High Frequencies of Mutated EZH2 and IRF8 and Other Epigenetic Genes in Primary Bone Lymphomas Are Indicative of GCB-Phenotype

Introduction Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma comprising 1-2% of all malignant lymphomas. This study aims to elucidate the genetic background of a homogeneous cohort of PB-DLBCL. Methods This retrospective study consists of primary DLBCL-patients with bone localization(s) of which pretreatment fresh frozen or formalin-fixed paraffin-embedded bone tissue samples were available. Patients were diagnosed (2003-2019) at Leiden University Medical Center (LUMC), a center of expertise for bone tumors, Amsterdam University Medical Center (AUMC), Erasmus MC and affiliated Dutch hospitals. Based on strict definitions regarding radiological assessment of anatomical disease localizations at diagnosis three subgroups were categorized: solely osseous involvement (single or multiple bone lesions; PB-DLBCL), osseous involvement and locoregional lymphadenopathy (locoregional disease), and osseous and (multiple) extra-osseous localizations (disseminated disease). Cell-of-origin (COO) was determined by immunohistochemistry (BCL6, CD10, and MUM1) and classified according to the Hans' algorithm. Additionally, COO was confirmed with NanoString and the Lymph2Cx assay (Scott et al., Blood 2014), in a subset of patients. With similar procedures (Vermaat et al., Haematologica 2019), molecular profiles were determined with an in-house developed and validated targeted next-generation sequencing (tNGS) panel, comprising 52 DLBCL-specific genes, for sequencing with the Ion S5TM System. Obtained results were compared to sequencing data of (1) an independent 'in-house' cohort of 23 primary GCB (Germinal Center B-Cell)-DLBCL patients without bone localization ('non-osseous') and (2) pooled data of 651 GCB-DLBCL patients from literature (Chapuy et al., Nature Medicine 2018, Karube et al., Leukemia 2018, Reddy et al., Cell 2017, Schmitz et al., NEJM 2018). Results Our cohort contained 56 patients (males, N=33, (59%)) with a median age at diagnosis of 62 years (range 13-92). Twenty-four patients had PB-DLBCL (45%), 8 had locoregional disease (14%), and 23 had disseminated disease (41%). In general, immunohistochemistry and Lymph2Cx identified a GCB subtype for the majority of all DLBCL with bone localizations (Figure-1A) and these results for the hitherto unperformed cases will follow shortly. tNGS identified 48 genes with 'pathogenic' mutations, with on average four mutated genes per patients (range 0-10; Figure-1A). Overall, high mutation frequencies were observed in TNFRSF14 (33%), KMT2D (27%), EZH2 (25%), CREBBP (22%), B2M (22%), and TP53 (20%) in DLBCL with bone localizations and mainly genes involved in epigenetic machinery. In PB-DLBCLs, high frequency of mutated EZH2 (38%) and IRF8 (25%) were identified. Both are epigenetic genes that regulates tumor suppression and type I interferon, respectively. In four PB-DLBCLs EZH2 and IRF8 were concomitantly mutated. Locoregional disease showed a similar molecular profile as PB-DLBCL. Association with clinical characteristics will be performed shortly. Compared to our cohort of non-osseous GCB-DLBCL (Figure-1B) and pooled data of GCB-DLBCL in large sequencing studies (Figure-1C), EZH2 (Chi-square; P=0.046 and P=0.005, respectively) was significantly more frequently mutated in PB-DLBCL, though IRF8 did not attain this significance (Chi-square; P=0.121 and P=0.111, respectively; Figure-1D). Conclusion This study is the first that provides integrative analyses of immunohistochemistry, Lymph2Cx, and tNGS of a homogeneous cohort of PB-DLBCL, demonstrating the importance of epigenetic genes in lymphomagenesis. In contrast to (non-osseous) GCB-DLBCLs, the molecular profile of PB-DLBCL is characterized by significantly frequent mutations in EZH2 and frequent mutations in IRF8 and other epigenetic genes, which is indicative for a GCB phenotype (Scherer F. et al., Sci Transl Med 2016) and supported by immunohistochemistry and Lymph2Cx data. These results suggest that PB-DLBCL is a specific DLBCL-entity with a unique molecular profile and provide a rationale for exploration of novel targeted treatment with EZH2 (and IRF8) inhibitors for PB-DLBCL patients. Disclosures Lugtenburg: Genmab: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy; Celgene: Consultancy, Honoraria; Janssen Cilag: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Kersten:Gilead: Honoraria; Mundipharma: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda Oncology: Research Funding; Miltenyi: Honoraria; Kite Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria.

