tbuckley/cabot-search huggingface dataset:
Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with <i>EGFR</i>-mutant lung cancers.
Authors: Adam Jacob Schoenfeld, Joseph Minhow Chan, Hira Rizvi, Natasha Rekhtman, Yahya Daneshbod, Daisuke Kubota, Jason C. Chang, Maria E. Arcila, Marc Ladanyi, Romel Somwar, Mark G. Kris, Dana Pe'er, Gregory J. Riely, Helena Alexandra Yu
Journal: Journal of Clinical Oncology (2019)

9028 Background: Even though osimertinib (osi) is now the initial treatment for patients with EGFR-mutant lung cancers, our knowledge about mechanisms of resistance (MOR) is largely derived from patients who received osi after developing acquired resistance to initial EGFR inhibitor. Further, studies of osi resistance to date have mainly reported genotyping of plasma which suboptimally detects lineage plasticity, copy number changes, and chromosomal rearrangements. Methods: To identify MOR to osi and characterize clinical, molecular and histologic factors associated with duration of response, we identified patients with EGFR-mutant lung cancers who had next-generation sequencing performed on tumor tissue after developing acquired resistance to osi. Results: From January 2016 to December 2018, post-osi tumor tissue was collected from 71 patients (42 with paired pre-treatment specimens). See mechanisms of resistance below. Histologic transformation was identified in 19% of initial cases and 14% of all cases. When osi is given as initial treatment, with median follow up of 17 months, early emerging MOR rarely included on-target resistance mechanisms (1/16 cases of acquired EGFR G724S). Acquired alterations representing potential resistance mechanisms included CCNE1 and MYC amplifications, and mutations in MTOR and MET H1094Y. We confirmed in preclinical studies that an amino acid substitution at MET H1094 can reduce sensitivity to osi. Conclusions: In this analysis of MOR identified on NGS from tumor tissue, we found a different spectrum of resistance mechanisms to initial and later-line osi, with histologic transformation (including squamous cell transformation) a dominant MOR, particularly in the first-line setting, that cannot be identified on plasma testing. Subsequent studies are needed to assess patients with a longer time on initial osi as there may be a temporal bias to MOR, with off-target MOR emerging earlier and on-target resistance mutations later. [Table: see text]
Differences in breast cancer outcomes amongst Black United States-born and Caribbean-born immigrants.
Authors: Priscila Barreto Coelho, Danielle Cerbon, Matthew Schlumbrecht, Carlos Parra, Judith Hurley, Sophia George
Journal: Journal of Clinical Oncology (2019)

1088 Background: The Black population in the US constitutes of 4 million immigrants, with 50% from the Caribbean. It has been shown that breast cancer is responsible for 14%-30% of cancer deaths in the Caribbean; this is up to two times higher than the USA. Methods: Retrospective cohort of 1369 self-identified Black women with breast cancer. Data was obtained from Jackson Memorial Health Systems and University of Miami Health System Tumor Registry. Individual-level data from 1132 cases was used to estimate hazard rations (HRs) of women born in the Caribbean (CB) or in the USA (USB) using Cox proportional hazards regression analysis for overall survival. Median follow-up was 115 months (interquartile range, 91.9-138.1 months) per participant. Results: Data from 622 (54.9%) USB women and 507 (45%) CB women diagnosed with breast cancer between 2006-2017. 90% (n = 1232) of the cohort is of non-Hispanic ethnicity. Caribbean immigrants from Haiti (18.3%), Jamaica (6.5%), Bahamas (3.1%), Cuba and Dominica Republic (2.8% each), Trinidad and Tobago (1%) and other nationalities from the Organization of Eastern Caribbean States were included, mean age 55.7 [95% CI, 54.7-56.8]; USB mean age 57.6 [95% CI, 56.4-58.7] (P = 0.02). Compared to USB, CB had lower BMI at diagnosis 29.6 [95% CI, 28.9-30.3] versus 30.9 [95% CI, 30.1-31.7, P = 0.015]. Compared to CB patients, USB patients had more ER- [31.4% vs 39.1 %, P = 0.018] and triple negative breast cancers [19.6% vs 27.9%, P = 0.003]. Compared to USB patients, CB presented at more advanced stage, III and IV [44.2% vs 35.2%], p = 0.016. In spite of higher advanced stage at diagnoses, CB patients had a better breast cancer overall survival [HR = 0.75; 95%CI, 0.59-0.96; P = 0.024]. Black Hispanic patients had a better overall survival [HR = 0.51; 95%CI, 0.28-0.93; p = 0.028] compared to non-Hispanic Blacks. Compared to Hispanic Caribbean, non-Hispanic Caribbean had a worse overall survival [HR = 1.98; 95%CI, 1.00-3.94; P = 0.048]. The distribution of patients treated at the private cancer center and the safety net hospital were the same, differences in outcomes observed are due to intrinsic differences. Conclusions: This is the largest analysis to date of self-identified Black breast cancer patients in the context of nativity, race, ethnic identity and overall survival with clinico-pathologic characteristics. CB immigrants diagnosed with breast cancer have a better overall survival than US born Black patients. This finding suggests that within the African diaspora in the USA, additional factors beyond race contribute to the outcomes.
