Diagnosis Of Hematological Malignancies Research Articles

Hematologic malignancies in Li-Fraumeni syndrome.

10613 Background: Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by mutations in the tumor suppressor gene TP53. Since its discovery, a growing list of cancers have been described in association with LFS, predominantly solid tumors. However, hematologic malignancies (HMs) cumulatively account for 4-10% of cancer diagnoses in LFS. In this study, we present the largest series of HMs in families with LFS with detailed clinical courses. Methods: This was a two-center retrospective observational cohort study conducted at the University of Utah and the University of Wisconsin-Madison with IRB approval. Cancer genetics clinic registries were reviewed to identify all families with LFS who also had a confirmed diagnosis of a HM. To meet criteria for LFS, the patient had to have a confirmed germline pathologic or likely pathologic TP53 variant. Patients with a TP53 variant of unknown significance (VUS) were also included if they met classical LFS testing criteria. Data was gathered by manual chart review of both the families’ histories and electronic health records. Results: Among the 121 families identified with LFS, 35 (29%) families had one or more HM. Of these, 17 individuals from 16 families (13%) had confirmed germline TP53 mutations. The most frequent HMs found were acute lymphoblastic leukemia (ALL) (n=6), non-Hodgkin lymphoma (NHL) (n=5), myelodysplastic syndromes (MDS) (n=3), and chronic lymphocytic leukemia (CLL) (n=2). Acute myeloid leukemia (AML), Langerhans cell histiocytosis (LCH), and chronic myeloid leukemia (CML) were each diagnosed once. Most cases were identified in adulthood (n=12, 71%). Of the 19 total HMs, the minority (n=5, 26%) were diagnosed post-cytotoxic therapy and only six (35%) individuals had received a diagnosis of LFS prior to HM diagnosis. The MDS/AML cohort (n=4) all exhibited bi-allelic inactivation of TP53. Two of these four patients achieved long term survival after matched-unrelated donor (MUD) hematopoietic stem cell transplant (HSCT). All three patients who underwent MUD donor HSCT had immune-mediated adverse events. Conclusions: In this study we found a significantly higher incidence of HMs in LFS than previously described, with a predominance of lymphoid over myeloid malignancies. The majority of patients had excellent outcomes after standard of care therapy pointing towards more favorable outcomes for patients with LFS and HMs than previously reported. We also report several unusual immune-mediated adverse events in our patients indicating possible immunogenicity of some TP53 variants. Most patients did not have prior exposure to cytotoxic treatments and were diagnosed with the HM prior to their LFS diagnosis. We also show that 38% of individuals with an HM have multiple family members with an HM, consistent with a familial HM pattern. This underscores the importance of detailed family and personal histories in HM patients found to carry a somatic TP53 variant.

Pseudohyperkalemia in pediatric patients with newly diagnosed hematological malignancies

Patients with newly diagnosed hematological malignancies often present with a considerable cellular burden, leading to complications including hyperkalemia. However, pseudohyperkalemia, arising from in vitro cell lysis, can pose challenges in clinical practice. Although pseudohyperkalemia is frequently reported in adult hematological malignancies, its occurrence in pediatric patients is underreported, and its incidence in this demographic remains unclear. We retrospectively reviewed the medical records of pediatric patients who received a new diagnosis of hematological malignancies from 2011 to 2022 at Taichung Veterans General Hospital. Hyperkalemia was defined by a serum or plasma potassium level exceeding 5.5 mEq/L. Pseudohyperkalemia was defined by 1) a potassium decrease of over 1 mEq/L in within 4 h without intervention or 2) the absence of electrocardiography changes indicative of hyperkalemia. Cases with apparent red blood cell hemolysis were excluded. A total of 157 pediatric patients with a new diagnosis of hematological malignancies were included, 14 of whom exhibited hyperkalemia. Among these 14 cases, 7 cases (4.5%) were of pseudohyperkalemia. This rate increased to 21.2% in patients with initial hyperleukocytosis. Pseudohyperkalemia was associated with a higher initial white blood cell count and lower serum sodium level. All episodes of pseudohyperkalemia occurred in the pediatric emergency department, where samples were obtained as plasma, whereas all true hyperkalemia cases were observed in the ordinary ward or intensive care unit, where samples were obtained as serum. Timely recognition of pseudohyperkalemia is crucial to avoiding unnecessary potassium-lowering interventions in pediatric patients with newly diagnosed hematological malignancies.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

Recommendations for using artificial intelligence in clinical flow cytometry.