Download Full-text

Genomic Characterization of Diffuse Large B-Cell Lymphoma Transformation from Nodular Lymphocyte Predominant Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-125095 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1486-1486

Author(s):

Joo Y. Song ◽

Caoimhe Egan ◽

Alyssa Bouska ◽

Weiwei Zhang ◽

Qiang Gong ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

Immune Surveillance ◽

B Cell Lymphoma ◽

Pi3k Pathway ◽

Large B Cell Lymphoma ◽

Frequent Mutations ◽

Large B Cell

Introduction: Transformed nodular lymphocyte predominant Hodgkin lymphoma (tNLPHL) with a typical diffuse large B-cell lymphoma (DLBCL) pattern is rare and not well studied by genomic analysis. We employed next generation sequencing and copy number analysis (CNA) to examine the pathogenesis of these tumors. Methods: We identified 19 cases of tNLPHL with DLBCL morphology and sheet-like growth from three institutions. NLPHL preceded transformation in 5 patients and was concurrent with transformation in 11. All cases of tNLPHL were sequenced using a targeted sequencing panel of 356 genes that included commonly mutated genes associated with lymphoma. We had 8 cases with matched germline DNA. We also performed CNA using Oncoscan on 18 cases of tNLPHL. Library preparation with paired end 100 bp sequencing and 6-10 million reads/case was performed on an Illumina HiSeq 2500. Fisher's exact test was used to compare the role of mutations in tNLPHL to three large series of de novo DLBCL. Results: The CNA showed frequent gains in REL and loss of CDKN2A. Mutation analysis showed frequent mutations of genes associated with the PI3K pathway such as SGK1 (26%), ZFP36L1 (16%), PIK3R1 (11%), and IL7R (11%), the NF-kB pathway such as CARD11 (21%), JUNB (21%), BCL10 (11%), NFKBIA (11%), TNFAIP3 (11%), histone/DNA modification such as KMT2D (26%), EP300 (21%), TET2 (11%), TET3 (11%), and the NOTCH pathway such as NOTCH2 (16%), NOTCH1 (1 case), CTBP2 (11%). Mutations in genes involved in immune surveillance and TP53 abnormalities were infrequent. Compared to de novo DLBCL, mutations in IL7R (10.5% vs 0.6%, p=0.03), JUNB (21% vs 4.2%, p=0.01), and SMARCAL1 (11% vs 0%, p=0.01) were significantly higher in tNLPHL than in germinal center B-cell (GCB) subtype of DLBCL. Conclusion: The mutational spectrum of tNLPHL resembles the DLBCL Cluster 4 of Chapuy et al (Nat Med, 2018), which were primarily GCB-DLBCL with frequent mutations in the PI3K pathway (SGK1), NF-kB pathway (CARD11, JUNB), and histone modification. The mutational spectrum is also distinctive in having frequent mutations that are not often seen together in DLBCL, such as TET2, JUNB and NOTCH2. Distinct from transformed follicular lymphoma, TP53 abnormalities and mutations affecting immune surveillance are uncommonly observed. This study provides new insights into the biology of tNLPHL and may highlight potential targets for therapy in the future. Disclosures Herrera: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding.

Download Full-text

AGMT MALT-2: A Phase II Study of Rituximab Plus Lenalidomide in Patients with Extranodal Marginal Zone B-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALT lymphoma)

Blood ◽

10.1182/blood.v126.23.3973.3973 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3973-3973 ◽

Cited By ~ 3

Author(s):

Barbara Kiesewetter ◽

Richard Greil ◽

Wolfgang Willenbacher ◽

Peter Neumeister ◽

Michael A. Fridrik ◽

...

Keyword(s):

