Outcomes of patients with blastoid and pleomorphic variant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma; data indicate that blastoid and pleomorphic variants have a poor prognosis. We report characteristics and outcomes of patients with blastoid/pleomorphic variants of MCL. We retrospectively studied adults with newly diagnosed MCL treated from 2000 to 2015. Primary objectives were to describe progression-free survival (PFS) and overall survival (OS). Secondary objectives included characterization of patient characteristics and treatments. Of the 1029 patients with MCL studied, a total of 207 neoplasms were blastoid or pleomorphic variants. Median follow-up period was 82 months (range, 0.1-174 months); median PFS was 38 months (95% confidence interval [CI], 28-66) and OS was 68 months (95% CI, 45-96). Factors associated with PFS were receipt of consolidative autologous hematopoietic transplantation (auto-HCT; hazard ratio [HR], 0.52; 95% CI, 0.31-0.80; P < .05), MCL International Prognostic Index (MIPI) intermediate (HR, 2.3; 95% CI, 1.2-4.3; P < .02) and high (HR, 3.8; 95% CI, 2.0-7.4; P < .01) scores, and complete response to induction (HR, 0.29 (95% CI, 0.17-0.51). Receipt of auto-HCT was not associated with OS (HR, 0.69; 95% CI, 0.41-1.16; P = .16) but was associated with MIPI intermediate (HR, 5.7; 95% CI, 2.5-13.2; P < .01) and high (HR, 10.8; 95% CI, 4.7-24.9; P < .01) scores. We report outcomes in a large cohort of patients with blastoid/pleomorphic variant MCL. For eligible patients, receipt of auto-HCT after induction was associated with improved PFS but not OS. Higher MIPI score and auto-HCT ineligibility were associated with worse survival.

Life Cycle Greenhouse Gas Emissions of Brazilian Sugar Cane Ethanol Evaluated with the GREET Model Using Data Submitted to RenovaBio.

Brazil is the second-largest ethanol producer in the world, primarily using sugar cane as feedstock. To foster biofuel production, the Brazilian government implemented a national biofuel policy, known as RenovaBio, in which greenhouse gas (GHG) emission reduction credits are provided to biofuel producers based on the carbon intensities (CI) of the fuels they produce. In this study, we configured the GREET model to evaluate life cycle GHG emissions of Brazilian sugar cane ethanol, using data from 67 individual sugar cane mills submitted to RenovaBio in 2019/2020. The average CI per megajoule of sugar cane ethanol produced in Brazil for use in the U.S. was estimated to be 35.2 g of CO2 equivalent, a 62% reduction from U.S. petroleum gasoline blendstock without considering the impacts of land use change. The three major GHG sources were on-field N2O emissions (24.3%), sugar cane farming energy use (24.2%), and sugar cane ethanol transport (19.3%). With the probability density functions for key input parameters derived from individual mill data, we performed stochastic simulations with the GREET model to estimate the variations in sugar cane ethanol CI and confirmed that despite the larger variations in sugar cane ethanol CI, the fuel provided a robust GHG reduction benefit compared to gasoline blendstock.

Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2.

Inhibition of the B-cell receptor (BCR) signaling pathway is highly effective in B-cell neoplasia through Bruton tyrosine kinase inhibition by ibrutinib. Ibrutinib also disrupts cell adhesion between a tumor and its microenvironment. However, it is largely unknown how BCR signaling is linked to cell adhesion. We observed that intrinsic sensitivities of mantle cell lymphoma (MCL) cell lines to ibrutinib correlated well with their cell adhesion phenotype. RNA-sequencing revealed that BCR and cell adhesion signatures were simultaneously downregulated by ibrutinib in the ibrutinib-sensitive, but not ibrutinib-resistant, cells. Among the differentially expressed genes, RAC2, part of the BCR signature and a known regulator of cell adhesion, was downregulated at both the RNA and protein levels by ibrutinib only in sensitive cells. RAC2 physically associated with B-cell linker protein (BLNK), a BCR adaptor molecule, uniquely in sensitive cells. RAC2 reduction using RNA interference and CRISPR impaired cell adhesion, whereas RAC2 overexpression reversed ibrutinib-induced cell adhesion impairment. In a xenograft mouse model, mice treated with ibrutinib exhibited slower tumor growth, with reduced RAC2 expression in tissue. Finally, RAC2 was expressed in ∼65% of human primary MCL tumors, and RAC2 suppression by ibrutinib resulted in cell adhesion impairment. These findings, made with cell lines, a xenograft model, and human primary lymphoma tumors, uncover a novel link between BCR signaling and cell adhesion. This study highlights the importance of RAC2 and cell adhesion in MCL pathogenesis and drug development.

Survival Outcomes of Younger Patients With Mantle Cell Lymphoma Treated in the Rituximab Era.

PURPOSE: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed. RESULTS: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

Internal consistency and item-total correlation of patient-reported outcome instruments and hemophilia joint health score v2.1 in US adult people with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.

