Managing common toxicities associated with checkpoint inhibitor and chemotherapy combinations for untreated classic Hodgkin lymphoma.

Combination checkpoint inhibitor (CPI) and chemotherapy is an effective and safe treatment strategy for patients with untreated classic Hodgkin lymphoma. Recent studies of programmed cell death protein 1 inhibitors combined with doxorubicin, vinblastine and dacarbazine have demonstrated high overall and complete response rates. This combination has a unique toxicity profile that should be managed appropriately so as not to compromise treatment efficacy. Common toxicities include rash, hepatoxicity, neutropenia and thyroid dysfunction. Here, we present four cases and the management strategies around such toxicities. In addition, we highlight key clinical decision-making around the administration of subsequent doses of CPI and chemotherapy.

Depression in patients with hematologic malignancies: The current landscape and future directions.

Patients with hematologic malignancies experience high rates of depression. These patients are vulnerable to depression throughout the disease trajectory, from diagnosis to survivorship, and at the end of life. In addition to the distressing nature of depression, it has substantial downstream effects including poor quality of life, increased risk of treatment complications, and worse survival. Therefore, systematic screening for depression and integration of robust psychological interventions for affected patients is crucial. Although depression has been historically studied mostly in patients with solid malignancies, research focusing on patients with hematologic malignancies is growing. In this article, we describe what is known about depression in patients with hematologic malignancies, including its assessment, prevalence, risk factors, and implications. We also describe interventions to ameliorate depression in this population. Future research is needed to test effective and scalable interventions to reduce the burden of depression among patients with blood cancers.

Mortality among patients with diffuse large B-cell lymphoma and mental disorders: a population-based study.

BACKGROUND: Mental disorders have been reported in patients with diffuse large B-cell lymphoma (DLBCL), but studies examining their association with mortality are lacking. METHODS: We conducted a population-based study using linked administrative health-care databases from Ontario, Canada. All patients with DLBCL 18 years of age or older treated with rituximab-based therapy between January 1, 2005, and December 31, 2017, were identified and followed until March 1, 2020. Mental disorders were defined as either preexisting or postdiagnosis (after lymphoma treatment initiation). Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) between mental disorders and 1-year and all-cause mortality while controlling for covariates. RESULTS: We identified 10 299 patients with DLBCL. The median age of the cohort was 67 years; 46% of patients were female, and 28% had a preexisting mental disorder. At 1-year follow-up, 892 (9%) had a postdiagnosis mental disorder, and a total of 2008 (20%) patients died. Preexisting mental disorders were not associated with 1-year mortality (adjusted HR = 1.06, 95% confidence interval [CI] = 0.96 to 1.17, P = .25), but postdiagnosis disorders were (adjusted HR = 1.51, 95% CI = 1.26 to 1.82, P = .0001). During a median follow-up of 5.2 years, 2111 (22%) patients had a postdiagnosis mental disorder, and 4084 (40%) patients died. Both preexisting and postdiagnosis mental disorders were associated with worse all-cause mortality (preexisting adjusted HR = 1.12, 95% CI = 1.04 to 1.20, P = .0024; postdiagnosis adjusted HR = 1.63, 95% CI = 1.49 to 1.79, P < .0001). CONCLUSIONS: Patients with DLBCL and mental disorders had worse short-term and long-term mortality, particularly those with postdiagnosis mental disorders. Further studies are needed to examine mental health service utilization and factors mediating the relationship between mental disorders and inferior mortality.

Mental health disorders and survival among older patients with diffuse large B-cell lymphoma in the USA: a population-based study.

BACKGROUND: Mental health disorders can potentially decrease quality of life and survival in patients with cancer. Little is known about the survival implications of mental health disorders in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to evaluate the effect of pre-existing depression, anxiety, or both on survival in a US cohort of older patients with DLBCL. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database, we identified patients aged 67 years or older, diagnosed with DLBCL in the USA between Jan 1, 2001, and Dec 31, 2013. We used billing claims to identify patients with pre-existing depression, anxiety, or both before their DLBCL diagnosis. We compared 5-year overall survival and lymphoma-specific survival between these patients and those without pre-existing depression, anxiety, or both using Cox proportional analyses, adjusting for sociodemographic and clinical characteristics, including DLBCL stage, extranodal disease, and B symptoms. FINDINGS: Among 13 244 patients with DLBCL, 2094 (15·8%) had depression, anxiety, or both disorders; 6988 (52·8%) were female, and 12 468 (94·1%) were White. The median follow-up for the cohort was 2·0 years (IQR 0·4-6·9 years). 5-year overall survival was 27·0% (95% CI 25·1-28·9) for patients with these mental health disorders versus 37·4% (36·5-38·3) for those with no mental health disorder (hazard ratio [HR] 1·37, 95% CI 1·29-1·44). Although survival differences between mental health disorders were modest, those with depression alone had the worst survival compared with no mental health disorder (HR 1·37, 95% CI 1·28-1·47), followed by those with depression and anxiety (1·23, 1·08-1·41), and then anxiety alone (1·17, 1·06-1·29). Individuals with these pre-existing mental health disorders also had lower 5-year lymphoma-specific survival, with depression conferring the greatest effect (1·37, 1·26-1·49) followed by those with depression and anxiety (1·25, 1·07-1·47) and then anxiety alone (1·16, 1·03-1·31). INTERPRETATION: Pre-existing depression, anxiety, or both disorders present within 24 months before DLBCL diagnosis, worsens prognosis for patients with DLBCL. Our data underscore the need for universal and systematic mental health screening for this population, as mental health disorders are manageable, and improvements in this prevalent comorbidity might affect lymphoma-specific survival and overall survival. FUNDING: American Society of Hematology, National Cancer Institute, Alan J Hirschfield Award.