Adverse Events ◽

B Cell ◽

Phase Ii ◽

Malt Lymphoma ◽

Research Funding ◽

Systemic Treatment ◽

Phase Ii Study ◽

Gastric Malt Lymphoma ◽

Best Response ◽

Disseminated Disease

Abstract Background: Chemotherapy-containing regimens are effective for the treatment of advanced MALT lymphoma. However, due to the indolent course of this disease immunomodulatory strategies appear reasonable. Lenalidomide was active as monotherapy for MALT lymphoma and addition of rituximab (R) achieved promising results in several B-cell malignancies. Methods: The AGMT MALT-2 study is a multicenter phase II study for the treatment of MALT lymphoma with R-lenalidomide (also referred to as "R2"). Treatment consisted of R 375 mg/m2 day 1 and lenalidomide 20 mg day 1-21 in a four-week cycle. In the case of gastric MALT lymphoma and Helicobacter pylori (HP)-infection patients had to be refractory to HP-eradication prior to inclusion. HP-negative or extragastric patients were directly eligible. In case of complete remission (CR) after 6 courses treatment stopped while those with partial remission (PR) or stabilization (SD) were eligible for 8 courses. All patients received prophylactic ASA (100 mg/day) during treatment and allopurinol (300 mg/day) for the first 8 weeks. The primary endpoint of the study was the objective response rate (ORR) defined by radiological or GELA histological response criteria, respectively. The secondary endpoint was safety. These are our final results. Results: A total of 50 patients were enrolled but four patients were excluded and replaced according to protocol, including two patients who withdrew informed consent before the first dose of treatment due to personal reasons. Of 46 evaluable patients 28 (60.9%) were female while 18 (39.1%) were male. Median age at initiation of treatment was 64 years with an interquartile range of 53-72 years. 28.3% (13/46) of patients had primary gastric MALT lymphoma while the majority of patients i.e. 71.7% (33/46) had primary extragastric manifestations (28% ocular adnexa, 11% lung, 11% disseminated disease, 7% parotid gland and 15% other localizations). 63.0% (29/46) of patients had localized disease and 37.0% (17/46) presented with advanced/ disseminated disease. ECOG status was 0 or 1 in 97.8% (45/46) of patients. 23.9% (11/46) of patients had received prior systemic treatment including one patient pretreated with lenalidomide and 9 pretreated with R-containing regimens. Treatment with R-lenalidomide resulted in an ORR of 80.4%. 54.3% (25/46) achieved CR, 26.1% (12/46) PR, and 17.4% (8/46) SD as best response. One patient progressed at cycle three but received successful salvage treatment. Median time to best response was 5.2 months (95% CI; 2.8-5.7). The mean number of applied treatment cycles was 6 (95% CI; 5.6-6.6). Fourteen patients (30.4%; 14/46) benefited from the extended treatment phase and converted to a deeper response between restaging at cycle three and restaging at cycle 6 (11/14) or 8 (3/14), respectively. Univariate analysis for response according to gender (male vs. female) (p = 0.691), primary localization of MALT lymphoma (gastric vs. extragastric) (p = 0.654), prior systemic treatment (p = 0.895), and localized vs. disseminated disease (p = 0.197) was not significantly different for groups. 48 patients received at least one dose of R-lenalidomide and were included in the toxicity analysis. Tolerability in terms of non-hematologic adverse events was good with no toxicity grade IV reported. 37.5% (18/48) of patient experienced mild infusion reactions following R. Common adverse reactions to lenalidomide consisted of mild fatigue in 33.3% (grade I/II = 16), musculoskeletal pain in 41.7% (I/II = 18, III = 2), cough or respiratory infections in 33.3% (I/II = 13, III = 3), diarrhea in 22.9% (I/II = 10, III = 1) and mild vertigo in 22.9% (I/II = 9, III = 2). Typical lenalidomide-associated exanthema occurred in 45.8% patients but was usually mild (I/II = 19, III = 3). Hematologic adverse events were rare with a rate of grade III/IV neutropenia below 20% (18.8%; 9/48). Dose reduction of lenalidomide due to adverse events was necessary in 34.8% (15 mg = 12, 10 mg = 4). Four patients discontinued treatment early due to adverse events. After a median follow-up of 27.2 months (range; 13.2-36.3) three patients have relapsed at 5.0-8.8 months suggesting durable responses in the majority of cases. No second malignancies were observed. Conclusion: This is the first study on efficacy of R-lenalidomide for MALT lymphoma. With an ORR of 80% and a CRR of 54% we could improve the results achieved with lenalidomide-monotherapy in a prior pilot trial. Disclosures Off Label Use: lenalidomide for MALT lymphoma. Greil:AOP Orphan: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Merck: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Sanofi Aventis: Honoraria; GSK: Research Funding; Ratiopharm: Research Funding; Celgene: Consultancy; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche, Celgene: Honoraria, Research Funding. Willenbacher:Roche, Celgene: Consultancy, Honoraria, Research Funding. Fridrik:Roche: Consultancy, Honoraria. Markus:Celgene, Roche, EISAI, Novartis, IPSEN: Honoraria.