AB0685 ACROOSTEOLYSIS AND BONE METABOLISM PARAMETERS DISTINGUISH FEMALE PATIENTS WITH LIMITED SYSTEMIC SCLEROSISWITH AND WITHOUT CALCINOSIS: A CASE CONTROL STUDY
Authors: Marilia Sampaio-Barros, Lorena Castelo Branco, Liliam Takayama, Marco antonio G Pontes Filho, Percival D. Sampaio-Barros, Rosa M. Pereira
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Calcinosis represents a late manifestation of limited systemic sclerosis (lSSc), inducing tissue damage and chronic calcifications. Bone metabolism studies in lSSc patients are rare in literature and there are few studies that analyzed clinical, laboratory and bone mineral density (BMD) parameters together. <h3>Objectives:</h3> The aim of this study was to compare and analyze clinical aspects and laboratory parameters, including bone metabolism variables in female lSSc patients with and without calcinosis, paired by age, disease duration and body mass index (BMI). <h3>Methods:</h3> Thirty-six female lSSc patients with calcinosis were compared to 36 female lSSc patients without calcinosis, matched by age, disease duration and BMI. Organ involvement, autoantibodies, BMD by DXA and laboratory parameters were analyzed. The past and current treatment modalities were also questioned. Statistical significance was considered if p&lt;0.05. <h3>Results:</h3> Esophageal hypomotility, digital ulcers, and interstitial lung disease were the most frequent clinical manifestations of lSSc patients, present in similar frequency in both groups. Calcinosis was significantly associated with acroosteolysis (69% vs. 22%, p&lt;0.001), higher modified Rodnan skin score (mRSS: 4.28±4.66 vs 1.17±2.50, p&lt;0.001), higher 25OHD (24.46±8.15 vs. 20.80±6.60ng/ml, p=0.040) and phosphorus (3.81±0.41 vs. 3.43±0.45mg/dl; p&lt;0.001) serum levels. 25OHD levels &gt;30ng/ml were also significantly more frequent in patients with calcinosis (p=0.041). ANA was positive in 89% in both groups. Anticentromere antibody was frequent (44% and 31%), while positive anti-Scl70 was rare in both groups. Regarding treatment, current use of corticosteroids was lower in patients with calcinosis compared to patients without calcinosis (8% vs. 28%; p=0.032). Osteoporosis was more frequent in the group with calcinosis (31% vs.17%), although not statistically significant. <h3>Conclusion:</h3> This study showed that lSSc patients with calcinosis can present a distinct clinic and biochemical profile when compared to a matched group without calcinosis. Presence of calcinosis in female patients with lSSc can be associated with acroosteolysis and higher serum levels of 25OHD and phosphorus when compared with patients without calcinosis paired by age, disease duration and BMI. <h3>Disclosure of interests:</h3> MARILIA SAMPAIO-BARROS: None declared, LORENA CASTELO BRANCO: None declared, LILIAM TAKAYAMA: None declared, Marco antonio G Pontes Filho Speakers bureau: Novartis and Janssen, Percival D. Sampaio-Barros: None declared, Rosa M. Pereira: None declared
Myopenia as a significant prognostic factor in BCLC-B intermediate-stage hepatocellular carcinoma treated with sorafenib.
