Cdk4, Ccnd1, CARD11 and mTOR genes. The association between Cdk4 or/and Ccnd1 amplification with innate resistance to anti-PD-1 therapy was validated in 46 acral melanoma patients (P < 0.01). The CDK4/6 inhibitor treatment increased PD-L1 protein levels in primary acral melanoma cell line and PDX model. Moreover, CDK4/6 inhibitor augments the response to PD-1 blockade in PD-1 humanized mouse (C57BL/6-hPD-1) and PDX models. Tumor growth curves for each treatment group demonstrate the improved efficacy of combining PD-1 blockade with the CDK4/6 inhibitor (P < 0.05). Conclusions: In summary, we discovered the genetic aberrations in the CDK4 pathways were associated with innate resistance to anti-PD-1 therapy in patients with advanced acral melanoma. Moreover, our study provides evidence for the testing of CDK4/6 inhibitors combined with anti-PD-1 antibody monotherapy in acral melanoma.
TCT-295 Differential Prognostic Value of Galectin-3 According to Levels of Carbohydrate Antigen 125 in Transcatheter Aortic Valve Implantation
Authors: Tobias Rheude, Costanza Pellegrini, Julio Núñez Villota, Teresa Trenkwalder, Michael Joner, Markus Kasel, Wolfgang Koenig, Vicente Bodi, Heribert Schunkert, Adnan Kastrati, Christian Hengstenberg, Oliver Husser
Journal: Journal of the American College of Cardiology (2018)
Association of age at diagnosis and stage of disease with <i>ATRX</i> mutations in neuroblastoma.
Authors: Sara Michele Federico, Xiang Chen, John Easton, Jianrong Wu, Shenghua Mao, Yanling Liu, Arlene Naranjo, Alberto S. Pappo, Michael D. Hogarty, Michael A. Dyer
Journal: Journal of Clinical Oncology (2016)

10525 Background: Older age at diagnosis is associated with poor outcome in neuroblastoma (NB). A recent study identified ATRX mutations in older patients with stage 4 NB (JAMA 307:1062, 2012). We performed targeted sequence analysis in patients with NB to better describe the frequency of ATRX mutations and relation to patient's age, stage of disease, MYCN status and presence of ALK mutations. Methods: NB tumors were obtained from the Children's Oncology Group (122 unpaired tumor, 353 paired tumor/germline). Age groups at diagnosis included infants (0 - <18mo), toddlers (18mo - <5yr), children (5 - <12yr) and adolescent/young adult (AYA, >12yr). Seven cohorts represent the diversity of disease including: infants stage 1 - 3; infants stage 4; infants stage 4S; toddlers stage 1 - 3; children stage 1 - 3; children stage 4; AYA all stages. Whole exome sequencing (WES) was performed on all 828 samples. Intragenic deletions in ATRX were evaluated by custom-designed capture probes followed by deep sequencing (100x). MYCN amplification was detected by comparing MYCN exonic coverage against genome-wide median exonic coverage in WES. Sequence mutations were determined from WES for paired samples. Associations of ATRX mutations with age at diagnosis, stage of disease and MYCN status were evaluated. Results: There were 19 ATRX mutations (4%), 21 ALK mutations (4.4%), and 28 tumors with MYCN amplification (5.9%). Frequency of mutations in the ATRX gene by age and stage are presented in table 1. Using Fisher's exact test, older age and stage 4 disease are significantly associated with mutations in the ATRX gene (p<0.0001 and p=0.0007 respectively). MYCN amplification was mutually exclusive from ATRX. Conclusions: This study is the largest comprehensive targeted sequence analysis of ATRX in NB and confirms that ATRX mutations are associated with an older age at diagnosis, stage 4 disease and are mutually exclusive from MYCN amplification. Cohort Size (n) ATRX mutations (n, %) 95% C.I. Infants, stage 1 - 3 100 0, 0% 0% - 3.5% Infants, stage 4 103 0, 0% 0% - 3.4% Infants, stage 4S 10 0, 0% 0% - 26.7% Toddlers, stage 1 - 3 76 1, 1.3% 0% - 7.1% Children, stage 1 - 3 98 2, 2% 0% - 7.2% Children, stage 4 54 13, 24.1% 13.5% - 37.6% AYA, all stages (n=5 stage 4) 33 3, 9.1% 1.9% - 24.3%
Germ-line biomarkers disrupting microRNA regulatory pathways to predict toxicity and response to anti-PD-1 and anti-PD-L1 therapies.
Authors: Joanne B. Weidhaas, Donatello Telesca, Anusha Kalbasi, David Salzman, Antoni Ribas
Journal: Journal of Clinical Oncology (2017)