Flow cytometry is a key clinical tool in the diagnosis of many hematologic malignancies and traditionally requires close inspection of digital data by hematopathologists with expert domain knowledge. Advances in artificial intelligence (AI) are transferable to flow cytometry and have the potential to improve efficiency and prioritization of cases, reduce errors, and highlight fundamental, previously unrecognized associations with underlying biological processes. As a multidisciplinary group of stakeholders, we review a range of critical considerations for appropriately applying AI to clinical flow cytometry, including use case identification, low and high risk use cases, validation, revalidation, computational considerations, and the present regulatory frameworks surrounding AI in clinical medicine. In particular, we provide practical guidance for the development, implementation, and suggestions for potential regulation of AI-based methods in the clinical flow cytometry laboratory. We expect these recommendations to be a helpful initial framework of reference, which will also require additional updates as the field matures.

Aptamer-Based Multiparameter Analysis for Molecular Profiling of Hematological Malignancies.

The subtypes of hematological malignancies (HM) with minimal molecular profile differences display an extremely heterogeneous clinical course and a discrepant response to certain treatment regimens. Profiling the surface protein markers offers a potent solution for precision diagnosis of HM by differentiating among the subtypes of cancer cells. Herein, we report the use of Cell-SELEX technology to generate a panel of high-affinity aptamer probes that are able to discriminate subtle differences among surface protein profiles between different HM cells. Experimental results show that these aptamers with apparent dissociation constants (Kd) below 10 nM display a unique recognition pattern on different HM subtypes. By combining a machine learning model on the basis of partial least-squares discriminant analysis, 100% accuracy was achieved for the classification of different HM cells. Furthermore, we preliminarily validated the effectiveness of the aptamer-based multiparameter analysis strategy from a clinical perspective by accurately classifying complex clinical samples, thus providing a promising molecular tool for precise HM phenotyping.

“I don’t have a choice but to keep getting up and doing the things that protect her”: The informal caregiver’s adaptation to the cancer diagnosis

Purpose Patients with hematologic malignancies (HM) typically rely on informal caregivers for support. Caregivers experience distress, poorer health, and lower quality of life. This study aimed to understand caregivers’ experiences adapting to, and making meaning of, their family members’ cancer diagnosis and treatment. Approach Qualitative, constructivist approach. Participants Caregivers (N = 28) of patients with HM within three months of diagnosis. Methods A descriptive content analysis was used to analyze semi-structured interview responses and generate themes. Findings Six themes emerged: power and control (powerlessness, empowerment, relinquishing control/accepting help), protection (gatekeeping, protective buffering), integrating the diagnosis, tolerating uncertainty, preparedness for the caregiver role, and maintaining positivity. Conclusions Findings highlight challenges and resilience-promoting processes for caregivers adapting to HM diagnosis and treatment. Implications for Psychosocial Providers Psychological and supportive care interventions can promote acceptance of the diagnosis, preparation for caregiving, navigation of power and control, and targeted coping strategies.

Hematological Neoplasms with Eosinophilia.

Eosinophils in peripheral blood account for 0.3-5% of leukocytes, which is equivalent to 0.05-0.5 × 109/L. A count above 0.5 × 109/L is considered to indicate eosinophilia, while a count equal to or above 1.5 × 109/L is defined as hypereosinophilia. In bone marrow aspirate, eosinophilia is considered when eosinophils make up more than 6% of the total nuclear cells. In daily clinical practice, the most common causes of reactive eosinophilia are non-hematologic, whether they are non-neoplastic (allergic diseases, drugs, infections, or immunological diseases) or neoplastic (solid tumors). Eosinophilia that is associated with a hematological malignancy may be reactive or secondary to the production of eosinophilopoietic cytokines, and this is mainly seen in lymphoid neoplasms (Hodgkin lymphoma, mature T-cell neoplasms, lymphocytic variant of hypereosinophilic syndrome, and B-acute lymphoblastic leukemia/lymphoma). Eosinophilia that is associated with a hematological malignancy may also be neoplastic or primary, derived from the malignant clone, usually in myeloid neoplasms or with its origin in stem cells (myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, acute myeloid leukemia with core binding factor translocations, mastocytosis, myeloproliferative neoplasms, myelodysplastic/myeloproliferative neoplasms, and myelodysplastic neoplasms). There are no concrete data in standardized cytological and cytometric procedures that could predict whether eosinophilia is reactive or clonal. The verification is usually indirect, based on the categorization of the accompanying hematologic malignancy. This review focuses on the broad differential diagnosis of hematological malignancies with eosinophilia.