Precancer and cancer-associated depression and anxiety among older adults with blood cancers in the United States.

For patients with blood cancers, comorbid mental health disorders at diagnosis likely affect the entire disease trajectory, as they can interfere with disease information processing, lead to poor coping, and even cause delays in care. We aimed to characterize the prevalence of depression and anxiety in patients with blood cancers. Using the Surveillance, Epidemiology, and End Results-Medicare database, we identified patients ≥67 years old diagnosed with lymphoma, myeloma, leukemia, or myelodysplastic syndromes between 2000 and 2015. We determined the prevalence of precancer depression and anxiety and cancer-associated (CA) depression and anxiety using claims data. We identified factors associated with CA-depression and CA-anxiety in multivariate analyses. Among 75 691 patients, 18.6% had at least 1 diagnosis of depression or anxiety. Of the total cohort, 13.7% had precancer depression and/or precancer anxiety, while 4.9% had CA-depression or CA-anxiety. Compared with patients without precancer anxiety, those with precancer anxiety were more likely to have subsequent claims for CA-depression (odds ratio [OR] 2.98; 95% CI 2.61-3.41). Other factors associated with a higher risk of CA- depression included female sex, nonmarried status, higher comorbidity, and myeloma diagnosis. Patients with precancer depression were significantly more likely to have subsequent claims for CA-anxiety compared with patients without precancer depression (OR 3.01; 95% CI 2.63-3.44). Female sex and myeloma diagnosis were also associated with CA-anxiety. In this large cohort of older patients with newly diagnosed blood cancers, almost 1 in 5 suffered from depression or anxiety, highlighting a critical need for systematic mental health screening and management for this population.

Impact of cryopreservation and transit times of allogeneic grafts on hematopoietic and immune reconstitution.

We sought to evaluate the impact of cryopreservation of unrelated donor (URD) peripheral blood stem cell (PBSC) grafts on engraftment, chimerism, and immune reconstitution in the context of the COVID-19 pandemic. We reviewed stem cell product characteristics and clinical outcomes in 101 patients receiving cryopreserved PBSCs from URDs between January 1, 2019 and 31 December, 2020, compared with 203 patients receiving fresh URD PBSCs. We observed no differences in 6-month overall survival, progression-free survival, or nonrelapse mortality. Patients receiving cryopreserved PBSCs had delayed platelet engraftment and impaired reconstitution of white blood cells and T-cell subsets at day 30. Thirty-four percent of patients receiving cryopreserved grafts had CD3 chimerism <50% at day 30 after transplantation, compared with 14% of patients receiving fresh PBSCs (P = .0002). At day 100, this difference persisted (CD3+ chimerism <50%: 17% of cryopreserved cohort vs 6% of fresh cohort; P = .016). Greater product age at infusion was associated with increased graft failure, independent of cryopreservation. Receipt of grafts >48 hours old at time of cryopreservation or infusion significantly increased the risk of graft failure (subdistribution hazard ratio = 4.57; 95% confidence interval, 1.71-12.3; P = .0025). Our data indicate that cryopreservation is associated with similar overall short-term clinical outcomes compared with fresh PBSC. However, patients must be monitored closely for increased risk of other potentially adverse outcomes, including graft failure and poor immune recovery, particularly for grafts with older overall age at infusion. Longer-term follow-up is needed to determine impact on relapse and survival.

Goal of a "Good Death" in End-of-Life Care for Patients with Hematologic Malignancies-Are We Close?

