tbuckley/cabot-search huggingface dataset:
Functional Consequences of Mutations in Myeloproliferative Neoplasms
Authors: Stefan N. Constantinescu, William Vainchenker, Gabriel Levy, Nicolas Papadopoulos
Journal: HemaSphere (2021)

Driver mutations occur in Janus kinase 2 ( JAK2 ), thrombopoietin receptor ( MPL ), and calreticulin ( CALR ) in BCR-ABL1 negative myeloproliferative neoplasms (MPNs). From mutations leading to one amino acid substitution in JAK2 or MPL, to frameshift mutations in CALR resulting in a protein with a different C-terminus, all the mutated proteins lead to pathologic and persistent JAK2-STAT5 activation. The most prevalent mutation, JAK2 V617F, is associated with the 3 entities polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF), while CALR and MPL mutations are associated only with ET and MF. Triple negative ET and MF patients may harbor noncanonical mutations in JAK2 or MPL . One major fundamental question is whether the conformations of JAK2 V617F, MPL W515K/L/A, or CALR mutants differ from those of their wild type counterparts so that a specific treatment could target the clone carrying the mutated driver and spare physiological hematopoiesis. Of great interest, a set of epigenetic mutations can co-exist with the phenotypic driver mutations in 35%–40% of MPNs. These epigenetic mutations, such as TET2 , EZH2 , ASXL1 , or DNMT3A mutations, promote clonal hematopoiesis and increased fitness of aged hematopoietic stem cells in both clonal hematopoiesis of indeterminate potential (CHIP) and MPNs. Importantly, the main MPN driver mutation JAK2 V617F is also associated with CHIP. Accumulation of several epigenetic and splicing mutations favors progression of MPNs to secondary acute myeloid leukemia. Another major fundamental question is how epigenetic rewiring due to these mutations interacts with persistent JAK2-STAT5 signaling. Answers to these questions are required for better therapeutic interventions aimed at preventing progression of ET and PV to MF, and transformation of these MPNs in secondary acute myeloid leukemia.
Frequency of longitudinal changes in <i>TP53</i> mutation status from gene sequencing of serial tumor biopsies from a large cohort of cancer patients.
Authors: D. Allen Allen Annis, Dean C. Pavlick, Garrett M. Frampton, Lee A. Albacker, Vojislav M. Vukovic, Manuel Aivado
Journal: Journal of Clinical Oncology (2021)

3124 Background: The p53 pathway is one of the most important in cancer biology, with mutation of the TP53 gene that encodes the p53 tumor suppressor protein observed in ≈50% of all cancers. We evaluated the frequency of changes in TP53 mutation status in a large cohort of serial tumor biopsies. Methods: From a database of &gt;200,000 next-generation gene sequencing results we identified 16,592 samples arising from repeat biopsies from 7840 patients (pts), average 2.12 per pt, 1007 pts with ≥3, max 11; over an interval up to 234 months (mos), average 11.0 mos. TP53 mutations with known or unknown significance in successive biopsies and changes in assignment from TP53-Wild-Type (WT) to Mutant (Mut), or Mut to WT, were evaluated vs. cancer type and time between biopsies. Results: Table: N (%) of samples vs. change in TP53 status from previous biopsy vs. mos from initial biopsy in all samples (7840 initial + 8752 successive, 46% TP53-Mut) and the three most represented cancers: non-small cell lung cancer (NSCLC, 1189 initial + 1268 successive, 60% Mut), breast (947 initial + 993 successive, 55% Mut), multiple myeloma (MM, 578 initial + 981 successive, 18% Mut). Conclusions: Changes in TP53 status were rare (&lt;10% of samples). Differences may occur in serial biopsy samples for pathophysiological reasons, e.g., a mutant clone becoming dominant and/or heterogeneity at different tumor biopsy sites, or analytical differences in biopsy tumor content or assay sensitivity between samples. In this analysis, WT-to-Mut changes were more frequent (5.9%) than Mut-to-WT changes (3.3%), suggesting a small selection pressure for TP53 alterations later in oncogenesis and indicating that these alterations are truncal. Mut-to-WT changes are not readily explained physiologically and may suggest these infrequent changes are mostly due to sampling or analytical variability, and genuine changes in TP53 mutation status are quite rare.[Table: see text]
Randomized study to investigate FOLFOXIRI plus either bevacizumab or cetuximab as first-line treatment of BRAF V600E-mutant mCRC: The phase-II FIRE-4.5 study (AIO KRK-0116).
Authors: Sebastian Stintzing, Kathrin Heinrich, David Tougeron, Dominik Paul Modest, Ingo Schwaner, Jan Euker, Rudolf Pihusch, Martina Stauch, Florian Kaiser, Christoph Kahl, Meinolf Karthaus, Christian Mueller, Christof Burkart, Anke C. Reinacher-Schick, Stefan Kasper, Ludwig Fischer von Weikersthal, Beate Krammer-Steiner, Gerald W. Prager, Julien Taieb, Volker Heinemann
Journal: Journal of Clinical Oncology (2021)