3040 Background: Identifying responders to developing immune therapies is of high priority, yet identifying patients who will suffer from toxicity, which represents a unique spectrum of side effects, termed immune-related adverse events (irAEs), is critical. The complex host-specific response to immune therapies led us to hypothesize that germ-line mutations, present in both the tumor and in the host’s immune system, may be a source of biomarkers. As there is compelling evidence that recently discovered germ-line mutations disrupting microRNA (miRNA) networks act as biomarkers of treatment response and baseline immune status, we evaluated such mutations in patients treated with these therapies. Methods: Patients treated with anti-PD1 or anti-PDL1 therapy alone and clinically documented response and toxicity were tested with a panel of over 150 vetted germ-line miRNA based biomarkers. Of 85 patients evaluated for response, 75 had melanoma, and 10 had NSCLC. For analysis of toxicity, an additional 4 patients with other cancer types were included. Subjects were classified as responders (Complete, Partial) versus non-responders (Progressive, Stable), or as experiencing low irAEs (grade 0 and 1) versus high irAEs (grade 2 and above). We used Chi-squared analysis for base evaluation and then compared three classification techniques including classification trees, random forests and Bayesian probit regression with non-local priors. We estimated classification performance via leave-one-out cross validation. Results: By Chi-Squared analysis we found over a dozen biomarkers associated with response, and a dozen biomarkers associated with toxicity. These included germ-line mutations in 3’ untranslated regions as well as in miRNA promoter regions. We found that both classification trees and Bayesian probit compared reasonably well with random forests. We found a response signature with a specificity of 89% by Random Forests, and a toxicity signature with a specificity of 76% by Random Forests. Conclusions: We have shown that a new class of germ-line mutations disrupting miRNA regulatory networks can act as biomarkers of response and toxicity to anti-PD1 and anti-PDL1 therapy.
Abstract 18557: Low Galectin-3 Identifies Heart Failure Patients at Minimal Risk for Death or Rehospitalization
Authors: Wouter C Meijers, Rudolf A de Boer, Dirk J van Veldhuisen, Tiny Jaarsma, Alan S Maisel, Salvatore D Somma, W. F Peacock
Journal: Circulation (2014)