BACKGROUND: The Pain, Functional Impairment, and Quality of Life study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adult people with hemophilia (PWH) of any severity in the USA who experience joint pain and/or bleeding. OBJECTIVE: To assess internal consistency (IC) and item-total correlation (ITC) of assessment tools used in the Pain, Functional Impairment, and Quality of Life study. METHODS: Participants completed 5 patient-reported outcome instruments (EQ-5D-5L with visual analog scale, Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], Short Form 36 Health Survey v2 [SF-36v2], and Hemophilia Activities List [HAL]) and underwent an optional physiotherapist-administered musculoskeletal exam (Hemophilia Joint Health Score v2.1) during routine visits. Reliability assessment included IC and ITC of each instrument. RESULTS: A total of 381 adult PWH (median age, 34 years) were enrolled. Participants were predominantly white/non-Hispanic (69.2%); 75% had congenital hemophilia A, and 70.5% had severe hemophilia. A total of 310 subjects reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]). IC was generally high across the instruments employed (Cronbach's alpha 0.79-0.98) with the exception of HAL use of transportation (0.58) and IPAQ total physical activity (0.51). ITC was high (Pearson's product-moment correlation coefficient >0.20) for all items except the "vigorous intensity activities" item of IPAQ, which was applicable to less than one-third of participants. The ITCs were generally highest in domains/scores that measured the functional consequences of hemophilic arthropathy on mobility and pain. CONCLUSION: The demonstrated reliability (IC/ITC) of the patient-reported outcome instruments and Hemophilia Joint Health Score v2.1 support a role for these instruments in evaluating adult PWH in US clinical and research settings.

Known-group validity of patient-reported outcome instruments and hemophilia joint health score v2.1 in US adults with hemophilia: results from the Pain, Functional Impairment, and Quality of life (P-FiQ) study.

BACKGROUND: The Pain, Functional Impairment, and Quality of Life (P-FiQ) study was an observational, cross-sectional assessment of the impact of pain on functional impairment and quality of life in adults with hemophilia in the United States who experience joint pain or bleeding. OBJECTIVE: To describe known-groups validity of assessment tools used in the P-FiQ study. PATIENTS AND METHODS: Participants completed 5 patient-reported outcome (PRO) instruments (5-level EuroQoL 5-dimensional questionnaire [EQ-5D-5L] with visual analog scale [VAS], Brief Pain Inventory v2 Short Form [BPI], International Physical Activity Questionnaire [IPAQ], Short-Form Health Survey [SF-36v2], and Hemophilia Activities List [HAL]) and underwent a musculoskeletal examination (Hemophilia Joint Health Score [HJHS]) during a routine clinical visit. RESULTS: P-FiQ enrolled 381 adults with hemophilia (median age, 34 years). Participants were predominantly white/non-Hispanic (69.2%), 75% had congenital hemophilia A, and 70.5% had severe hemophilia. Most (n=310) reported bleeding within the past 6 months (mean [SD] number of bleeds, 7.1 [13.00]). All instruments discriminated between relevant known (site- or self-reported) participant groups. Domains related to pain on EQ-5D-5L, BPI, and SF-36v2 discriminated self-reported pain (acute/chronic/both; P<0.05), domains related to functional impairment on IPAQ, SF-36v2, and HAL discriminated self-reported functional impairment (restricted/unrestricted; P<0.05), and domains related to mental health on the EQ-5D-5L and SF-36v2 discriminated self-reported anxiety/depression (yes/no; P<0.01). HJHS ankle and global gait domains and global score discriminated self-reported arthritis/bone/joint problems, percentage of lifetime on prophylaxis, current treatment regimen, and hemophilia severity (P<0.01); knee and elbow domains discriminated all of these (P<0.01) except for current treatment regimen. CONCLUSION: All assessment tools demonstrated known-group validity and may have practical applicability in evaluating adults with hemophilia in clinical and research settings in the United States.

Identification of patients with congenital hemophilia in a large electronic health record database.

BACKGROUND: Electronic health records (EHRs) are an important source of information with regard to diagnosis and treatment of rare health conditions, such as congenital hemophilia, a bleeding disorder characterized by deficiency of factor VIII (FVIII) or factor IX (FIX). OBJECTIVE: To identify patients with congenital hemophilia using EHRs. DESIGN: An EHR database study. SETTING: EHRs were accessed from Humedica between January 1, 2007, and July 31, 2013. PATIENTS: Selection criteria were applied for an initial ICD-9-CM diagnosis of 286.0 (hemophilia A) or 286.1 (hemophilia B), and confirmation of records 6 months before and 12 months after the first diagnosis. Additional selection criteria included mention of "hemophilia" and "blood" or "bleed" within physician notes identified via natural language processing. RESULTS: A total of 129 males and 35 females were identified as the analysis population. Of those patients for whom both prothrombin time and activated partial thromboplastin time test results were available, only 56% of males and 7% of females exhibited a pattern of test results consistent with congenital hemophilia (normal prothrombin time and prolonged activated partial thromboplastin time). Few patients had a prescription for a hemophilia treatment; males most commonly received Amicar (10.8%) or FVIII (9.0%), whereas females most commonly received DDAVP (11.0%). The most identifiable sites of pain were the chest and the abdomen; 41% of males and 37% of females had joint pain. To evaluate whether patients had been correctly identified with congenital hemophilia, EHRs of 6 patients were reviewed; detailed assessment of their data was found to be inconsistent with a conclusive diagnosis of congenital hemophilia. LIMITATIONS: Inconsistent coding practices may affect data integrity. CONCLUSION: A potentially high number of false positive identifications, particularly among female patients, suggests that ICD-9-CM coding alone may be insufficient to identify patient cohorts. In-depth reviews and multimodal analysis of chart notes may improve data integrity.