3502 Background: FIRE-4.5 (AIO KRK-0116) compared FOLFOXIRI plus either cetuximab or bevacizumab in BRAF V600E-mutant metastatic colorectal cancer (mCRC) patients not treated for metastatic disease before. Methods: Within this 1:2 randomized, controlled, open-label phase-II study, patients received FOLFOXIRI every two weeks at the following schedule: irinotecan 150mg/m² (30-90min, day 1), folinic acid 400mg/m² (120min, day 1), oxaliplatin 85mg/m² (120 min, day 1), followed by 5-fluorouracil 3,000 mg/m², 48h. FOLFOXIRI was combined with either bevacizumab (arm A) at a dose of 5mg/kg body weight, every 2 weeks or cetuximab (arm B) at a loading dose of 400mg/m² and subsequent weekly doses of 250mg/m². FOLFOXIRI was applied for a maximum of 12 cycles before maintenance treatment was recommended. Primary endpoint was superiority of Arm B with respect to overall response rate (ORR) according to RECIST 1.1 criterions. Secondary endpoints included PFS, OS, and tolerability. Results: From November 2016 to December 2020 108 patients were randomized in 90 German and 10 French centers (35 arm A and 73 in arm B). No new or unexpected toxicities were observed. Primary endpoint was not met with an ORR of 66.7% and 52.0% (p =0.23) in the respective arms. Median PFS was significantly longer in arm A vs arm B (8.3 months vs 5.9 months; logrank p = 0.03; HR 1.8). While OS data is still immature, median OS time are comparable at the time of analysis. Patients with left-sided primary tumors had comparable results with either bevacizumab or cetuximab, whereas those with right-sided primary tumors showed a trend towards better efficacy of the bevacizumab combination. Updated results will be presented at the annual meeting. Conclusions: FIRE-4.5 is the first prospective and randomized study investigating efficacy of FOLFOXIRI combined with targeted therapy in the first-line treatment of BRAF V600E-mutant mCRC. FOLFOXIRI plus either bevacizumab or cetuximab have comparable efficacy with differential effects according to primary tumor sidedness supporting the heterogeneity of BRAF V600E-mutant subpopulation of mCRC. Clinical trial information: NCT04034459.
Risk of Subsequent Fractures in Postmenopausal Women After Nontraumatic vs Traumatic Fractures
Authors: Carolyn J. Crandall, Joseph C. Larson, Andrea Z. LaCroix, John A. Robbins, Jean Wactawski-Wende, Karen C. Johnson, Maryam Sattari, Katie L. Stone, Julie C. Weitlauf, Tanya R. Gure, Jane A. Cauley
Journal: JAMA Internal Medicine (2021)