Introduction: Acute heart failure (AHF) patients have a very high mortality and unplanned hospital readmission rate approaching 25% within 30 days, up to 30% within 90 days. Stratification tools that predict a (very) low risk for mortality or rehospitalization would be potentially useful as such patients may be discharged early. We aimed to determine if the emerging biomarker galectin-3 could identify AHF patients at low risk for death or rehospitalization compared to BNP after discharge. Methods: This was a substudy of the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). Enrollment of AHF patients occurred prior to discharge. We evaluated the relationship between percentiles of galectin-3 (and BNP) and the prediction of low risk in 592 patients. Results: In this cohort, the median [IQR] age, BNP and left ventricular ejection fraction were 73 years [64-79], 448 pg/mL [197-911], and 30% [23-43], respectively. Overall, the median [IQR] galectin-3 level was 20 ng/mL [15-26], with a maximum of 67 ng/mL. Patients with elevated galectin-3 levels had more severe disease, reflected by higher age, worse renal function, and higher BNP. No patient died within 30, 90 or 180 days with a galectin-3 level &lt;11.8 ng/mL (10th percentile). No patient below this value was rehospitalized during 90 days follow-up and only one patient within 180 days. In comparison, the 10% lowest BNP levels (&lt;96 pg/mL) failed to identify patients who died (N=7) or were rehospitalized (N=8) within 180 days. Also in higher percentiles (20-50th), galectin-3 remained superior over BNP in identifying low risk patients. We created a cox-hazard regression model, and this showed that galectin-3 level &lt;11.8 remained a significant predictor of death or rehospitalization, also after adjustment for age, sex, (log) BNP, eGFR, NYHA class and LVEF: HR (CI) 0.32 (0.15-0.70); p&lt;0.01). On top of these predictors for outcome, galectin-3 &lt;11.8 ng/mL added significantly to the receiver operator characteristic curve for the composite outcome of 180 day death and rehospitalization (p&lt;0.05). Conclusion: A galectin-3 level &lt;11.8 ng/mL identifies discharged AHF patients without 30, 90 and 180 day mortality, and with a minimal risk for repeated HF rehospitalization.
Response to first-line chemotherapy regimen to predict efficacy of nivolumab in lung cancer.
Authors: Coureche Guillaume Kaderbhai, Corentin Richard, Jean david Fumet, Anne Aarnink, Sandra Ortiz-Cuaran, Maurice Perol, Pascal Foucher, Bruno P. Coudert, Laure Favier, Aurelie Lagrange, Emeric Limagne, Paul Hofman, Pierre Saintigny, Francois Ghiringhelli
Journal: Journal of Clinical Oncology (2017)

3026 Background: Nivolumab is a monoclonal antibody, targeting PD-1 receptor and demonstrating durable clinical benefit in 20% of metastatic NSCLC patients in second and further treatment lines. The expression of one of the PD-1 ligand, PD-L1 assessed by IHC is associated with better outcome. However, robust predictive markers of efficacy are lacking. Methods: 115 pts with stage IV NSCLC (42 squamous, 73 adenocarcinoma) were included in this retrospective study in 4 different institutions. They received nivolumab (3 mg/kg IV Q2W) after at least one line of systemic platinum-based chemotherapy. Response to first line chemotherapy and to nivolumab (RECIST 1.1) was determined on CT scan by two physicians. Association between best response to first-line regimen and PFS, OS or response to nivolumab was determined using both Chi2 and Cox analysis. Results: 46 (40%), 44 (38%) and 25 (22%) patients experimented PR, SD and PD to first-line platinum-based chemotherapy. 25 (22%), 34 (29.5%), 56 (48.5%) experimented PR, SD and PD to nivolumab. 59.5% (53/89) of patients who experimented clinical benefit (SD+PR) to first-line also experimented clinical benefit to nivolumab while only 20% (5/25) of patients with PD as best response to chemotherapy experimented clinical benefit to nivolumab (Chi2 test p = 0.002). The type of first-line doublet chemotherapy did not influence the response rate to nivolumab. Cox uni and multivariate models included age, histology and performance status underlined that patients with clinical benefit from chemotherapy had improved PFS with nivolumab (P = 0.002) (median PFS on nivolumab regimen of 4.9, 3.3 and 1.8 months for patients with PR, SD and PD to first-line, respectively). Similar results were obtained for OS (P = 0.03). Conclusions: Our data suggest that response to first-line chemotherapy may be a good surrogate marker of response, PFS and OS to post-platinum nivolumab in metastatic NSCLC.
Randomized trial of an inpatient palliative care intervention in patients hospitalized for hematopoietic stem cell transplantation (HCT).
Authors: Areej El-Jawahri, Thomas William LeBlanc, Lara Traeger, Harry VanDusen, Vicki A. Jackson, Joseph A. Greer, William F. Pirl, Jason Telles, Alison Rhodes, Thomas R. Spitzer, Yi-Bin Albert Chen, Stephanie Lee, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2016)