Identification of people with acquired hemophilia in a large electronic health record database.

BACKGROUND: Electronic health records (EHRs) can provide insights into diagnoses, treatment patterns, and clinical outcomes. Acquired hemophilia (AH) is an ultrarare bleeding disorder characterized by factor VIII inhibiting autoantibodies. AIM: To identify patients with AH using an EHR database. METHODS: Records were accessed from a large EHR database (Humedica) between January 1, 2007 and July 31, 2013. Broad selection criteria were applied using the International Classification of Diseases, Ninth Revision, clinical modification (ICD-9-CM) code for intrinsic circulating anticoagulants (286.5 and all subcodes) and confirmation of records 6 months before and 12 months after the first diagnosis. Additional selection criteria included mention of "bleeding" within physician notes identified via natural language processing output and a normal prothrombin time and prolonged activated partial thromboplastin time. RESULTS: Of 6,348 patients with a diagnosis code of 286.5 or any subcodes, 16 males and 15 females met the selection criteria. The most common bleeding locations reported was gastrointestinal (23%), vaginal (16%), and endocrine (13%). A wide range of comorbidities was reported. Natural language processing identified chart note mention of "hemophilia" in 3 patients (10%), "bruise" in 15 patients (48%), and "pain" in all 31 patients. No patients received a prescription for approved/recommended AH treatments. Four patient cases were reviewed to validate whether the identified cohort had AH; each patient had bleeding symptoms and a normal prothrombin time and prolonged activated partial thromboplastin time, although none received hemostatic treatments. CONCLUSION: In ultrarare disorders, ICD-9-CM coding alone may be insufficient to identify patient cohorts; multimodal analysis combined with in-depth reviews of physician notes may be more effective.

Multicentric Castleman disease presenting with fever.

Multicentric Castleman disease (MCD) is a rare lymphoproliferative disorder that usually manifests with nonspecific symptoms, including fever and lymphadenopathy. Treatment of pediatric MCD varies greatly. A 21-month-old child was diagnosed with MCD after presenting with fever. He had incomplete response to initial therapy directed at interleukin-6, but improved with subsequent chemotherapy.

Treatment, survival, and thromboembolic outcomes of thrombotic storm in children.

OBJECTIVE: To describe the course and management of thrombotic storm in 8 children. STUDY DESIGN: Clinical data were collected and analyzed for consecutive children diagnosed with thrombotic storm, aged 6 months to 21 years inclusive, in the context of a single-institution prospective inception cohort study. Thrombotic storm was defined as newly diagnosed multisite venous thromboembolism (VTE) with acute thrombus progression despite conventional or higher than conventional dosing of heparin or low molecular weight heparin. All evaluations and therapies were ordered by the treating physicians in the context of clinical decision making. RESULTS: Eight of the 178 children with VTE enrolled in the cohort between March 2006 and November 2009 were diagnosed with thrombotic storm. Antiphospholipid antibodies were acutely positive in 6 children, of whom heparin-induced thrombocytopenia was confirmed by serotonin release assay in 2 and atypical in 1. One child died. Five children received a direct thrombin inhibitor, titrated to achieve normalization of markedly elevated D-dimer levels. All children were transitioned to fondaparinux or enoxaparin before receiving extended anticoagulation with warfarin. Immunomodulatory therapy was instituted in all children. During follow-up (median duration, 3 years; range, 2-6 years), 3 of the 7 surviving children experienced recurrent VTE, and 4 children had clinically significant postthrombotic syndrome. CONCLUSION: Thrombotic storm is an infrequent but potentially fatal presentation of VTE in children. Administration of direct thrombin inhibitors and immune modulation can achieve quiescence, although long-term adverse outcomes are common.

The new University of Colorado medical school curriculum: a pediatric perspective.

The University of Colorado School of Medicine has developed an innovative 4-year undergraduate curriculum. As a strong advocate for education and curriculum reform, Dr M. Douglas Jones Jr. created an environment for pediatrics to flourish in this new curriculum. Pediatric content has increased in all years of the curriculum, and pediatric faculty have had greater opportunities to teach and seek career development in medical education. In this report, we review the process that led to curriculum reform, provide an overview of the new curriculum design, and highlight examples of the positive impact this process has had on education in pediatrics. We hope that sharing our experience, may benefit others in medical education.