Patterns of Diagnostic Evaluation and Determinants of Treatment in Older Patients With Non-transfusion Dependent Myelodysplastic Syndromes.

BACKGROUND: Older patients with myelodysplastic syndromes (MDS), particularly those with no or one cytopenia and no transfusion dependence, typically have an indolent course. Approximately, half of these receive the recommended diagnostic evaluation (DE) for MDS. We explored factors determining DE in these patients and its impact on subsequent treatment and outcomes. PATIENTS AND METHODS: We used 2011-2014 Medicare data to identify patients ≥66 years of age diagnosed with MDS. We used Classification and Regression Tree (CART) analysis to identify combinations of factors associated with DE and its impact on subsequent treatment. Variables examined included demographics, comorbidities, nursing home status, and investigative procedures performed. We conducted a logistic regression analysis to identify correlates associated with receipt of DE and treatment. RESULTS: Of 16 851 patients with MDS, 51% underwent DE. patients with MDS with no cytopenia (n = 3908) had the lowest uptake of DE (34.7%). Compared to patients with no cytopenia, those with any cytopenia had nearly 3 times higher odds of receiving DE [adjusted odds ratio (AOR), 2.81: 95% CI, 2.60-3.04] and the odds were higher for men than for women [AOR, 1.39: 95%CI, 1.30-1.48] and for Non-Hispanic Whites [vs. everyone else (AOR, 1.17: 95% CI, 1.06-1.29)]. The CART showed DE as the principal discriminating node, followed by the presence of any cytopenia for receiving MDS treatment. The lowest percentage of treatment was observed in patients without DE, at 14.6%. CONCLUSION: In this select older patients with MDS, we identified disparities in accurate diagnosis by demographic and clinical factors. Receipt of DE influenced subsequent treatment but not survival.

Multisite 11-year experience of less-intensive vs intensive therapies in acute myeloid leukemia.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Lower Extremity Response to Blast Loading: A Computational Study.

This study has investigated the response of the Total Human Model for Safety (THUMS) lower extremity finite element model under blast loading. Response of the model was estimated in simulated underbody blast (UBB) loading using floorplate impact velocities of increasing severity. Correlation and analysis (CORA) ratings suggested a good match between numerical response and available experimental data. The model response was then investigated in an antipersonnel landmine explosion. The model was found stable in the nearfield blast and sensitive to the threat definition. The lower extremity injury was predicted when detonation occurred below the heel. The model predicted major injuries localized to the hindfoot and midfoot with minimal damage to the forefoot, consistent with the findings in the literature. The damage to the individual bones of the foot was measured in terms of percentage change in mass and element eroded.

Excess cancer prevalence in men with HIV: A nationwide analysis of Medicaid data.

BACKGROUND: Cancer is one of the most common comorbidities in men living with HIV (MLWH). However, little is known about the MLWH subgroups with the highest cancer burden to which cancer prevention efforts should be targeted. Because Medicaid is the most important source of insurance for MLWH, we evaluated the excess cancer prevalence in MLWH on Medicaid relative to their non-HIV counterparts. METHODS: In this cross-sectional study using 2012 Medicaid Analytic eXtract data nationwide, we flagged the presence of HIV, 13 types of cancer, symptomatic HIV, and viral coinfections using codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. The study population included individuals administratively noted to be of male sex (men), aged 18 to 64 years, with (n = 82,495) or without (n = 7,302,523) HIV. We developed log-binomial models with cancer as the outcome stratified by symptomatic status, age, and race/ethnicity. RESULTS: Cancer prevalence was higher in MLWH than in men without HIV (adjusted prevalence ratio [APR], 1.84; 95% confidence interval [CI], 1.78-1.90) and was higher among those with symptomatic HIV (APR, 2.74; 95% CI, 2.52-2.97) than among those with asymptomatic HIV (APR, 1.73; 95% CI, 1.67-1.79). The highest APRs were observed for anal cancer in younger men, both in the symptomatic and asymptomatic groups: APR, 312.97; 95% CI, 210.27-465.84, and APR, 482.26; 95% CI, 390.67-595.32, respectively. In race/ethnicity strata, the highest APRs were among Hispanic men for anal cancer (APR, 198.53; 95% CI, 144.54-272.68) and for lymphoma (APR, 9.10; 95% CI, 7.80-10.63). CONCLUSIONS: Given the Medicaid program's role in insuring MLWH, the current findings highlight the importance of the program's efforts to promote healthy behaviors and vaccination against human papillomavirus in all children and adolescents and to provide individualized cancer screening for MLWH.

Efficacy and safety of regimens used for the treatment of multicentric Castleman disease: A systematic review.