PURPOSE OF REVIEW: The medical field has a critical role not only in prolonging life but also in helping patients achieve a good death. Early studies assessing end-of-life quality indicators to capture if a good death occurred demonstrated low rates of hospice use and high rates of intensive healthcare utilization near death among patients with hematologic malignancies, raising concerns about the quality of death. In this review, we examine trends in end-of-life care for patients with hematologic malignancies to determine if we are close to the goal of a good death. RECENT FINDINGS: Several cohort studies show that patients with blood cancers are often inadequately prepared for the dying process due to late goals of care discussions and they experience low rates of palliative and hospice care. More recent analyses of population-based data demonstrate some improvements over time, with significantly more patients receiving palliative care, enrolling in hospice, and having the opportunity to die at home compared to a decade ago. These encouraging trends are paradoxically accompanied by concomitant increases in late hospice enrollment and intensive healthcare utilization near death. Although we are closer to the goal of a good death for patients with hematologic malignancies, there is ample room for growth. To close the gap between the current state of care and a good death, we need research that engages patients, caregivers, hematologic oncologists, and policy-makers to develop innovative interventions that improve timeliness of goals of care discussions, expand palliative care integration, and increase hospice use.

Medical history of chemotherapy or immunosuppressive drug treatment and risk of amyotrophic lateral sclerosis (ALS).

A recent population-based analysis demonstrated lower risk of the lethal degenerative neuromuscular disease, amyotrophic lateral sclerosis (ALS) associated with history of the use of 'antineoplastic agents' and 'immunosuppressants'. To see if this finding was generalizable to other ALS cohorts, we examined associations between use of these agents and ALS risk in an independent case-control study of n = 414 ALS patients and n = 361 controls in an Eastern US population. Controls were sampled from the general population and among non-neurodegenerative disease patients. A history of chemotherapy treatment was significantly associated with a decreased ALS risk (OR 0.46, 95% CI 0.22-0.89, P = 0.026). We did not observe an association between risk of ALS and immunosuppressant therapy use (OR 0.78, 95% CI 0.50-1.02, P = 0.23). Analyses were adjusted for age, gender, and smoking. Our results support the prior report for chemotherapy treatment and lead to further discussion of the underlying mechanism.

How do Medical Societies Select Science for Conference Presentation? How Should They?

INTRODUCTION: Nothing has been published to describe the practices of medical societies in choosing abstracts for presentations at their annual meetings. We surveyed medical societies to determine their practices, and also present a theoretical analysis of the topic. METHODS: We contacted a convenience sample of large U.S. medical conferences, and determined their approach to choosing abstracts. We obtained information from web sites, telephone, and email. Our theoretical analysis compares values-based and empirical approaches for scoring system development. RESULTS: We contacted 32 societies and obtained data on 28 (response rate 88%). We excluded one upon learning that research was not presented at its annual meeting, leaving 27 for analysis. Only 2 (7%) made their abstract scoring process available to submitters. Reviews were blinded in most societies (21;78%), and all but one asked reviewers to recuse themselves for conflict of interest (96%). All required ≥3 reviewers. Of the 24 providing information on how scores were generated, 21 (88%) reported using a single gestalt score, and three used a combined score created from pooled domain-specific sub-scores. We present a framework for societies to use in choosing abstracts, and demonstrate its application in the development of a new scoring system. CONCLUSIONS: Most medical societies use subjective, gestalt methods to select research for presentation at their annual meetings and do not disclose to submitters the details of how abstracts are chosen. We present a new scoring system that is transparent to submitters and reviewers alike with an accompanying statement of values and ground rules. We discuss the challenges faced in selecting abstracts for a large scientific meeting and share the values and practical considerations that undergird the new system.

MannDB - a microbial database of automated protein sequence analyses and evidence integration for protein characterization.

BACKGROUND: MannDB was created to meet a need for rapid, comprehensive automated protein sequence analyses to support selection of proteins suitable as targets for driving the development of reagents for pathogen or protein toxin detection. Because a large number of open-source tools were needed, it was necessary to produce a software system to scale the computations for whole-proteome analysis. Thus, we built a fully automated system for executing software tools and for storage, integration, and display of automated protein sequence analysis and annotation data. DESCRIPTION: MannDB is a relational database that organizes data resulting from fully automated, high-throughput protein-sequence analyses using open-source tools. Types of analyses provided include predictions of cleavage, chemical properties, classification, features, functional assignment, post-translational modifications, motifs, antigenicity, and secondary structure. Proteomes (lists of hypothetical and known proteins) are downloaded and parsed from Genbank and then inserted into MannDB, and annotations from SwissProt are downloaded when identifiers are found in the Genbank entry or when identical sequences are identified. Currently 36 open-source tools are run against MannDB protein sequences either on local systems or by means of batch submission to external servers. In addition, BLAST against protein entries in MvirDB, our database of microbial virulence factors, is performed. A web client browser enables viewing of computational results and downloaded annotations, and a query tool enables structured and free-text search capabilities. When available, links to external databases, including MvirDB, are provided. MannDB contains whole-proteome analyses for at least one representative organism from each category of biological threat organism listed by APHIS, CDC, HHS, NIAID, USDA, USFDA, and WHO. CONCLUSION: MannDB comprises a large number of genomes and comprehensive protein sequence analyses representing organisms listed as high-priority agents on the websites of several governmental organizations concerned with bio-terrorism. MannDB provides the user with a BLAST interface for comparison of native and non-native sequences and a query tool for conveniently selecting proteins of interest. In addition, the user has access to a web-based browser that compiles comprehensive and extensive reports. Access to MannDB is freely available at http://manndb.llnl.gov/.