Download Full-text

Upregulation of CD47 Expression in De Novo Diffuse Large B-Cell Lymphoma Is More Frequent in Activated B-Cell Type

Blood ◽

10.1182/blood-2021-152071 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3507-3507

Author(s):

Winston Y Lee ◽

Anamarija M. Perry ◽

Vero Azcutia ◽

Alex F. Herrera ◽

Pamela Skrabek ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Surface Receptor ◽

Large B Cell Lymphoma ◽

Frequent Mutations ◽

Large B Cell

Abstract CD47 is a marker of self that provides a "don't-eat-me-signal" through activation of signal-regulatory protein alpha (SIRPa), a cell surface receptor expressed on monocytes/macrophages and granulocytes. This interaction negatively regulates effector functions such as, phagocytosis, migration, and superoxide production. Upregulation of CD47 expression in cancer, including diffuse large B-cell lymphoma (DLBCL), has emerged as a mechanism to escape innate immune surveillance. Using conventional immunohistochemical detection, we assessed CD47 expression in DLBCL and interrogated its association with clinicopathologic features. Patients with de novo DLBCL were identified from two large institutions and were uniformly treated with R-CHOP and had sufficient material for study. Immunohistochemical stains (IHC) were performed on FFPE tissue (Hans algorithm, BCL2, MYC, and CD47) and scored semi-quantitatively from no reactivity (0) to strong (2 and 3; Figure 1). Mutational analysis using a 334 gene target sequencing panel, gene expression profiling using Lymph2Cx to determine the cell of origin (COO), and FISH analysis for MYC, BCL2, and BCL6 translocations, were performed. The Lymphgen tool (Wright et al, 2020) was also used to determine the DLBCL group. Fisher's exact test and Kaplan-Meier survival analysis for overall survival (OS) were performed and P <0.05 was considered significant. CD47 expression was assessed by IHC in a cohort of 152 cases of de novo DLBCL, including 107 cases of germinal center B-cell (GCB) type (70%), 37 cases of activated B-cell (ABC) type (24%), and 8 cases of intermediate type (5%). A total of 17 cases (11%) showed strong and diffuse CD47 expression with IHC scores of 2 or above (CD47hi). CD47hi cases were significantly more frequent in ABC DLBCL (24%, 9/37) than GCB DLBCL (6%, 6/107; P=0.003). The remaining 2 CD47hi cases were in the intermediate DLBCL group (25%, 2/8). ABC DLBCL with CD47hi showed more frequent mutations with TET2 (33% vs 7%; P=0.08) and ZFP36L1 (22% vs 0%; P=0.05) compared to cases with low expression of CD47 with IHC scores of less than 2 (CD47low). ABC DLBCL with CD47low showed more frequent mutations of NOTCH2 (18% vs 0%; P=0.31) and MYD88 (29% vs 11%; P=0.4) compared to CD47hi. GCB DLBCL with CD47hi showed frequent mutations of TP53 (67% vs 21%; P=0.026) and CCND1 (33% vs 0%; P=0.003) compared to CD47low. None of the 13 cases with double- or triple-hit for MYC, BCL2 and/or BCL6 showed CD47 expression. The Lymphgen tool showed that cases of DLBCL with CD47hi were mostly in the 'other' group (50%), with other groups represented such as ST2 (21%), EZB (14%), MCD and BN2 (1 case each). There was no difference in overall survival (OS) between CD47hi and CD47low DLBCL (5-year OS, 75% vs 72%; P=0.57), or with the GCB or ABC subtypes. Strong expression with CD47 is more frequent in ABC DLBCL and is seen in a subset of GCB DLBCL with mutations in TP53 and/or CCND1. The level of CD47 expression does not appear to predict OS in patients with DLBCL treated with R-CHOP. This study demonstrates that conventional immunohistochemical methods can readily identify DLBCL with high CD47 expression, and these patients may benefit from the use of anti-CD47 therapy. Figure 1 Figure 1. Disclosures Herrera: Gilead Sciences: Research Funding; Takeda: Consultancy; Tubulis: Consultancy; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Seagen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding.

Download Full-text

Obesity Is Associated with Increased Relapse Risk in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-154153 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1449-1449

Author(s):

Kevin Tang ◽

Jorge Mazzini ◽

Martha P. Mims ◽

Gustavo Rivero ◽

Purnima Sravanti Teegavarapu

Keyword(s):