Ophthalmic manifestations in hematological malignancies: An observational study from a tertiary care health center in Eastern India.

This study aimed to document the spectrum of ocular manifestations of hematological malignancies presenting to a tertiary health center in Eastern India and their association with blood parameters. This hospital-based cross-sectional study was conducted from August 2021 to July 2022. Patients diagnosed with leukemia, lymphoma, and multiple myeloma were enrolled in the study. A comprehensive ophthalmic evaluation was done in each case. A total of 97 patients with a confirmed diagnosis of hematological malignancies and meeting the inclusion and exclusion criteria were included in the study. Ocular manifestations were noted in 48 (49.48%) patients. Acute lymphocytic leukemia accounted for 35.4% of cases, followed by acute myeloid leukemia (31.25%), lymphoma (4.2%), and minimum manifestation in multiple myeloma (2.1%) patients. Among 48 patients with ocular manifestations, anterior segment involvement was found in 6.2% of cases, with subconjunctival hemorrhage being the most common, and the posterior segment was involved in 100% of patients, with intraretinal hemorrhages being the most common manifestation. A statistically significant association was noted between hemoglobin, total red blood cell count, and total platelet count with posterior segment manifestations ( p < 0.001). On multivariable logistic regression, only total leucocyte count and total platelet count were significant predictors for ocular manifestation. Indirect involvement of the retina is the most common ocular pathology in hematological malignancies, with intraretinal hemorrhages being the most common finding. Ophthalmic examination is highly recommended as a part of the routine evaluation at the time of diagnosis of hematological malignancies and periodically thereafter to diagnose any ocular involvement.

Artificial Intelligence and Machine Learning in Early Diagnosis of Hematological Malignancies

In this Era of Machine Learning (ML) and Artificial Intelligence (AI), there is no field left in which these two have not left their impact. Blood cancer or Leukemia is now a days one of the very common hematological disorders. It is very difficult to diagnose leukemia in its very early stages, when it is diagnosed in its later stages it is very difficult to treat it because there are very limited treatments available. So, it is now very important to improve the diagnostic tools and techniques in traditional diagnostics procedures. ML and AI methods have recently garnered a great deal of attention in the field of cancer research by making a noticeable contribution to the growth of predictive medicine and modern oncological practices. Considerable focus has been particularly directed toward hematologic malignancies because of the complexity of detecting early symptoms. Many patients with blood cancer do not get properly diagnosed until their cancer has reached an unnumbered stage with limited treatment prospects. Hence, the state-of-the-art revolves around the latest artificial intelligence applications in hematology management.

Venous thromboembolism in critically ill adult patients with hematologic malignancy: a population-based cohort study.

The aim of this study was to describe the incidence of venous thromboembolism (VTE) and major bleeding among hospitalized patients with hematologic malignancy, assessing its association with critical illness and other baseline characteristics. We conducted a population-based cohort study of hospitalized adults with a new diagnosis of hematologic malignancy in Ontario, Canada, between 2006 and 2017. The primary outcome was VTE (pulmonary embolism or deep venous thrombosis). Secondary outcomes were major bleeding and in-hospital mortality. We compared the incidence of VTE between intensive care unit (ICU) and non-ICU patients and described the association of other baseline characteristics and VTE. Among 76,803 eligible patients (mean age 67years [standard deviation, SD, 15]), 20,524 had at least one ICU admission. The incidence of VTE was 3.7% in ICU patients compared to 1.2% in non-ICU patients (odds ratio [OR] 3.08; 95% confidence interval [CI] 2.77-3.42). The incidence of major bleeding was 7.6% and 2.4% (OR 3.33; 95% CI 3.09-3.58), respectively. The association of critical illness and VTE remained significant after adjusting for potential confounders (OR 2.92; 95% CI 2.62-3.25). We observed a higher incidence of VTE among specific subtypes of hematologic malignancy and patients with prior VTE (OR 6.64; 95% CI 5.42-8.14). Admission more than 1year after diagnosis of hematologic malignancy (OR 0.64; 95% CI 0.56-0.74) and platelet count ≤ 50 × 109/L at the time of hospitalization (OR 0.63; 95% CI 0.48-0.84) were associated with a lower incidence of VTE. Among patients with hematologic malignancy, critical illness and certain baseline characteristics were associated with a higher incidence of VTE.