System to assess genome sequencing needs for viral protein diagnostics and therapeutics.

Computational analyses of genome sequences may elucidate protein signatures unique to a target pathogen. We constructed a Protein Signature Pipeline to guide the selection of short peptide sequences to serve as targets for detection and therapeutics. In silico identification of good target peptides that are conserved among strains and unique compared to other species generates a list of peptides. These peptides may be developed in the laboratory as targets of antibody, peptide, and ligand binding for detection assays and therapeutics or as targets for vaccine development. In this paper, we assess how the amount of sequence data affects our ability to identify conserved, unique protein signature candidates. To determine the amount of sequence data required to select good protein signature candidates, we have built a computationally intensive system called the Sequencing Analysis Pipeline (SAP). The SAP performs thousands of Monte Carlo simulations, each calling the Protein Signature Pipeline, to assess how the amount of sequence data for a target organism affects the ability to predict peptide signature candidates. Viral species differ substantially in the number of genomes required to predict protein signature targets. Patterns do not appear based on genome structure. There are more protein than DNA signatures due to greater intraspecific conservation at the protein than at the nucleotide level. We conclude that it is necessary to use the SAP as a dynamic system to assess the need for continued sequencing for each species individually and to update predictions with each additional genome that is sequenced.

Limitations of TaqMan PCR for detecting divergent viral pathogens illustrated by hepatitis A, B, C, and E viruses and human immunodeficiency virus.

Recent events illustrate the imperative to rapidly and accurately detect and identify pathogens during disease outbreaks, whether they are natural or engineered. Particularly for our primary goal of detecting bioterrorist releases, detection techniques must be both species-wide (capable of detecting all known strains of a given species) and species specific. Due to classification restrictions on the publication of data for species that may pose a bioterror threat, we illustrate the challenges of finding such assays using five nonthreat organisms that are nevertheless of public health concern: human immunodeficiency virus (HIV) and four species of hepatitis viruses. Fluorogenic probe-based PCR assays (TaqMan; Perkin-Elmer Corp., Applied Biosystems, Foster City, Calif.) may be sensitive, fast methods for the identification of species in which the genome is conserved among strains, such as hepatitis A virus. For species such as HIV, however, the strains are highly divergent. We use computational methods to show that nine TaqMan primer and probe sequences, or signatures, are needed to ensure that all strains will be detected, but this is an unfeasible number, considering the cost of TaqMan probes. Strains of hepatitis B, C, and E viruses show intermediate divergence, so that two to three TaqMan signatures are required to detect all strains of each virus. We conclude that for species such as hepatitis A virus with high levels of sequence conservation among strains, signatures can be found computationally for detection by the TaqMan assay, which is a sensitive, rapid, and cost-effective method. However, for species such as HIV with substantial genetic divergence among strains, the TaqMan assay becomes unfeasible and alternative detection methods may be required. We compare the TaqMan assay with some of the alternative nucleic acid-based detection techniques of microarray, chip, and bead technologies in terms of sensitivity, speed, and cost.

High-density microarray of small-subunit ribosomal DNA probes.

Ribosomal DNA sequence analysis, originally conceived as a way to provide a universal phylogeny for life forms, has proven useful in many areas of biological research. Some of the most promising applications of this approach are presently limited by the rate at which sequences can be analyzed. As a step toward overcoming this limitation, we have investigated the use of photolithography chip technology to perform sequence analyses on amplified small-subunit rRNA genes. The GeneChip (Affymetrix Corporation) contained 31,179 20-mer oligonucleotides that were complementary to a subalignment of sequences in the Ribosomal Database Project (RDP) (B. L. Maidak et al., Nucleic Acids Res. 29:173-174, 2001). The chip and standard Affymetrix software were able to correctly match small-subunit ribosomal DNA amplicons with the corresponding sequences in the RDP database for 15 of 17 bacterial species grown in pure culture. When bacteria collected from an air sample were tested, the method compared favorably with cloning and sequencing amplicons in determining the presence of phylogenetic groups. However, the method could not resolve the individual sequences comprising a complex mixed sample. Given these results and the potential for future enhancement of this technology, it may become widely useful.