Tumor Microenvironment ◽

Regression Model ◽

B Cell ◽

Research Funding ◽

Cox Regression ◽

Cell Lymphoma ◽

Medical Center ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive Non-Hodgkin's lymphoma (NHL) characterized by clinical, biological and genetic heterogeneity. Despite the tremendous advancement in anticancer therapy against DLBCL, up to 40% of patients are refractory and/or relapse after first-line chemo-immunotherapy. Mechanisms responsible for chemo-immunotherapy failure are largely uncharacterized; however, it is believed the microenvironment contributes to tumor adaptation and survival. Several studies have shown that high body mass index (BMI) is associated with increased risk of developing DLBCL and obesity is an independent prognostic indicator of worse outcome when compared to non-obese patients. Weight gain alters the metabolic landscape of tumor microenvironment to inhibit T cell function and promote cellular growth. Obesity induced proinflammatory mediators can activate numerous signaling pathways including nuclear factor (NF)-KB that result in anti-apoptotic and increased proliferative efficiency in B-cells Here, we report the results of our retrospective study from two hospital systems in Houston, Texas evaluating the impact of BMI on progression-free-survival (PFS) in DLBCL patients receiving standard induction chemotherapy. Methods: After Institutional Review Boards (IRB) approval, patients (pts) were identified by electronic medical record database query. Inclusion criteria included: (a) age>18 years old, (b) DLBCL diagnosis confirmed by pathology review at Ben Taub Medical Center and Baylor St. Luke's Medical Center. BMI was calculated using patient's height and weight at diagnosis. For all comparison, we selected DLBCL pts with World Health Organization (WHO) predefined overweight, class I, II, III obesity to better capture effect of extreme BMI on DLBCL PFS. Cell-of-origin (COO) was determined by Hans classification. R-CHOP/R-EPOCH were classified as intense therapy whereas R-CVP/R-CEOP as non-intense therapy. Descriptive statistics was used to evaluate differential expression of clinical and laboratory variables. PFS among pts with BMI <35 and BMI >35 was estimated with Kaplan Meier Method. Cox regression model evaluated effect of independent variables on PFS for pts with DLBCL exhibiting obesity. SAS was used for all analysis. Results: 123 pts were identified. Demographic, clinical and laboratory data was balanced among DLBCL pts with and without BMI >35 (Table 1). Median BMI was 25.9 for pts with BMI<35 v 37.3 in pts with BMI >35. In the pts with BMI <35, 36.9% were classified as germinal center b-cell (GCB) subtype and 63.1% were classified as non-GCB subtype (p= NS). Within the BMI >35, 46.2% were GCB subtype and 53.9% were non-GCB subtype. 45.9% of pts had low International Prognostic Index (IPI) score in BMI<35 compared to 56.52% in BMI>35, whereas 54% had high IPI in BMI<35 compared to 43.48% in BMI>35. PFS was 2,864 days vs 763 days in patients with BMI <35 and >35, respectively (p=0.02). (Fig 1). To address effect of "type of therapy administered" (low v high intensity), COO, and age as confounders for our observation that PFS is inferior in DLBCL pts with BMI >35, Cox regression model was performed confirming the independent predictive role for BMI >35 only on DLBCL PFS. Conclusions: Our study demonstrates that obesity (BMI >35) results in increased relapse risk in DLBCL patients. In our population, risk of relapse was enhanced by higher BMI independent of age, therapy administered and COO. Obesity, by itself, especially BMI>35 (Class II and Class III) may represent a unique factor for adverse outcome in DLBCL. The mechanism for which extreme obesity leads to inferior PFS in DLBCL is unclear. It is possible that obesity induces "high risk" mutations acquisition and/or adversely modifies tumor microenvironment resulting in chemotherapy cytotoxic attenuation. Larger studies are needed to externally validate our observation. Figure 1 Figure 1. Disclosures Mims: Biogen: Current holder of individual stocks in a privately-held company; Incyte: Research Funding; IDEC: Current holder of individual stocks in a privately-held company; Celgene: Research Funding; Pfizer: Research Funding; AVEO: Research Funding.

Download Full-text

Venous Thromboembolism and High Grade Gliomas

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649592 ◽

1993 ◽

Vol 70 (03) ◽

pp. 393-396 ◽

Cited By ~ 38

Author(s):

Mandeep S Dhami ◽

Robert D Bona ◽

John A Calogero ◽

Richard M Hellman

Keyword(s):

Risk Factors ◽

Venous Thromboembolism ◽

Medical Center ◽

Significant Risk ◽

Bleeding Complications ◽

Fisher Exact Test ◽

High Grade ◽

Chi Square ◽

Exact Test ◽

High Grade Gliomas

SummaryA retrospective study was done to determine the incidence of and the risk factors predisposing to clinical venous thromboembolism (VTE) in patients treated for high grade gliomas. Medical records of 68 consecutive patients diagnosed and treated at Saint Francis Hospital and Medical Center from January 1986 to June 1991 were reviewed. The follow up was to time of death or at least 6 months (up to December 1991). All clinically suspected episodes of VTE were confirmed by objective tests. Sixteen episodes of VTE were detected in 13 patients for an overall episode rate of 23.5%. Administration of chemotherapy (p = 0.027, two tailed Fisher exact test) and presence of paresis (p = 0.031, two tailed Fisher exact test) were statistically significant risk factors for the development of VTE. Thrombotic events were more likely to occur in the paretic limb and this difference was statistically significant (p = 0.00049, chi square test, with Yates correction). No major bleeding complications were seen in the nine episodes treated with long term anticoagulation.We conclude that venous thromboembolic complications are frequently encountered in patients being treated for high grade gliomas and the presence of paresis and the administration of chemotherapy increases the risk of such complications.