10004 Background: During hospitalization for HCT, patients experience physical and psychological symptoms that contribute to a substantial deterioration in their quality of life (QOL). Palliative care is rarely consulted to assist with symptom management in patients with hematologic malignancies. We assessed the impact of an inpatient palliative care intervention on patient-reported QOL, mood, and symptom burden during hospitalization for HCT. Methods: We randomly assigned 160 patients with hematologic malignancies admitted for autologous or allogeneic HCT to an inpatient palliative care intervention (n = 81) integrated with standard transplant care compared to standard transplant care alone (n = 79). We used the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) to assess QOL, the Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire (PHQ-9) to assess mood, and Edmonton Symptom Assessment Scale (ESAS) to measure symptom burden at baseline and week-2 of HCT hospitalization. We compared changes in patient’s QOL, mood, and symptom burden from baseline to week-2 between the study arms using a two-sample t-test. Results: Between 8/1/2014 and 1/15/2016, we enrolled 160/186 (86%) of potentially eligible patients undergoing HCT. Patients randomized to the palliative care intervention (vs. control) reported less decline in QOL (-14.7 vs. -21.5, P = 0.04), and less increase in depression symptoms (HADS-Depression: 2.4 vs. 3.9, P = 0.02), and symptom burden (ESAS: 30.3 vs. 38.3, P = 0.007) from baseline to week-2. Intervention participants reported a decline in anxiety symptoms compared to control patients who reported an increase in anxiety from baseline to week-2 (HADS-Anxiety: -0.80 vs. 1.1, P = 0.0006). There were no significant differences in PHQ-9 between the study arms. Conclusion: Palliative care improved QOL, decreased depression, anxiety, and symptom burden in patients with hematologic malignancies hospitalized for HCT. Involvement of palliative care for patients with hematologic malignancies can improve their outcomes and substantially reduce the physical and psychological burden experienced during HCT. Clinical trial information: NCT02207322.
White matter changes in primary central nervous system lymphoma patients treated with high-dose methotrexate with or without rituximab.
Authors: Fayez Estephan, Xiaobu Ye, Stuart A. Grossman, Doris D. Lin, Matthias Holdhoff
Journal: Journal of Clinical Oncology (2018)

e14038 Background: White matter changes (WMC) can develop following systemic chemotherapy and may be associated with neurocognitive decline. High-dose methotrexate (HD-MTX) is the most commonly used chemotherapeutic agent for primary central nervous system lymphoma (PCNSL), and combination with rituximab (R) is common. We aimed to determine rate and grade of WMC in PCNSL patients treated with HD-MTX-R or HD-MTX alone. Methods: MRI scans of patients with newly-diagnosed PCNSL treated with either HD-MTX-R (1995-2008) or HD-MTX (2008-2017) at Johns Hopkins were retrospectively reviewed for development of WMC. Patients had serial MRIs including a baseline and post treatment exams. Severity of WMC on FLAIR MRI was assessed by a neuroradiologist blinded to treatment arm and clinical status. A WMC grade of 1-4 (minimal to severe) was assigned for each cerebral hemisphere and then summed. Results: Forty-seven patients with newly-diagnosed PCNSL, treated with HD-MTX-R (n = 34; median age 66, 50% male) or HD-MTX (n = 13; median age 53, 54% male) were included. WMC were detected 62% of all and in 68% of patients in the HD-MTX-R, and 46% in the HD-MTX group. Among the patients who did develop WMC (n = 29), these were first detected in the MTX-R group at a median of 2.8 months and in the MTX group 10.7 months following treatment initiation. Average WMC non-zero scores when first detected were 2.5 (±1.1) in HD-MTX-R and 1.5 (±0.6) in HD-MTX. Among these patients, the average WMC score was higher in HD-MTX-R compared to HD-MTX (p = 0.04). The average age of all patients with WMC versus without WMC was similar with 62 years versus 58 years, respectively (p = 0.4). Conclusions: Development of WMC in PCNSL patients treated with MTX and MTX-R is common. Based on this limited retrospective pilot study, WMC changes appear to be more frequent, occur earlier and are more extensive in patients treated with HD-MTX-R compared to HD-MTX. Further studies are needed to determine the underlying mechanism and clinical consequences of these new observations.
Differences in genomic signatures and opportunities for targeted and immunotherapy treatment between castrate-resistant <i>TMPRSS2:ERG</i> fusion-positive and -negative refractory acinar (CRPC) and neuroendocrine prostate cancer (CRNEPC).
Authors: Leszek Kotula, Gennady Bratslavsky, Hugh A.G. Fisher, Timothy Byler, Robert John Corona, Joseph Jacob, Alina Basnet, Jon Chung, Julia Andrea Elvin, Jo-Anne Vergilio, James Suh, Shakti H. Ramkissoon, Sugganth Daniel, Eric Allan Severson, Alexa Betzig Schrock, Siraj Mahamed Ali, Vincent A. Miller, Laurie M. Gay, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