Deciphering Disease: The Critical Role of Bone Marrow Aspirate and Biopsy in Diagnostic Medicine

Background: Haematological malignancies, such as non-Hodgkin lymphomas and multiple myeloma, present diagnostic challenges due to the heterogeneity and complexity of their presentation. The importance of accurate diagnostic methods, like bone marrow aspirate (BMA) and bone marrow biopsy (BMB), is paramount for patient prognosis and therapeutic decisions. Objective: This manuscript aims to critically evaluate the role of bone marrow aspiration and its efficacy with bone marrow biopsy in diagnosing and assessing different medical conditions, offering an in-depth understanding of their individual and combined implications. Methods: Diverse studies exploring on lymphomas, Leukaemia and research on multiple myeloma were analysed. The emphasis was on the diagnostic discrepancies and complementarities between BMA and BMB. Additionally, the evolving role of advanced tools like PET-CT, flow cytometry, and their integration with traditional methodologies were examined. Results: While BMA and BMB both play crucial roles in the diagnostic paradigm, there exists a tendency for BMA to underestimate plasma cell involvement in certain cases. Additionally, PET-CT scans and flow cytometry, when combined with conventional techniques, enhance diagnostic accuracy. However, the application of these techniques should be individualized based on specific clinical scenarios, with considerations for costeffectiveness and practical implications. Conclusion: The multifaceted diagnosis of haematological malignancies mandates a holistic approach, integrating both traditional and advanced methodologies. An interdisciplinary approach, prioritizing patient-specific nuances, ensures precise diagnoses, laying the groundwork for optimal therapeutic outcomes. Future research endeavours should focus on refining these diagnostic algorithms to align with the rapidly progressing field of haematology

Immunocytochemistry on frozen-embedded cell block for the diagnosis of hematolymphoid cytology specimen: a straightforward alternative to the conventional cell block.

Agarose-based cell block (CB) technique can be modified to be combined with the frozen section technique for the preparation of a high-quality frozen-embedded CB (F-CB) from an effusion or fine-needle aspiration (FNA) cytology sample. This combined technique can be effectively used for the immunocharacterization of the hematolymphoid cells on F-CB. To demonstrate the applicability of performing diagnostic ICC on F-CB, we have analyzed the immunophenotype of the hematolymphoid cells in a series of eight cases of effusions and eight cases of FNA cytology specimens by using CB-ICC on sections cut from frozen-embedded CBs. The SurePathTM residue or cytologic material scraped off from the FNA cytology smear that was diagnostic for or suspicious of hematolymphoid malignancy was pelleted and pre-embedded in agarose. Half of the agarose-embedded pellet was frozen-embedded in OCT compound for the preparation of F-CB, while the other half was processed for the preparation of paraffin-embedded CB. Sections cut from the F-CB and P-CB were used for CB-ICC. Panels of ICC on the F-CBs could enable the immunocytochemical differential diagnosis of large cell hematologic malignancies that encompass anaplastic large cell lymphoma and other forms of large-cell hematolymphoid malignancies such as large B-cell lymphomas, anaplastic plasma cell myeloma, myeloid sarcoma, and T-lymphoblastic lymphoma. It also appeared that the small B-cell lymphomas in the effusions or FNAs could be differentially diagnosed with the aid of CB-ICC on the F-CB. A modified agarose-based CB technique can be combined with the frozen-embedded CB method for the preparation of F-CB that can be directly used for the immunocytochemical differential diagnosis of hematolymphoid cytology samples.

An Attempt to Determine Hematological Malignancies in Selected Patients: A Cytogenetical Approach

Diagnosis and treatment of hematological malignancies, a diverse category of tumors that begin in the blood and bone marrow, are extremely difficult. Our knowledge of these conditions has been revolutionized by the development of cytogenetics, the study of chromosomes and genetic abnormalities. A total of 180 patients with benign and malignant hematological malignancy had peripheral bone marrow or blood samples obtained using the standard G-banding procedure. Fifty-one percent of patients had normal karyotypes. In addition, thirty individuals (15%) had a complicated karyotype whereas eighty-five percent (85%) had a normal one. Three-hundred and three percent of patients were diagnosed with Pre-B Acute Lymphoblastic Leukemia (Pre-B ALL), followed by twenty percent with Chronic Myelogenous Leukemia (CML), and fourteen percent with Acute Lymphocytic Leukemia.