Download Full-text

Characteristics and risk factors associated with stroke subtypes among adult patients admitted to stroke unit of JUMC

Current Hypertension Reviews ◽

10.2174/1573402115666191121120228 ◽

2019 ◽

Vol 15 ◽

Author(s):

Bekalu Getachew Gebreegziabher ◽

Tesema Etefa Birhanu ◽

Diriba Dereje Olana ◽

Behailu Terefe Tesfaye

Keyword(s):

Risk Factors ◽

Stroke Unit ◽

Medical Center ◽

Data Entry ◽

Public Health Problem ◽

Cross Sectional Study ◽

Chi Square ◽

Cross Sectional ◽

Factors Associated ◽

Stroke Subtypes

Background: Stroke is a great public health problem in Ethiopia. According to reports, in-hospital stroke mortality was estimated to be 14.7% in Ethiopia. Despite this, in this country researches done on factors associated with stroke sub-types were inadequate. Objective: To assess the Characteristics and risk factors associated with stroke sub-types among patients admitted to JUMC. Methods and materials: A retrospective cross sectional study was conducted from May 2017 to May 2018 in stroke unit of Jimma University Medical Center. A total of 106 medical charts of patients diagnosed with stroke were reviewed. Checklist comprising of relevant variables was used to collect data. SPSS version 21 was employed for data entry and analysis. Chi-square test was used to point-out association and difference among stroke sub-types. The data was presented using text, tables and figures. Result: From a total of 106 patients, 67(63.2%) were men. The mean ± SD of age was 52.67±12.46 years, and no significant association was found. Of all the patients, 59(55.6%) had ischemic strokes and 47(44.4%) had hemorrhagic strokes. The most common risk factor in the patients was alcohol use with a prevalence of 69.9%. Of all the risk factors, only sex, cigarettes smoking and dyslipidemia were significantly associated to sub-types of stroke. Conclusion: Ischemic stroke was the most common subtype of stroke. Sex of patient, cigarette smoking and dyslipidemia are significantly associated with the two stroke subtypes.

Download Full-text

Perceptions of Seasonal Influenza Vaccine Among U.S. Army Civilians and Dependents in the Kaiserslautern Military Community: A Mixed-Methods Survey

Military Medicine ◽

10.1093/milmed/usaa572 ◽

2021 ◽

Author(s):

Veronica M Burns ◽

Fritz M Castillo ◽

Rodney L Coldren ◽

Trisha Prosser ◽

Renee L Howell ◽

...

Keyword(s):

Online Survey ◽

Seasonal Influenza ◽

Medical Center ◽

Vaccine Uptake ◽

Free Text ◽

Chi Square ◽

Military Health ◽

Influenza Outbreak ◽

Flu Vaccination ◽

Flu Vaccine

ABSTRACT Introduction Influenza is a globally occurring viral respiratory infection that can lead to hospitalizations and death. An influenza outbreak can interfere with combat readiness in a military setting, as the infection can incapacitate soldiers. Vaccination remains the most effective tool to prevent and mitigate seasonal influenza. Although influenza vaccinations for U.S. Army soldiers can be monitored through military health systems, those systems cannot capture DoD civilians and Army dependents who may not use military health services. This study aims to gauge flu vaccine uptake and perceptions in U.S. Army civilians and dependents. Materials and Methods An online survey was e-mailed to civilian and dependent enrollees of Landstuhl Regional Medical Center. The survey contained 24 questions pertaining to demographics, vaccine history, history of the flu, and beliefs toward vaccines. Chi-square tests, t-tests, and logistic regressions were performed to investigate the association between demographic, behavior, and belief factors with vaccine uptake. Free-text answers were coded and categorized by themes. Results Over 70% of respondents were vaccinated for the flu. There were differences between vaccinated and unvaccinated respondents regarding their perceptions of barriers to vaccination, benefits of the flu vaccine, severity of flu symptoms, and personal risk of getting ill with the flu. After controlling for confounders, flu vaccination in the previous season and healthcare worker status were associated with increased vaccine uptake, while perceived barriers to influenza vaccination were associated with decreased vaccine uptake. Conclusions Flu vaccine uptake may be increased by increasing access to vaccination, promoting vaccination and addressing concerns at the provider level, and engaging positively framed public messaging. Increasing flu vaccine uptake is of particular importance as the flu season approaches during the COVID-19 (Coronavirus disease 2019) pandemic.