5061 Background: We hypothesized that sub-categorization of TMPRSS2 fusion status would impact therapy opportunities in patients with clinically advanced CRPC and CRNEPC. Methods: CGP was performed on FFPE samples of 2,424 CRPC and 143 CRNEPC. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined by principal components analysis of optimal homopolymer loci. Results: All (100%) CRPC and CRNEPC were advanced and therapy resistant. TMPRSS2+ CRPC features significantly more TP53 and PTEN GA, whereas TMPRSS2- CRPC featured more MYC and ATM GA; differences in BRCA2 and RB1 GA were not significant. RB1 GA were significantly more frequent in CRNEPC than CRPC, whereas GA in AR and ATM were more frequent in CRPC. TP53 GA frequencies were higher in TMPRSS2+ CRNEPC than in TMPRSS+ CRPC, whereas GA in PTEN and MYC were similar in comparative groups. Median TMB was higher in CRNEPC than CRPC, and higher in TMPRSS2- compared with TMPRSS+ tumors; TMB was more often ≥10 or ≥20 mut/Mb in TMPRSS2- tumors. MSI-High status was more frequently identified in the TMPRSS2- CRPC and CRNEPC groups. Conclusions: The 31% frequency of TMPRSS2+ CRPC in this study, lower than the 46% reported in early stage disease (TCGA data) suggests that this biomarker may be linked to a favorable prognosis. For CRNEPC, the higher frequency of TMPRSS2- tumors is not as striking. CGP reveals significant differences in both targetable GA and markers of immunotherapy response between TMPRSS+ and TMPRSS2- prostate tumors. TMPRSS2:ERG+ CRPC (755) TMPRSS2:ERG- CRPC (1,669) Significance TMPRSS2:ERG+ CRNEPC (57) TMPRSS2:ERG- CRNEPC (86) Significance Median Age (years) 66 65 64 66 GA/tumor 4.5 4.3 NS 4.9 5.3 NS TP53 55% 39% P < 0.0001 60% 65% NS PTEN 45% 27% P < 0.0001 51% 25% P < 0.0001 AR 25% 22% NS 11% 10% NS MYC 9% 14% P = 0.0004 9% 11% NS BRCA2 8% 10% NS 7% 14% NS ATM 4% 7% P = 0.0032 0% 5% NS RB1 8% 6% NS 58% 52% NS MSI-High 1% 3% P = 0.01 0% 3% NS TMB median (mut/Mb) 1.7 2.7 NS 2.7 3.6 NS TMB ≥ 10 mut/Mb 3% 6% P = 0.04 2% 18% P = 0.003 TMB ≥ 20 mut/Mb 2% 4% P = 0.01 2% 7% NS
NHS staff get online service to voice concerns about working conditions
Authors: Gareth Iacobucci
Journal: BMJ (2018)

NHS staff in England will be able to voice concerns and air their frustrations about working conditions through a new online service launched by the government this week.

The Department of Health and Social Care is inviting 3.1 million NHS and social care staff in England to post ideas, questions, and challenges through the new digital service, called Talk Health and Care (https://dhscworkforce.crowdicity.com).

The secretary for …