Authors: Mao Okada, Hiroyuki Nakanishi, Masayuki Kurosaki, Sakura Kirino, Leona Osawa, Keiya Watakabe, Wan Wang, Takao Shimizu, Kenta Takaura, Hitomi Takada, Shun Kaneko, Nobuharu Tamaki, Yutaka Yasui, Kaoru Tsuchiya, Jun Itakura, Yuka Takahashi, Namiki Izumi
Journal: Journal of Clinical Oncology (2019)

e15639 Background: Tyrosine kinase inhibitors (TKI) are important treatment options for unresectable hepatocellular carcinoma (HCC). The survival benefit of sorafernib was demonstrated not only in advanced stage but also for BCLC-B intermediate stage who are refractory to transcatheter arterial chemoembolization by OPTIMIS study. Skeletal muscle mass depletion (Myopenia) is a poor prognostic factor in HCC treated by resection or loco-reginal ablation, but its effect on survival in TKI treated patients, especially in those within BCLC-B stage remains unclear. The aim of the present study is to elucidate the impact of myopenia on survival among HCC treated with sorafenib, especially in BCLC-B stage. Methods: In 213 patients who started treatment with sorafenib between 2009 and 2016, myopenia at baseline was determined by using skeletal muscle index calculated from CT images of the third lumber vertebra level. The impact of myopenia on survival was analyzed in whole patients, after stratification by BCLC stage, and after matching for backgrounds within BCLC-B patients. Results: The median survival in whole, BCLC-C, and –B was 13.7, 8.7 and 15.2 months, respectively. Myopenia was not a significant prognostic factor in whole patients and in BCLC-C stage. However, among BCLC-B patients (n = 104), survival was significantly better in patients with no myopenia (p = 0.05). Among them, 85 patients who continued sorafenib for more than 8 weeks were extracted and those with or without myopenia were matched for backgrounds by propensity score. Backgrounds including etiology, Child-Pugh score, BMI, AFP and PIVKA-Ⅱwas not different between myopenia (n = 30) and no myopenia group (n = 30) after matching. The overall survival at 6-, 12-, and 24-months was 96%, 74%, and 62% in no myopenia group which was significantly better compared to 89%, 64%, and 28% in myopenia group (p = 0.019). The hazard ratio was 2.12 (95% CI 1.11-4.03). Conclusions: Absence of myopenia predicts favorable outcome in sorafenib treated HCC patients within BCLC-B intermediate stage.
Cytopenia following axicabtagene ciloleucel (axi-cel) for refractory large B-cell lymphoma (LBCL).
Authors: Jennifer Marilyn Logue, Gabriel S Krivenko, Victoria Larson, Christina A Bachmeier, Julio C. Chavez, Marco L. Davila, Farhad Khimani, Aleksandr Lazaryan, Hien D Liu, Javier Pinilla-Ibarz, Bijal D. Shah, Bhagirathbhai R. Dholaria, Michael D. Jain, Frederick Lundry Locke
Journal: Journal of Clinical Oncology (2019)

e14019 Background: Axi-cel is an anti-CD19 CAR T-cell therapy that can lead to long term disease control for patients with refractory LBCL including DLBCL, PMBCL, HGBL, and tFL. Beyond day 30, grade 3 or higher cytopenias were reported in 17% of patients (Locke 2019). We sought to further characterize cytopenias after axi-cel. Methods: We evaluated patients with LBCL treated with axi-cel at Moffitt from May 2015 to May 2018. Counts at apheresis and days 30, 90 and 180 after axi-cel infusion were recorded. Data was censored at date of progression, death or last follow-up. AEs were per CTCAE v4.03. Results: 52 patients were identified. Count data at each time is presented in the table. In total, 37.8% (17/45), 17.8% (8/45), and 28.9% (13/45) of patients experienced any grade 3-4 neutropenia, anemia or thrombocytopenia beyond day 30. Beyond day 30: 24.4% (11/45) received G-CSF; one (2.2%) received a TPO-agonist; none received an EPO-agonist; 15.6% (7/45) IVIG; 11.1% (5/45) PRBC; and 8.9% (4/45) platelet transfusion. 11 patients had bone marrow biopsies to evaluate cytopenias, at a median of 50 days (range 29-434) following axi-cel infusion. Median cellularity was 16.3% (range 5-45%), and 3/11 had reticulin staining indicating fibrosis. One patient, previously reported (Locke, Mol. Ther, 2017), had therapy related MDS and evidence of prior CHIP mutation. Conclusions: Prolonged neutropenia, lymphopenia, anemia, and thrombocytopenia occurred at least 180 days following axi-cel therapy in LBCL patients, in the absence of disease progression. Transfusion burden was low, and most patients recovered without an intervention.[Table: see text]
Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase III study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: The PROOF trial
Authors: G.K. Abou-Alfa, I. Borbath, S.J. Clarke, E. Hitre, C. Louvet, T. Macarulla, D.-Y. Oh, J.L. Spratlin, J.W. Valle, K.H. Weiss, C. Berman, M. Howland, Y. Ye, T. Cho, S. Moran, M.M. Javle
Journal: Annals of Oncology (2019)
Real-world assessment of practice efficiency with the introduction of subcutaneous rituximab.
