Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. FINDINGS: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR \u3c 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p \u3c 0·01) compared to controls. INTERPRETATION: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. FUNDING: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842

Variability in the practice of fertility preservation for patients with cancer

Fertility is important to women and men with cancer. While options for fertility preservation (FP) are available, knowledge regarding the medical application of FP is lacking. Therefore we examined FP practices for cancer patients among reproductive endocrinologists (REs). A 36 item survey was sent to board-certified REs. 98% of respondents reported counseling women with cancer about FP options. Oocyte and embryo cryopreservation were universally offered by these providers, but variability was noted in reported management of these cases-particularly for women with breast cancer. 86% of the respondents reported using letrozole during controlled ovarian stimulation (COS) in patients with estrogen receptor positive (ER+) breast cancer to minimize patient exposure to estrogen. 49% of respondents who reported using letrozole in COS for patients with ER+ breast cancer reported that they would also use letrozole in COS for women with ER negative breast cancer. Variability was also noted in the management of FP for men with cancer. 83% of participants reported counseling men about sperm banking with 22% recommending against banking for men previously exposed to chemotherapy. Overall, 79% of respondents reported knowledge of American Society for Clinical Oncology FP guidelines-knowledge that was associated with providers offering gonadal tissue cryopreservation (RR 1.82, 95% CI 1.14-2.90). These findings demonstrate that RE management of FP in cancer patients varies. Although some variability may be dictated by local resources, standardization of FP practices and communication with treating oncologists may help ensure consistent recommendations and outcomes for patients seeking FP

Venous thromboembolism in multiple myeloma is associated with increased mortality

BACKGROUND: In multiple myeloma, venous thromboembolism (VTE) is common, and treatments for myeloma, such as lenalidomide, increase the risk of thrombosis while improving survival. The association between VTE and survival is not well known. OBJECTIVES: To determine the association between VTE and survival in multiple myeloma (MM) while adjusting for known confounders that affect risk of thrombosis and survival, including patient characteristics and treatment in a retrospective cohort of US veterans. PATIENTS/METHODS: A cohort of patients with newly diagnosed MM treated within Veterans Health Administration between September 1, 1999, and June 30, 2014, was created to assess the association between VTE and mortality using Cox proportional hazards regression modeling while accounting for known prognostic factors and treatments. RESULTS: The cohort comprised 4446 patients with myeloma, including 2837 patients diagnosed after lenalidomide approval in July 2006. VTE occurred in 327 (7.4%) patients within 1 year and occurred at a median of 77 days (interquartile range, 37-153) after starting therapy for MM. In all patients, VTE was associated with increased mortality at 6 months (adjusted hazard ratio [aHR], 1.67; 95% confidence interval [CI], 1.18-2.37). Patients in the post-lenalidomide cohort with VTE had an increased mortality at both 6 months (aHR, 2.31; 95% CI, 1.52-3.51) and 12 months (aHR, 1.66; 95% CI, 1.19-2.33) after treatment initiation. DISCUSSION: This study shows that VTE during the first 6-12 months of therapy is associated with increased mortality in patients with MM. Studies evaluating thromboprophylaxis in patients at high risk of thrombosis are needed

Impact of sarcopenia on treatment tolerance in United States veterans with diffuse large B‐cell lymphoma treated with CHOP‐based chemotherapy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134181/1/ajh24465_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134181/2/ajh24465.pd

Obesity and Cancer

The article examines the importance of managing weight to reduce risk for developing cancer and for survival among cancer patients and presents a set of strategies that can be useful to guide clinical advice to patients for whom weight control is an important adjunct to risk management or to improve quality of life and disease-free survival after diagnosis

Identifying existing Choosing Wisely recommendations of high relevance and importance to hematology

Choosing Wisely (CW) is a medical stewardship initiative led by the American Board of Internal Medicine Foundation in collaboration with professional medical societies in the United States. In an effort to learn from and leverage the work of others, the American Society of Hematology CW Task Force developed a method to identify and prioritize CW recommendations from other medical societies of high relevance and importance to patients with blood disorders and their physicians. All 380 CW recommendations were reviewed and assessed for relevance and importance. Relevance was assessed using the MORE TM relevance scale. Importance was assessed with regard to six guiding principles: harm avoidance, evidence, aggregate cost, relevance, frequency and impact. Harm avoidance was considered the most important principle. Ten highly relevant and important recommendations were identified from a variety of professional societies. Recommendations focused on decreasing unnecessary imaging, blood work, treatments and transfusions, as well as on increasing collaboration across disciplines and considering value when recommending treatments. Many CW recommendations have relevance beyond the society of origin. The methods developed by the ASH CW Task Force could be easily adapted by other Societies to identify additional CW recommendations of relevance and importance to their fields. Am. J. Hematol. 91:787–792, 2016. © 2016 Wiley Periodicals, Inc

Clinical Features and Associated Likelihood of Primary Ciliary Dyskinesia in Children and Adolescents

Rationale: Primary ciliary dyskinesia (PCD), a genetically heterogeneous, recessive disorder of motile cilia, is associated with distinct clinical features. Diagnostic tests, including ultrastructural analysis of cilia, nasal nitric oxide measurements, and molecular testing for mutations in PCD genes, have inherent limitations

Standardized Urine-Based Tuberculosis (TB) Screening With TB-Lipoarabinomannan and Xpert MTB/RIF Ultra in Ugandan Adults With Advanced Human Immunodeficiency Virus Disease and Suspected Meningitis.