Memorial lecture to the 100th anniversary of the birth of Professor Yu.I. Lorie

In 2022, the 100th anniversary of the birth of Professor Yu.I. Lorie was celebrated. Yuri Ivanovich Lorie is a talented Russian internal medicine specialist and hematologist, a wonderful teacher, and a person of great personal charm. Yu.I. Lorie is the founder of a new direction of hematology in Russia – oncohematology – and the establisher of a school based on deep knowledge and understanding of the oncological principles of hematological malignancies. Yuri Ivanovich Lorie lived a short (only 54 years) but bright life, utterly devoted to Russian medicine. He left a great legacy – a modern, rapidly developing direction in Russian medicine and a school of students who successfully continued the work he started. Looking back at the scientific and practical activities of Yu.I. Lorie and those emotional scientific debates that his colleagues and students remember, it becomes clear how many modern trends in the understanding of oncogenesis, diagnosis and treatment of hematological malignancies this legendary scientist established.

Analytic Validation of Optical Genome Mapping in Hematological Malignancies.

Structural variations (SVs) play a key role in the pathogenicity of hematological malignancies. Standard-of-care (SOC) methods such as karyotyping and fluorescence in situ hybridization (FISH), which have been employed globally for the past three decades, have significant limitations in terms of resolution and the number of recurrent aberrations that can be simultaneously assessed, respectively. Next-generation sequencing (NGS)-based technologies are now widely used to detect clinically significant sequence variants but are limited in their ability to accurately detect SVs. Optical genome mapping (OGM) is an emerging technology enabling the genome-wide detection of all classes of SVs at a significantly higher resolution than karyotyping and FISH. OGM requires neither cultured cells nor amplification of DNA, addressing the limitations of culture and amplification biases. This study reports the clinical validation of OGM as a laboratory-developed test (LDT) according to stringent regulatory (CAP/CLIA) guidelines for genome-wide SV detection in different hematological malignancies. In total, 60 cases with hematological malignancies (of various subtypes), 18 controls, and 2 cancer cell lines were used for this study. Ultra-high-molecular-weight DNA was extracted from the samples, fluorescently labeled, and run on the Bionano Saphyr system. A total of 215 datasets, Inc.luding replicates, were generated, and analyzed successfully. Sample data were then analyzed using either disease-specific or pan-cancer-specific BED files to prioritize calls that are known to be diagnostically or prognostically relevant. Sensitivity, specificity, and reproducibility were 100%, 100%, and 96%, respectively. Following the validation, 14 cases and 10 controls were run and analyzed using OGM at three outside laboratories showing reproducibility of 96.4%. OGM found more clinically relevant SVs compared to SOC testing due to its ability to detect all classes of SVs at higher resolution. The results of this validation study demonstrate the superiority of OGM over traditional SOC methods for the detection of SVs for the accurate diagnosis of various hematological malignancies.

Evaluation of Platelet and Clotting Parameters in Hematologic Malignancies and Hematopoietic Stem Cell Transplantation Patients with Candidemia