The burden of fractures among postmenopausal women is high. Although nontraumatic fractures are strong risk factors for future fracture, current clinical guidelines do not address traumatic fractures.To determine how future fracture risk varies according to whether an initial fracture is traumatic or nontraumatic.We conducted a prospective observational study using data from the Women's Health Initiative Study (WHI) (enrollment, September 1994-December 1998; data analysis, September 2020 to March 2021), which enrolled postmenopausal women aged 50 to 79 years at baseline at 40 US clinical centers. The WHI Clinical Trials and WHI Bone Density Substudy, conducted at 3 of the clinical centers, asked participants to report the mechanism of incident fractures. Of 75 335 participants, information regarding incident fracture and covariates was available for 66 874 participants (88.8%), who comprised the analytic sample of this study. Mean (SD) follow-up was 8.1 (1.6) years.None.Incident clinical fractures were self-reported at least annually and confirmed using medical records. Participants reported the mechanism of incident fracture as traumatic or nontraumatic.Among the 66 874 participants in the analytic sample (mean [SD] age, 63.1 [7.0] years and 65.3 [7.2] years among women without and with clinical fracture, respectively), 7142 participants (10.7%) experienced incident fracture during the study follow-up period. The adjusted hazard ratio (aHR) of subsequent fracture after initial fracture was 1.49 (95% CI, 1.38-1.61). Among women whose initial fracture was traumatic, the association between initial fracture and subsequent fracture was significantly increased (aHR, 1.25; 95% CI, 1.06-1.48). Among women whose initial fracture was nontraumatic, the association between initial fracture and subsequent fracture was also increased (aHR, 1.52; 95% CI, 1.37-1.68). Confidence intervals for associations between initial fracture and subsequent fracture were overlapping for traumatic and nontraumatic initial fracture strata.In this cohort study, among postmenopausal women older than 50 years, fracture was associated with a greater risk of subsequent fracture regardless of whether the fracture was traumatic or nontraumatic. These findings suggest that clinical osteoporosis assessment should include high-trauma as well as low-trauma fractures.
Corresponding about death: Analyzing letters from patients with cancer to medical students.
Authors: Tianyi Zhang, Mekaleya Tilahun, Cynthia Perlis, Sam Brondfield
Journal: Journal of Clinical Oncology (2021)

11021 Background: Clinicians frequently discuss death and dying with patients who have cancer. However, the doctor-patient hierarchy and the unfamiliar clinical environment may prevent these patients from discussing death and dying authentically. Patients may feel more comfortable expressing themselves when given the time and space to write at home. Firefly, an award-winning program at UCSF, facilitates written correspondence between patients with cancer and medical students over the course of one year. Firefly’s archive contains thousands of patient letters and constitutes a unique resource for analyzing authentic patient expression outside of the clinical context. The aim of the current study is to improve curricula pertaining to severe illness and end-of-life by providing educators with an analysis of authentic patient perspectives about death and dying expressed in these letters. Methods: We (two medical students, an expressive artist, and an oncologist) read all Firefly letters written by patients between 2014 and 2019 and identified 12 patients whose letters meaningfully discussed death or dying. We performed a thematic analysis of these letters using the Buckman three-stage model of dying as a reference. Results: Four themes emerged: turmoil; grief; making peace; and past, present and future. The first three themes aligned with the Buckman stages. The fourth theme—past, present and future—spanned the three stages and also elaborated the Buckman model by describing multiple paths that patients may take after passing through these stages. Conclusions: The authentic ways in which patients with cancer discussed death and dying in their letters provided deep insight into their coping process. The Buckman model appears useful for framing death and dying from the patient perspective but may not fully reflect modern oncologic care in which many patients live for years beyond a severe or terminal diagnosis. Educators can use the identified themes to shape medical school curricula pertaining to severe illness and end-of-life care.
CaboRISE: A phase II study evaluating reduced starting dose and dose escalation of cabozantinib as second-line therapy for advanced HCC in patients with compensated liver cirrhosis.
Authors: Jorg Trojan, Stefan Pluntke, Florian van Boemmel, Ursula Ehmer, Thorsten Oliver Goetze, Lutz Jacobasch, Daniel Pink, Christina Kopp, Sarah Lehnerts, Johanna Riedel, Oliver Waidmann, Fabian Finkelmeier, Michael Geißler
Journal: Journal of Clinical Oncology (2021)