BACKGROUND: Diagnosis of extrapulmonary tuberculosis (TB) remains challenging. We sought to determine the prevalence of disseminated TB by testing urine with TB-lipoarabinomannan (TB-LAM) lateral flow assay and Xpert MTB/RIF Ultra (Ultra) in hospitalized adults. METHODS: We prospectively enrolled human immunodeficiency virus (HIV)-positive adults with suspected meningitis in Uganda during 2018-2020. Participants underwent standardized urine-based TB screening. Urine (60 mcL) was tested with TB-LAM (Alere), and remaining urine was centrifuged with the cell pellet resuspended in 2 mL of urine for Xpert Ultra testing. RESULTS: We enrolled 348 HIV-positive inpatients with median CD4 of 37 cells/mcL (interquartile range, 13-102 cells/mcL). Overall, 26% (90 of 348; 95% confidence interval [CI], 21%-30%) had evidence of disseminated TB by either urine assay. Of 243 participants with both urine TB-LAM and Ultra results, 20% (48 of 243) were TB-LAM-positive, 12% (29 of 243) were Ultra-positive, and 6% (14 of 243) were positive by both assays. In definite and probable TB meningitis, 37% (14 of 38) were TB-LAM-positive and 41% (15 of 37) were Ultra-positive. In cryptococcal meningitis, 22% (40 of 183) were TB-LAM-positive and 4.4% (6 of 135) were Ultra-positive. Mortality trended higher in those with evidence of disseminated TB by either assay (odds ratio = 1.44; 95% CI, 0.83-2.49; P = .19) and was 6-fold higher in those with definite TB meningitis who were urine Ultra-positive (odds ratio = 5.67; 95% CI, 1.13-28.5; P = .04). CONCLUSIONS: In hospitalized Ugandans with advanced HIV disease and suspected meningitis, systematic screening with urine TB-LAM and Ultra found a high prevalence of urine TB test positivity (26%). In those with TB meningitis, urine tests were positive in over one third. There was little concordance between Ultra and TB-LAM, which warrants further investigation

Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score.

OBJECTIVE: To develop and validate a pragmatic risk score to predict mortality in patients admitted to hospital with coronavirus disease 2019 (covid-19). DESIGN: Prospective observational cohort study. SETTING: International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study (performed by the ISARIC Coronavirus Clinical Characterisation Consortium-ISARIC-4C) in 260 hospitals across England, Scotland, and Wales. Model training was performed on a cohort of patients recruited between 6 February and 20 May 2020, with validation conducted on a second cohort of patients recruited after model development between 21 May and 29 June 2020. PARTICIPANTS: Adults (age ≥18 years) admitted to hospital with covid-19 at least four weeks before final data extraction. MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: 35 463 patients were included in the derivation dataset (mortality rate 32.2%) and 22 361 in the validation dataset (mortality rate 30.1%). The final 4C Mortality Score included eight variables readily available at initial hospital assessment: age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation, level of consciousness, urea level, and C reactive protein (score range 0-21 points). The 4C Score showed high discrimination for mortality (derivation cohort: area under the receiver operating characteristic curve 0.79, 95% confidence interval 0.78 to 0.79; validation cohort: 0.77, 0.76 to 0.77) with excellent calibration (validation: calibration-in-the-large=0, slope=1.0). Patients with a score of at least 15 (n=4158, 19%) had a 62% mortality (positive predictive value 62%) compared with 1% mortality for those with a score of 3 or less (n=1650, 7%; negative predictive value 99%). Discriminatory performance was higher than 15 pre-existing risk stratification scores (area under the receiver operating characteristic curve range 0.61-0.76), with scores developed in other covid-19 cohorts often performing poorly (range 0.63-0.73). CONCLUSIONS: An easy-to-use risk stratification score has been developed and validated based on commonly available parameters at hospital presentation. The 4C Mortality Score outperformed existing scores, showed utility to directly inform clinical decision making, and can be used to stratify patients admitted to hospital with covid-19 into different management groups. The score should be further validated to determine its applicability in other populations. STUDY REGISTRATION: ISRCTN66726260