OBJECTIVES: Treatment options for multicentric Castleman disease (MCD) remain limited. The only FDA-approved drug is siltuximab for idiopathic MCD (iMCD), but the response rate with siltuximab is less than 50%. We performed a systematic review to examine the efficacy and safety of various regimens used for the treatment of MCD. METHODS: A database search on PubMed, Embase, Cochrane, Web of Science, and Clinicaltrials.gov using the terms "Castleman disease," "treatment outcome," and "patient safety" was done. RESULTS AND CONCLUSIONS: Results from a randomized controlled trial and an extension study highlighted the efficacy and long-term safety of siltuximab for iMCD; other trials showed tocilizumab to be a suitable alternative. A recent trial reported high response rates with thalidomide in iMCD patients. Promising results were reported for bortezomib in relapsed/ refractory MCD. For human herpesvirus-8 (HHV8)-associated MCD, rituximab along with doxorubicin therapy followed by maintenance with zidovudine and valganciclovir is the most effective therapy. A single-arm trial has highlighted the potential role of tocilizumab in HHV8-MCD. Data for these regimens are limited and mostly comprise nonrandomized trials. Further research on emerging agents could have a major impact on the treatment of this rare disease.

Incidence, Clinical Features, and Outcomes of Langerhans Cell Histiocytosis in the United States.

Langerhans cell histiocytosis (LCH) is a disorder with highly diverse clinical manifestations. We explored if age, sex, race, organ system involved, and therapy approaches determine patient survival in the era of modern treatments. LCH patient data reported to the Surveillance, Epidemiology, and End Results (SEER) program in 2010-2016 (n=1282; age: 0 to 100 y) was analyzed. Age-specific LCH incidence flattening to a low level suggests an age cutoff for pediatric patients of 20 years. The overall survival probability is lower for patients 21 to 100 years old ( P <0.0001), irrespective of sex and race. The commonest sites involved in the 0- to 20-year age group were bone, skin, and bone marrow; this shifted to lung, bone, and skin as the commonest disease sites in patients 21 to 100 years of age. The treatments applied differed between age groups, as younger versus older patients were more likely to receive chemotherapy-based treatment (48.4% vs. 17%; P <0.0001). There also was a trend toward nonwhite versus white patients being less likely to receive chemotherapy-based treatment (31.7% vs. 38.2%; P =0.067). Whereas there are treatment disparities related to LCH patient age and perhaps race, patient age is the strongest predictor of survival, with patients 21 to 100 years of age with lung, lymph node, skin, and bone marrow disease having the worst outcomes ( P <0.0001).

A deep adversarial variational autoencoder model for dimensionality reduction in single-cell RNA sequencing analysis.

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) is an emerging technology that can assess the function of an individual cell and cell-to-cell variability at the single cell level in an unbiased manner. Dimensionality reduction is an essential first step in downstream analysis of the scRNA-seq data. However, the scRNA-seq data are challenging for traditional methods due to their high dimensional measurements as well as an abundance of dropout events (that is, zero expression measurements). RESULTS: To overcome these difficulties, we propose DR-A (Dimensionality Reduction with Adversarial variational autoencoder), a data-driven approach to fulfill the task of dimensionality reduction. DR-A leverages a novel adversarial variational autoencoder-based framework, a variant of generative adversarial networks. DR-A is well-suited for unsupervised learning tasks for the scRNA-seq data, where labels for cell types are costly and often impossible to acquire. Compared with existing methods, DR-A is able to provide a more accurate low dimensional representation of the scRNA-seq data. We illustrate this by utilizing DR-A for clustering of scRNA-seq data. CONCLUSIONS: Our results indicate that DR-A significantly enhances clustering performance over state-of-the-art methods.

Comparable outcomes of patients eligible vs ineligible for SWOG leukemia studies.

Patients may be deemed ineligible for a clinical trial for reasons that do not directly impact efficacy or safety. We identified reasons for ineligibility and compared outcomes of ineligible with eligible patients treated on Southwest Oncology Group (SWOG) Leukemia Committee protocols. Patients enrolled in SWOG phase 2, 2/3, or 3 protocols open since 2005 were analyzed for eligibility status, reasons for ineligibility, baseline characteristics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), serious adverse events (SAEs), complete remission (CR) status, and overall survival. A total of 2361 patients were enrolled in the 13 included studies. Of these, 247 (10%) were deemed ineligible; 78 were excluded from analyses, and 169 were included. Of the 169 included in analyses, 60% (101/169) were excluded due to missing baseline documentation. Baseline characteristics comparing ineligible to eligible patients were similar, with the exception of ECOG PS for S0325 (P = .02) and S0530 (P = .002). In multivariable analyses, neither the proportion of patients with ECOG PS ≥ 2 (P = .12) nor the rate of grade 5 SAEs (P = .62) differed between groups. There was no difference in survival between eligible and ineligible patients (P = .25), and CR rates were similar, with the exception of S0325 (P < .001) and S0703 (P = .004). The findings of this study suggest that nonessential eligibility criteria can be less restrictive, thus expanding patient enrollment and avoiding protocol deviations. The clinical trials included in this study were registered at www.clincialtrials.gov as #NCT00085709, #NCT00066794, #NCT00070499, #NCT00109837, #NCT00093418, #NCT00492856, #NCT00337168, #NCT00352365, #NCT00658814, #NCT00792948, #NCT00945815, #NCT00840177, and #NCT01522976.