TPS4163 Background: The multi-targeted tyrosine kinase inhibitor cabozantinib is approved for the treatment of advanced hepatocellular carcinoma (HCC) in adults, who have previously been treated with sorafenib. In the pivotal phase 3 CELESTIAL trial a significant improvement for OS and PFS was shown for cabozantinib in comparison to placebo treated patients (Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63). However, in 62% of patients a dose reduction of cabozantinib was necessary and the median average daily dose was 35.8 mg. The discontinuation rate due to treatment-related adverse events (TRAEs) was 16% and grade 3-4 TRAEs occurred in 68% of patients. For HCC patients treated with sorafenib in first-line, a reduced starting dose of 200 mg BID was not inferior in terms of OS but showed a trend toward a decreased rate of sorafenib discontinuation (Reiss KA et al. J Clin Oncol 2017; 35:3575-3581). The aim of the CaboRISE trial is to study the effect of a reduced starting dose of cabozantinib on tolerability, safety, and efficacy. Methods: The CaboRISE trial is an open-label, single arm, multicenter phase II trial, including patients with advanced stage hepatocellular carcinoma (HCC) with compensated liver cirrhosis (Child-Pugh A) in second line treatment, after first line treatment with sorafenib or lenvatinib. Forty evaluable patients will be enrolled in the study to receive a reduced starting dose of 40 mg cabozantinib once-daily for 4 weeks and subsequent dose escalation to 60 mg cabozantinib once-daily to be maintained until disease progression or intolerable toxicities. The objective of the trial is to assess the tolerability of a reduced starting dose of cabozantinib, in order to reduce the treatment discontinuation rates due to treatment-related adverse events below 10%. Primary endpoint is the treatment discontinuation rate due to TRAEs. Secondary endpoints are overall survival, progression free survival at 10 weeks, objective response rate, time on treatment, treatment exposure, toxicity, and quality of life. Study start of the CaboRISE trial was in October 2020. By February 2021, 7 centers across Germany have been initiated and a total of 4 out of 40 planned patients have been enrolled. The study is currently ongoing. This study is financially supported by Ipsen. ClinicalTrials.gov: NCT04522908 EudraCT: 2020-000775-20. Clinical trial information: NCT04522908.
Genomic profiling of <i>KRAS</i> wide-type pancreatic ductal adenocarcinomas identifies targetable genetic alterations.
Authors: Deng Wei, Xiaomo Li, Xinsheng Zhang, Tonghui Ma, Rong Liu
Journal: Journal of Clinical Oncology (2021)

4121 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the 5-year survival of PDAC patients is below 10%. The oncogenic KRAS mutations account for about 90% of PDAC cases. Unfortunately, there is no FDA-approved targeted therapy for KRAS mutations. Therefore, the genomic profiling of KRAS wide-type PDACs can provide invaluable sights to the etiology of these patients and offer them the opportunity of precision therapy trials. Methods: To characterize actionable targets in 521 Chinese PDAC patients, deep sequencing of a 831-gene panel (OncoPanscan, Genetronhealth) was applied to assess somatic mutations of their tumor tissues including SNV, insertions/deletions, CNV and re-arrangements, as well as possible pathogenic germline variants of paired genomic DNA sample. Results: There were 89% (463/521) of patients in our PDAC cohort harbored KRAS mutations. Among the remaining 58 patients in KRAS wild-type subgroup, 33% (19/58) carried activating mutations in the RTK/Ras/MAPK pathway. Targetable BRAF mutations were seen in five (9%) patients: V600E (1/5), G464V (1/5), N486_P490del (2/5) and BRAF fusion (1/5). The frequency of BRAF mutations was 9% (5/58) in KRAS wild-type PDACs but only 0.4% (2/463) in KRAS-mutated PDACs (P &lt; 0.001). We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively. An oncogenic ERBB3 mutation (V104L) was seen in one patient, who was eligible for HER2-targeted therapy clinical trials. We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively. Additionally, we observed a patient with high level amplification of MET and another patient with the NCOA4-RET fusion gene which can be targeted by MET inhibitor carbozantinib. Interestingly, we also identified two patients with inactivating mutations in ELF3 (one frameshift and one in splicing-site), which is a driver gene of ampullary carcinoma. Lastly, two patients carried deleterious germline mutations in BRCA1 and PALB2, which may be targeted with PARP inhibitors. Overall, at least 29% (17/58) KRAS wide-type patients harbored potentially actionable genomic alterations to currently used anticancer drugs. Conclusions: The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors. Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.
The global, regional, and national burden of cancer among adolescents and young adults in 204 countries and territories, 1990–2019: a population-based study
Authors: Yi Feng Wen, Meng Xuan Chen, Guosheng Yin, Ruitao Lin, Yu Jie Zhong, Qian Qian Dong, Hai Ming Wong
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Accurate appraisal of burden of adolescents and young adults (AYAs) cancers is crucial to informing resource allocation and policy making. We report on the latest estimates of burden of AYA cancers in 204 countries and territories between 1990 and 2019 in association with socio-demographic index (SDI). Patients and methods Estimates from the Global Burden of Disease study 2019 were used to analyse incidence, mortality, and disability-adjusted life years (DALYs) due to AYA cancers at global, regional, and national levels by sex. Association between AYA cancer burden and SDI were investigated. Burdens of AYA cancers were contextualized in comparison with childhood and older adult cancers. All estimates are reported as counts and age-standardized rates per 100,000 person-years. Results In 2019, there were 1.2 million incident cases, 0.4 million deaths, and 23.5 million DALYs due to AYA cancers globally. The highest age-standardized incidence rate occurred in Western Europe (75.3 [Females] and 67.4 [Males] per 100,000 person-years). Age-standardized death (23.2 [Females] and 13.9 [Males] per 100,000 person-years) and DALY (1328.3 [Females] and 1059.2 [Males] per 100,000 person-years) rates were highest in Oceania. Increasing SDI was associated with a higher age-standardized incidence rate. An inverted U-shaped association was identified between SDI and death and DALY rates. AYA cancers collectively is the second leading cause of non-communicable diseases-related deaths globally in 2019. DALYs of AYA cancers ranked the second globally and the first in low and low-middle SDI locations when compared with that of childhood and older adult cancers. Conclusion The global burden of AYA cancers is substantial and disproportionally affect populations in limited-resource settings. Capacity building for AYA cancers is essential in promoting equity and population health worldwide.
High within-host diversity found from direct genotyping on post-mortem tuberculosis specimens in a high-burden setting
Authors: Cristina Rodríguez-Grande, Juan Carlos Hurtado, Sandra Rodríguez-Maus, Isaac Casas, Paola Castillo, Mireia Navarro, Natalia Rakislova, Alberto García-Basteiro, Carla Carrilho, Fabiola Fernandes, Lucilia Lovane, Dercio Jordao, Mamudo R. Ismail, Cesaltina Lorenzoni, Anélsio Cossa, Inácio Mandomando, Quique Bassat, Clara Menéndez, Jaume Ordi, Patricia Muñoz, Laura Pérez-Lago, Darío García de Viedma, Miguel J. Martínez
Journal: Clinical Microbiology and Infection (2021)