1.Backgroud In recent years, the number and proportion of deaths from fungal infections have increased year by year. The fatality rate of fungemia is about 0.4 per 100 000 [Pfaller MA, et al. Clin Microbiol Rev. 2007]. Chemotherapy can effectively treat hematological malignancies. Data from multi-center studies in China show that the overall mortality rate of patients receiving chemotherapy for hematological malignancies is only 1.5%, and the mortality rate of patients with clinically diagnosed invasive fungi is as high as 11.7% [ Sun Y, et al. Tumor Biol, 2015]. The surveillance data of China Hospital Invasive Fungal Disease Surveillance Network from 2015 to 2017 showed that Candida albicans was the most common pathogen among 4 010 Candida strains isolated from patients with candidemia from 77 hospitals in China [Xiao M, et al. J Infect Dis, 2020]. 2.Methods We conducted a retrospective study that collected relevant clinical information from 34 hematologic malignancies and hematopoietic stem cell transplantation (HSCT) patients with candidemia between 2017 to 2022 in Hematology Hospital, Chinese Academy of Medical Sciences. The blood specimens of patients suspected to have candidemia were collected and cultured. After diagnosis, they were regarded as the candidemia group, and 107 healthy people were selected as the control group. Candidemia is classified as invasive or non-invasive according to whether it involves tissues or organs damage. Blood routine and clotting related tests were performed at the Clinical Laboratory Center of Hematology Hospital, Chinese Academy of Medical Sciences. 3.Results 3.1 General Characteristics of the Study Subjects A total of 34 hematologic malignancies and HSCT patients with candidemia were recruited. Of these 34 patients, 28 were male and 6 were female. Meanwhile, 107 healthy people were recruited as control group. The characteristics of two groups are presented in Table 1. 3.2 Hematologic malignancies and HSCT patients with abnormal blood routine are at increased risk of candidemia Hematologic malignancies and HSCT patients with candidemia present as lower white blood cell count, lower red blood cell count, higher lymphocyte ratio, lower lymphocyte count, lower monocyte count, lower neutrophil count and ratio, and lower NEU/PLT compared with control group. 3.3 Candidemia cause platelet activation in hematologic malignancies and HSCT patients The PLT and PCT of hematologic malignancies and HSCT patients with candidemia were significantly lower than control group. Meanwhile, MPV and P-LCR were higher than control group. It revealed that hematologic malignancies and HSCT patients with candidemia may present with platelet activation, while PLT and PCT level were low in this group. 3.4 Invasive candidemia can cause a decrease in platelets and an increase in MPV/PLT Furthermore, we found that PLT level was lower and MPV/PLT level was higher in hematologic malignancies and HSCT patients with invasive candidemia than hematologic malignancies and HSCT patients with non-invasive candidemia. 3.5 Candidemia can cause coagulation dysfunction in hematologic malignancies and HSCT patients Hematologic malignancies and HSCT patients with candidemia had coagulation dysfunction symptoms such as prolonged PT and APTT, reduced antithrombin III activity, and high INR. 3.6 Candidemia can cause hyperfibrinolysis in hematologic malignancies and HSCT patients Meanwhile, hematologic malignancies and HSCT patients with candidemia showed reduced TT, increasing fibrinogen, fibrinogen degradation products, and D-Dimer. 4.Conclusion In conclusion, we demonstrated for the first time that decreasing platelet count and activated platelet function in hematologic malignancies and HSCT patients with candidemia. Invasive candidemia may cause lower platelet count and more activated platelet function in hematologic malignancies and HSCT patients. At the same time, we found that candidemia can cause coagulation dysfunction and hyperfibrinolysis in hematologic malignancies and HSCT patients. We hope that our study can provide a new perspective on the cognition and diagnosis of hematologic malignancies and HSCT patients with candidemia.

Social Determinants of Health (SDoH) Scores for Adolescent and Young Adults (AYAs) at a Public Safety-Net Teaching Hospital: A Retrospective Cohort Analysis