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Considerations for Use of Hematopoietic Growth Factors in Patients With Cancer Related to the COVID-19 Pandemic.

Hematopoietic growth factors, including erythrocyte stimulating agents (ESAs), granulocyte colony-stimulating factors, and thrombopoietin mimetics, can mitigate anemia, neutropenia, and thrombocytopenia resulting from chemotherapy for the treatment of cancer. In the context of pandemic SARS-CoV-2 infection, patients with cancer have been identified as a group at high risk of morbidity and mortality from this infection. Our subcommittee of the NCCN Hematopoietic Growth Factors Panel convened a voluntary group to review the potential value of expanded use of such growth factors in the current high-risk environment. Although recommendations are available on the NCCN website in the COVID-19 Resources Section (https://www.nccn.org/covid-19/), these suggestions are provided without substantial context or reference. Herein we review the rationale and data underlying the suggested alterations to the use of hematopoietic growth factors for patients with cancer in the COVID-19 era.

NCCN Guidelines Insights: Hematopoietic Growth Factors, Version 1.2020.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.

Initiation of venovenous extracorporeal membrane oxygenation in a patient receiving induction chemotherapy for acute myelogenous leukemia.

BACKGROUND: Acute respiratory failure is a leading cause of intensive care unit admission in patients with hematological malignancies; it carries a mortality rate exceeding 50%. Venovenous extracorporeal membrane oxygenation use in patients with acute hematologic malignancies concurrently receiving induction chemotherapy is not well studied. CASE PRESENTATION: A 44-year-old male developed acute respiratory distress syndrome in the setting of newly diagnosed acute myelogenous leukemia. He underwent successful induction chemotherapy while on venovenous extracorporeal membrane oxygenation. His course was complicated by a devastating subarachnoid hemorrhage. Life support modalities were discontinued in accordance to the wishes of the family. CONCLUSION: There is a lack of data to guide use of induction chemotherapy in patients with acute hematologic malignancies requiring venovenous extracorporeal membrane oxygenation, particularly with regard to dosing, safety, and efficacy of chemotherapeutic agents. This case highlights a potential role of venovenous extracorporeal membrane oxygenation in select young acute myelogenous leukemia patients who might benefit from this intervention and warrants further research.

Bridging Microscopic and Macroscopic Mechanisms of p53-MDM2 Binding with Kinetic Network Models.

Under normal cellular conditions, the tumor suppressor protein p53 is kept at low levels in part due to ubiquitination by MDM2, a process initiated by binding of MDM2 to the intrinsically disordered transactivation domain (TAD) of p53. Many experimental and simulation studies suggest that disordered domains such as p53 TAD bind their targets nonspecifically before folding to a tightly associated conformation, but the microscopic details are unclear. Toward a detailed prediction of binding mechanisms, pathways, and rates, we have performed large-scale unbiased all-atom simulations of p53-MDM2 binding. Markov state models (MSMs) constructed from the trajectory data predict p53 TAD binding pathways and on-rates in good agreement with experiment. The MSM reveals that two key bound intermediates, each with a nonnative arrangement of hydrophobic residues in the MDM2 binding cleft, control the overall on-rate. Using microscopic rate information from the MSM, we parameterize a simple four-state kinetic model to 1) determine that induced-fit pathways dominate the binding flux over a large range of concentrations, and 2) predict how modulation of residual p53 helicity affects binding, in good agreement with experiment. These results suggest new ways in which microscopic models of peptide binding, coupled with simple few-state binding flux models, can be used to understand biological function in physiological contexts.

The Incidence and Health Care Resource Burden of the Myelodysplastic Syndromes in Patients in Whom First-Line Hypomethylating Agents Fail.