Authors: Annie Qiu, Sheila Shapouri, Esther N. Drill, Jake Schade, Arliene Ravelo, Ai Ni, Tu My To, Keith Lamont Dawson, Matthew J. Matasar
Journal: Journal of Clinical Oncology (2019)

e18025 Background: Rituximab (R), available as an intravenous (IV; R-IV) infusion or subcutaneous (SC; R-SC) injection, is used in the treatment of follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). This study evaluated real-world practice efficiency changes associated with the adoption of R-SC by studying differences in chair time by route of administration. Methods: We conducted a retrospective analysis of practice care delivery measures before and after adoption of R-SC at Memorial Sloan Kettering Cancer Center (MSKCC). Data for patients (pts) with FL, DLBCL, or CLL receiving R-based therapy from September 2016 to September 2018 were extracted from the electronic medical record. A linear mixed effect multivariate model with random intercept was used to analyze the association between treatment type (R-IV vs R-SC) and chair time (defined as the difference in pt room-in and room-out times) in the year prior to and following R-SC adoption at MSKCC. Model covariates included treatment time and location, therapy type (monotherapy vs combination), and pt demographics. Given the prolonged infusion time, patients’ first dose of R-IV was excluded from the analysis. Results: Data were collected during 6744 visits (3018 visits prior to R-SC adoption and 3726 after) for 1503 pts receiving R. Pts receiving R-IV combination therapy had a mean chair time of 203 minutes (min); overall, R-SC injection reduced chair time by a mean of 92 min (p &lt; 0.001 vs R-IV). Monotherapy, regardless of route, reduced chair time by a mean of 30 min (p &lt; 0.001) compared with combination therapy, and mean chair time was further reduced by 39 min (p &lt; 0.001) for R-SC pts receiving monotherapy. Reductions in chair time increased over time following initial adoption of R-SC (p = 0.042), and were greater at the lymphoma-specific site than multispecialty oncology infusion centers (p &lt; 0.001). Conclusions: Adoption of R-SC results in substantial time savings for both the pt and health system as measured by reduced chair time and improved pt throughput. Given increasing constraints on infusion chair space, increased utilization of R-SC may improve practice efficiency and pt access to care.
VONC: A solution for the clinical assessment of somatic genomic alterations.
Authors: Robert Kueffner, Hui Li, Kakit Cheung, Marc Fink, Zachry Soens, Jinlian Wang, Osman Siddiqui, Umadevi Thiumurthi, Andrew Uzilov, Chunying Song, Joaquin Villar, Andrew Pollock, Bharath Jeganathan, Michelle Zimmermann, Nefize Sertac Kip, Michael Rossi, Eric Schadt, Dan Li, Feras Hantash, Rong Chen
Journal: Journal of Clinical Oncology (2019)

e13155 Background: Next generation sequencing (NGS) technology is transforming the diagnosis and treatment of cancer. However, the massive scale of data has overwhelmed pathologists who need streamlined tools to process this data, automate report generation and minimize human errors. Methods: We developed the Variant interpretation station for ONCology, VONC, as an end-to-end solution for moving from NGS whole exome and transcriptome data to actionable clinical reports that support cancer diagnosis, prognosis, and personalized treatment strategies for solid and hematologic malignancies. Results: VONC integrates all steps for moving from raw NGS data, variant calling and LIMS, to comprehensive annotation of variants. The main functional feature of VONC is a transparent process that effectively combines automated and expert curation to identify clinically relevant and actionable driver variants. VONC also enables efficient management of multi-group, -role, -system and -site curation processes. In contrast to current tools, VONC handles all somatic and constitutional genomic alterations including SNV, indel, CNV, fusion, splicing, and gene expression. Key data sources include 1) 350,000 variants for 50 tumor types across 57,000 sequenced cancer patients; 2) variant frequencies estimated from 1.5M cancer patients; 3) expert curated literature evidence from 16,818 papers covering 26,496 alterations spanning 2,448 cancer driver genes; and 4) curated database of FDA-approved drugs and recruiting clinical trials. VONC presents a prioritized list of variants in oncogenes and tumor suppressors through functional (literature-based) and structure-based (hotspots) algorithms. This is coupled to all supporting information necessary for clinical decision making. Curators can quickly screen variant type, QC metrics, and frequency in sequencing cohorts of cancer patients as well as healthy subjects. Within minutes, variants can be triaged and annotated with FDA approved, NCCN guidelines reported, or literature supported therapeutics, including resistance and contraindicated. Conclusions: VONC is a clinically-ready tool with an intuitive end-user interface tailored for the rapid assessment of variants in cancer patients, to facilitate personalized cancer medicine in a high-throughput laboratory.