Download Full-text

Distinct Gene Expression Signatures in Patients with Richter's Syndrome and Chronic Lymphocytic Leukemia with Prior Exposure to Ibrutinib

Blood ◽

10.1182/blood-2020-136172 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-31

Author(s):

Hanyin Wang ◽

Shulan Tian ◽

Qing Zhao ◽

Wendy Blumenschein ◽

Jennifer H. Yearley ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Activation ◽

Expression Profiles ◽

Lymphocytic Leukemia ◽

B Cell Activation ◽

Advisory Committees ◽

Upregulated Genes

Introduction: Richter's syndrome (RS) represents transformation of chronic lymphocytic leukemia (CLL) into a highly aggressive lymphoma with dismal prognosis. Transcriptomic alterations have been described in CLL but most studies focused on peripheral blood samples with minimal data on RS-involved tissue. Moreover, transcriptomic features of RS have not been well defined in the era of CLL novel therapies. In this study we investigated transcriptomic profiles of CLL/RS-involved nodal tissue using samples from a clinical trial cohort of refractory CLL and RS patients treated with Pembrolizumab (NCT02332980). Methods: Nodal samples from 9 RS and 4 CLL patients in MC1485 trial cohort were reviewed and classified as previously published (Ding et al, Blood 2017). All samples were collected prior to Pembrolizumab treatment. Targeted gene expression profiling of 789 immune-related genes were performed on FFPE nodal samples using Nanostring nCounter® Analysis System (NanoString Technologies, Seattle, WA). Differential expression analysis was performed using NanoStringDiff. Genes with 2 fold-change in expression with a false-discovery rate less than 5% were considered differentially expressed. Results: The details for the therapy history of this cohort were illustrated in Figure 1a. All patients exposed to prior ibrutinib before the tissue biopsy had developed clinical progression while receiving ibrutinib. Unsupervised hierarchical clustering using the 300 most variable genes in expression revealed two clusters: C1 and C2 (Figure 1b). C1 included 4 RS and 3 CLL treated with prior chemotherapy without prior ibrutinib, and 1 RS treated with prior ibrutinib. C2 included 1 CLL and 3 RS received prior ibrutinib, and 1 RS treated with chemotherapy. The segregation of gene expression profiles in samples was largely driven by recent exposure to ibrutinib. In C1 cluster (majority had no prior ibrutinb), RS and CLL samples were clearly separated into two subgroups (Figure 1b). In C2 cluster, CLL 8 treated with ibrutinib showed more similarity in gene expression to RS, than to other CLL samples treated with chemotherapy. In comparison of C2 to C1, we identified 71 differentially expressed genes, of which 34 genes were downregulated and 37 were upregulated in C2. Among the upregulated genes in C2 (majority had prior ibrutinib) are known immune modulating genes including LILRA6, FCGR3A, IL-10, CD163, CD14, IL-2RB (figure 1c). Downregulated genes in C2 are involved in B cell activation including CD40LG, CD22, CD79A, MS4A1 (CD20), and LTB, reflecting the expected biological effect of ibrutinib in reducing B cell activation. Among the 9 RS samples, we compared gene profiles between the two groups of RS with or without prior ibrutinib therapy. 38 downregulated genes and 10 upregulated genes were found in the 4 RS treated with ibrutinib in comparison with 5 RS treated with chemotherapy. The top upregulated genes in the ibrutinib-exposed group included PTHLH, S100A8, IGSF3, TERT, and PRKCB, while the downregulated genes in these samples included MS4A1, LTB and CD38 (figure 1d). In order to delineate the differences of RS vs CLL, we compared gene expression profiles between 5 RS samples and 3 CLL samples that were treated with only chemotherapy. RS samples showed significant upregulation of 129 genes and downregulation of 7 genes. Among the most significantly upregulated genes are multiple genes involved in monocyte and myeloid lineage regulation including TNFSF13, S100A9, FCN1, LGALS2, CD14, FCGR2A, SERPINA1, and LILRB3. Conclusion: Our study indicates that ibrutinib-resistant, RS-involved tissues are characterized by downregulation of genes in B cell activation, but with PRKCB and TERT upregulation. Furthermore, RS-involved nodal tissues display the increased expression of genes involved in myeloid/monocytic regulation in comparison with CLL-involved nodal tissues. These findings implicate that differential therapies for RS and CLL patients need to be adopted based on their prior therapy and gene expression signatures. Studies using large sample size will be needed to verify this hypothesis. Figure Disclosures Zhao: Merck: Current Employment. Blumenschein:Merck: Current Employment. Yearley:Merck: Current Employment. Wang:Novartis: Research Funding; Incyte: Research Funding; Innocare: Research Funding. Parikh:Verastem Oncology: Honoraria; GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Kenderian:Sunesis: Research Funding; MorphoSys: Research Funding; Humanigen: Consultancy, Patents & Royalties, Research Funding; Gilead: Research Funding; BMS: Research Funding; Tolero: Research Funding; Lentigen: Research Funding; Juno: Research Funding; Mettaforge: Patents & Royalties; Torque: Consultancy; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding. Kay:Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; MEI Pharma: Research Funding; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees. Braggio:DASA: Consultancy; Bayer: Other: Stock Owner; Acerta Pharma: Research Funding. Ding:DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