BACKGROUND: Although hypomethylating agents (HMAs) are effective and approved therapies for patients with myelodysplastic syndromes (MDS), many patients do not benefit from treatment, and nearly all ultimately stop responding to HMAs. The incidence and cost burden of HMA failure are unknown yet needed to appreciate the magnitude and significance of such failure. METHODS: We analyzed a de-identified dataset of over 5 million individuals with private health insurance in the U.S. to estimate MDS incidence, prevalence, and treatments. Based on MDS provider interviews, a conceptual model of MDS patient management was constructed to create a new, claims-relevant and drug development-relevant definition of HMA treatment failure. This algorithm was used to define resource encumbrance of MDS patients in whom HMA treatment failed. RESULTS: We estimated an MDS incidence rate of ∼70 cases per 100,000 enrollees per year and a prevalence of 155 cases per 100,000 enrollees. The proportion of MDS patients receiving HMA treatment was low (∼3%), and treatment was typically initiated within 1 year of the first MDS claim. Notably, HMA-treated individuals were older and had more comorbidities than the overall MDS cohort. Total health care costs of managing MDS patients after HMA failure were high (∼$77,000 during the first 6 months) and were driven primarily by non-pharmacy costs. CONCLUSION: This study quantifies for the first time the burden of significant unmet need in caring for MDS patients following HMA treatment failure. The Oncologist 2017;22:379-385Implications for Practice: U.S.-based treatment patterns among MDS patients demonstrate the significant clinical, financial, and health care burden associated with HMA failure and call for active therapies for this patient population.

Myeloid Growth Factors, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

Myeloid growth factors (MGFs) are given as supportive care to patients receiving myelosuppressive chemotherapy to reduce the incidence of neutropenia. This selection from the NCCN Guidelines for MGFs focuses on the evaluation of regimen- and patient-specific risk factors for the development of febrile neutropenia (FN), the prophylactic use of MGFs for the prevention of chemotherapy-induced FN, and assessing the risks and benefits of MGF use in clinical practice.

Microsecond simulations of mdm2 and its complex with p53 yield insight into force field accuracy and conformational dynamics.

The p53-MDM2 complex is both a major target for cancer drug development and a valuable model system for computational predictions of protein-ligand binding. To investigate the accuracy of molecular simulations of MDM2 and its complex with p53, we performed a number of long (200 ns to 1 µs) explicit-solvent simulations using a range of force fields. We systematically compared nine popular force fields (AMBER ff03, ff12sb, ff14sb, ff99sb, ff99sb-ildn, ff99sb-ildn-nmr, ff99sb-ildn-phi, CHARMM22*, and CHARMM36) against experimental chemical shift data, and found similarly accurate results, with microsecond simulations achieving better agreement compared to 200-ns trajectories. Although the experimentally determined apo structure has a closed binding cleft, simulations in all force fields suggest the apo state of MDM2 is highly flexible, and able to sample holo-like conformations, consistent with a conformational selection model. Initial structuring of the MDM2 lid region, known to competitively bind the binding cleft, is also observed in long simulations. Taken together, these results show molecular simulations can accurately sample conformations relevant for ligand binding. We expect this study to inform future computational work on folding and binding of MDM2 ligands.

Allogeneic hematopoietic cell transplantation for myelodysplastic syndromes: lingering uncertainties and emerging possibilities.

The landscape of transplantation in myelodysplastic syndrome (MDS) has evolved rapidly in the last decade, driven mostly by advances in patient selection through better risk stratification, increasing age of allogeneic recipients, introduction of reduced-intensity conditioning regimens, increased availability of unrelated donors, new donor sources, and improvements in transplant technology and supportive care. Despite these advances, several issues, mostly centering on approaches to improve post-transplant survival while minimizing transplant-related mortality, continue to present significant challenges. Advances in understanding the molecular pathogenesis of MDS have made it feasible to construct clinically useful risk models that integrate prognostic genes with conventional risk parameters for better selection of patients likely to benefit from hematopoietic cell transplantation. Simultaneous research efforts in several areas, including comorbidity assessment, novel preparative regimens, optimal pretransplant cytoreductive strategy, and post-transplantation therapies, are expected to improve long-term disease-free survival and quality of life.

DOCK 6: Impact of new features and current docking performance.

This manuscript presents the latest algorithmic and methodological developments to the structure-based design program DOCK 6.7 focused on an updated internal energy function, new anchor selection control, enhanced minimization options, a footprint similarity scoring function, a symmetry-corrected root-mean-square deviation algorithm, a database filter, and docking forensic tools. An important strategy during development involved use of three orthogonal metrics for assessment and validation: pose reproduction over a large database of 1043 protein-ligand complexes (SB2012 test set), cross-docking to 24 drug-target protein families, and database enrichment using large active and decoy datasets (Directory of Useful Decoys [DUD]-E test set) for five important proteins including HIV protease and IGF-1R. Relative to earlier versions, a key outcome of the work is a significant increase in pose reproduction success in going from DOCK 4.0.2 (51.4%) → 5.4 (65.2%) → 6.7 (73.3%) as a result of significant decreases in failure arising from both sampling 24.1% → 13.6% → 9.1% and scoring 24.4% → 21.1% → 17.5%. Companion cross-docking and enrichment studies with the new version highlight other strengths and remaining areas for improvement, especially for systems containing metal ions. The source code for DOCK 6.7 is available for download and free for academic users at http://dock.compbio.ucsf.edu/.