Utilizing data from patient-derived xenograft mouse models of human tumors to inform clinical decision making in Molecular Tumor Boards (MTB) deliberations.
Authors: Jens Rueter, Susan D. Airhart, Carol J. Bult, Emily Jocoy, Kyle Draheim, Mingshan Cheng, Andrey Antov, Andrew Hesse, Honey Reddi, Derrick S. Haslem, Terence Duane Rhodes, Lincoln Nadauld
Journal: Journal of Clinical Oncology (2019)

e14660 Background: Molecular Tumor Boards (MTB) are often the critical decision-making step in identifying genome-guided treatments for patients with difficult-to-treat cancers, e.g. BRAF mutated metastatic colon cancers. A common challenge for MTBs is prioritizing between two or more actionable variants in a tumor. A potential solution to this challenge is to incorporate drug response in Patient-derived xenografts (PDX) models into MTB deliberations. The goal of this study was to evaluate the feasibility of using PDX models to elucidate drug-effectiveness in BRAF-mutated cancer as an example of a common clinical scenario. Methods: We selected BRAF-mutated PDX models from the JAX PDX resource based on the presence of an activating BRAF mutation and a second actionable variant from the JAX Cancer Treatment Profile (CTP). Somatic mutation data from PDX tumors were presented to members of the Intermountain MTB. PDX models were then treated with drugs recommended by the MTB; outcomes based on tumor growth inhibition (TGI) were shared with the MTB. Results: Gene/variant targets, associated drugs for the 2 nd mutation and responses are described in the table. The MTB members determined that PDX data presented in TGI format is helpful in MTB deliberations. Activity of BRAF-targeted therapy was expected while the low activity of olaparib in the BRCA1-mutated colon cancer model was unexpected. The MTB then discussed molecular mechanisms that contributed to these outcomes. Conclusions: The pilot study demonstrated that utilizing PDX drug response data as an additional molecular annotation for MTB deliberations is feasible. Future studies will further optimize this process. [Table: see text]
Paediatric and adult-onset male hypogonadism
Authors: Andrea Salonia, Giulia Rastrelli, Geoffrey Hackett, Stephanie B. Seminara, Ilpo T. Huhtaniemi, Rodolfo A. Rey, Wayne J. G. Hellstrom, Mark R. Palmert, Giovanni Corona, Gert R. Dohle, Mohit Khera, Yee-Ming Chan, Mario Maggi
Journal: Nature Reviews Disease Primers (2019)
SP0033 RHEUMATOLOGICAL REHABILITATION, WHAT”S NEXT
Authors: Thea Vliet Vlieland
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Over the past years, there have been major changes in the delivery of rheumatology rehabilitation and advances in its evidence base. To make rheumatology rehabilitation future-proof, a number of developments in the medical treatment of people with rheumatic and musculoskeletal diseases (RMDs), health systems and society as a whole need to be taken into account with the planning of services and their evaluation and the training of health professionals in rheumatology (HPRs). Regarding the health status and needs of people with RMDs, their profile has changed markedly over the past decades, to a large extent due to improvements in the medical treatment. But some patients may not respond well to treatment, and for those who do, there may still be challenges to keep up with the increasing demands of our society. For reasons of transparency, quality and efficiency there is a need to demonstrate the added value of rehabilitation, by working along defined rehabilitation care pathways. But care also needs to be personalized, tailored to a person"s individual situation, abilities and needs. This includes, among others, that people with RMDs must be involved in any treatment decision, requiring a specific level of health literacy. The actual delivery of rehabilitation services by means of extensive inpatient or outpatient trajectories is under pressure in many health care systems, for economic reasons but also because treatment in one"s own environment whenever possible, is preferred by many people with RMDs. For that purpose, adequate use of digital interventions, but also seamless care involving primary care clinicians with specific expertise is needed. All of the abovementioned developments require specific competences of HPRs, not only including the optimal assessment and treatment of individual people with RMD, but also makes a strong appeal to e.g. their communication, advocacy and organizational skills and abilities to monitor the quality of their practices and re-design when needed. This presentation addresses current and future challenges for HPRs in rheumatology rehabilitation and how they can anticipate to be prepared for the next phase. <h3>Disclosure of Interests:</h3> None declared