HUBUNGAN SIKAP PASIEN TERHADAP HAK DAN KEWAJIBAN RAWAT INAP DI RUMAH SAKIT PEKANBARU MEDICAL CENTER (PMC)

Testing Hearing ◽

10.35907/bgjk.v13i1.184 ◽

2021 ◽

Vol 13 (1) ◽

pp. 17-25

Author(s):

Nur Maimun ◽

Arnawilis ◽

Cindy Feby Fayza ◽

Nur Asikin

Keyword(s):

Patient Safety ◽

Medical Information ◽

Medical Center ◽

Patient Treatment ◽

Patient Attitudes ◽

Chi Square ◽

Cross Sectional ◽

The Right ◽

Relationship Of ◽

The Relationship

Patient as service users have right and obligations to be hospitalized and patients also have the right to medical information in receiving medical practice services. This study aims to determine the relationship between patient attitudes towards the rights and obligations of being hospitalized in the hospital Pekanbaru Medical Center (PMC). This research method using observational analytic method with cross sectional design. The total sample used in this study 107 sample were taken as simpel random sampling. Chi square test is used to determine the relationship between variables. The data were processed using SPSS statistical software and analyzed using univariate and bivariate analyzes. Of the result obtained of the study namely the relationship between patient attitude to the rights and obligations of patient with chi-suare obtained pvalue 0.016 (<0,05), the relationship of attitude patients to the rights and obligations of choosing a doctor and class of patient care with chi-square obtained pvalue 0,070 (<0,05), the relationship of patient attitudes to the right and obligations of confidentiality of disease by inpatient medical staff with chi-square obtained pvalue 0,000 (<0,05), the relationship of patient attitudes to the rights and obligations of consent to the patient treatment with chi-square obtained pvalue 0,000 (<0,05), the relationship of patient attitudes to the right and obligation of patient safety with chi-square obtained pvalue 0,000 (<0,05), the relationship between patient attitudes towards the right and obligations of patient safety with chi-square obtained pvalue 0,000 (<0,05). Suggestions in order to protect what has been achieved in this case is his ability as effort of service is getting better in the future Keyword : Attitudes of patient, Rights and Obligations inpatient, Hospital

Download Full-text

Six new cases confirm the clinical molecular profile of complete combined 17α-hydroxylase/ 17,20-lyase deficiency in Brazil

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302010000800008 ◽

2010 ◽

Vol 54 (8) ◽

pp. 711-716 ◽

Cited By ~ 7

Author(s):

Daiane Rodrigues Barbosa Belgini ◽

Maricilda Palandi de Mello ◽

Maria Tereza Matias Baptista ◽

Daniel Minutti de Oliveira ◽

Fernanda Canova Denardi ◽

...

Keyword(s):

Present Report ◽

Molecular Data ◽

The Other ◽

Renin Activity ◽

Inguinal Region ◽

Molecular Profile ◽

Hydroxylase Deficiency ◽

Lyase Deficiency ◽

Frequent Mutations ◽

Low Levels

In 2004, Costa-Santos and cols. reported 24 patients from 19 Brazilian families with 17α-hydroxylase deficiency and showed that p.W406R and p.R362C corresponded to 50% and 32% of CYP17A1 mutant alleles, respectively. The present report describes clinical and molecular data of six patients from three inbred Brazilian families with 17α-hydroxlyse deficiency. All patients had hypogonadism, amenorrhea and hypertension at diagnosis. Two sisters were found to be 46,XY with both gonads palpable in the inguinal region. All patients presented hypergonadotrophic hypogonadism, with high levels of ACTH (> 104 ng/mL), suppressed plasmatic renin activity, low levels of potassium (< 2.8 mEq/L) and elevated progesterone levels (> 4.4 ng/mL). Three of them, including two sisters, were homozygous for p.W406R mutation and the other three (two sisters and one cousin) were homozygous for p.R362C. The finding of p.W406R and p.R362C in the CYP17A1 gene here reported in additional families, confirms them as the most frequent mutations causing complete combined 17α-hydroxylase/17,20-lyase deficiency in Brazilian patients.

Download Full-text