To characterize the clonal complexity in Mycobacterium tuberculosis (MTB) infections considering factors that help maximize the detection of coexisting strains/variants.Genotypic analysis by Mycobacterial Interspersed Repetitive-Unit-Variable-Number Tandem-Repeats (MIRU-VNTR) was performed directly on 70 biopsy specimens from two or more different tissues involving 28 tuberculosis cases diagnosed post-mortem in Mozambique, a country with a high tuberculosis burden.Genotypic data from isolates collected from two or more tissues were obtained for 23 of the 28 cases (82.1%), allowing the analysis of within-patient diversity. MIRU-VNTR analysis revealed clonal diversity in ten cases (35.7%). Five cases showed allelic differences in three or more loci, suggesting mixed infection with two different strains. In half of the cases showing within-host diversity, one of the specimens associated with clonal heterogeneity was brain tissue.Direct MTB genotyping from post-mortem tissue samples revealed a frequent within-host Mycobacterium tuberculosis diversity, including mixed and polyclonal infections. Most of this diversity would have been overlooked if only standard analysis of respiratory specimens had been performed.
Differences in Administrative Claims Data for Coronary Artery Bypass Grafting Between <i>International Classification of Diseases, Ninth Revision</i> and <i>Tenth Revision</i> Coding
Authors: Justin M. Schaffer, John J. Squiers, Jasjit K. Banwait, Sarah Hale, William H. Ryan, Michael J. Mack, J. Michael DiMaio
Journal: JAMA Cardiology (2021)

This cross-sectional study examines the changes in coding of coronary artery bypass graft procedures after the transition from the International Classification of Diseases, Ninth Revision to the Tenth Revision.
Circulating Micrornas (miRNA) As a Novel Liquid Biopsy and Therapeutic Platform in MYC and Non-MYC Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Afshin Beheshti, Charles Vanderburg, Ravi Dashnamoorthy, John Tyson McDonald, Amanda L Christie, Kay Shigemori, Hallie Jester, Hong Zhang, David M. Weinstock, Andrew M Evens
Journal: Blood (2017)