Introduction The majority of AYAs, ages 15-39, are treated outside of major academic centers and recent data suggests inferior outcomes for these patients. Social determinants of health play an important role in the outcomes for AYAs due to longer duration of survival, less established social networks, diminished support systems, and financial toxicity. Here we report SDoH data from self-reported screening questionnaires in the EPIC electronic medical record (EMR). The purpose of this study was to examine differences in SDoH between AYAs and older adults from diagnosis of hematological malignancy through 5 years at a nonprofit public safety-net health system in Cleveland, Ohio. Methods Using a retrospective cohort design, patients with hematological malignancies (acute/chronic leukemia, lymphoma, myelodysplastic syndrome, myeloproliferative neoplasms, etc.) identified in the EMR by ICD code, were assigned two groups, AYAs (15-39) and older adults (&amp;gt;39 years of age). Social determinants of health data screenings for Alcohol Use, Depression, Financial Resource Strain, Food Insecurity, and Transportation Needs were evaluated beginning at malignancy diagnosis through 5 years. Scores for each item rated from 0 to 3 based on 3 questions pertaining to each item. Data was stratified by low scores (0 to 1) and high scores (2 to 3) and cumulative incidence was obtained at timepoints of diagnosis (-7 to +7 days), and annually through year 5 from diagnosis. Statistical significance was performed using Kruskal-Wallis chi square analysis and odds ratios (OR). Results A total of 1710 patients with 11010 screens were identified from days 7 prior to diagnosis to 12070 after diagnosis. Any positive score (score of 1 to 3) was obtained in 93% of AYA screens and 95% of &amp;gt;39 years of age screens. To further investigate the degree of positivity of SDoH screen, scores were stratified by low (0 to 1) and high (2 to 3). At initial diagnosis, no statistical difference between AYAs and &amp;gt;39 years was found (x 2=0.97, p=0.3251). A statistical difference was seen for cumulative incidence at all timepoints after diagnosis: 1 year x 2=9.23, p=.0024; 2 years x 2=15.86, p=0.0001; 3 years x 2=18.58, p&amp;lt;0.00001; 4 years x 2=25.47, p&amp;lt;0.00001; 5 years x 2=25.32, p&amp;lt;0.00001 (table 1). Odds ratios (with 95% CI) were statistically significant at all timepoints after diagnosis: 1 year 2.06 (1.28-3.13), p=0.0029; 2 years 1.77 (1.21-2.58), p=0.0031; 3 years 1.97 (1.44-2.69), p=&amp;lt;0.0001; 4 years 2.07 (1.55-2.76), p=&amp;lt;0.0001; 5 years 1.94 (1.49-2.53), p=&amp;lt;0.0001, (figure 1). Most prominently positive were self-reported depression screens in AYAs at 1 year (x 2=6.54, p=0.0105), 2 years (x 2=16.35, p=.0001), 3 years (x 2=21.42, p&amp;lt;0.00001), 4 years (x 2=19.09, p&amp;lt;0.00001), 5 years (x 2=26.86, p&amp;lt;0.00001). Lastly, we assessed annual incidences for total SDoH screens which showed significance at 1 year (x 2=8.73, p=.0031), 3 years (x 2=11.04, p=.0009), and 4 years (x 2=7.96, p=.0048) but not at 2 or 5 years (x 2=1.17, p=0.2798 and x 2=1.40, p=0.2373, respectively). Conclusions Within a highly vulnerable population at a public safety-net hospital, AYAs with hematological malignancies had a statistically significant higher proportion of self-reported Alcohol Use, Depression, Financial Resource Strain, Food Insecurity, and Transportation Needs versus older adults. While no statistical difference existed at time of diagnosis, a larger proportion of high-risk scores were seen beginning at 1 year after diagnosis through 5 years after diagnosis. In addition, odds ratios were most prominent at 1 year and 4 years after diagnosis possibly suggesting a higher social toxicity seen by AYAs in active treatment and survivorship. Specific attention should be given to mental health services for AYAs throughout treatment and prospective observation studies should be done in order to confirm the observed results. In addition, further research is needed to assess the role of hospital setting type (academic, county, community) and presence of an AYA program on social determinants of health for AYAs as well as implementation of social interventions that may mitigate these outcomes.

Clonal Hematopoiesis and Venous Thromboembolism in the UK Biobank

Background: Patients with myeloid malignancies have an increased risk of thrombosis, but less is known about the risk of thrombosis in clonal hematopoiesis of indeterminate potential (CHIP). We evaluated genotype-specific associations between CHIP and both prevalent and incident venous thromboembolism (VTE) in the largest such analysis to date of the UK Biobank. Methods: We examined 425,573 individuals without a prevalent hematologic malignancy diagnosis from the UK Biobank. Whole exome sequencing and single nucleotide polymorphism array data were analyzed to identify individuals with CHIP and/or mosaic chromosomal alterations (mCA), respectively. Prevalent and incident VTE cases were ascertained with respect to the time of DNA sampling. VTE events were identified based on ICD10 codes, including but not limited to, pulmonary embolism, phlebitis/thrombophlebitis of deep veins of lower veins, portal vein thrombosis, and Budd Chiari syndrome. Median follow-up time for incident VTE was 11.8 years. Associations of CHIP and VTE were assessed using logistic regression for prevalent analyses and Cox proportional hazards for incident analyses. The association analyses were adjusted for age at the time of DNA sampling, sex, Caucasian ancestry, genetic principal components, ever smoked status, and body mass index (BMI) as covariates. Results: Prevalent VTE and CHIP: While CHIP overall was not associated with an increased risk of prevalent VTE (odds ratio (OR) 1.06; 95% CI 0.87-1.28, P= 0.56) (Figure 1), JAK2-mutant CHIP and JAK2 CHIP with loss of heterozygosity at the JAK2 locus (LOH 9p) were powerfully associated with increased risk of thrombosis, OR = 7.49 (95% CI 3.02-18.56, P=1.41e-05) and 6.74 (95% CI 1.62-28.08; P=8.71e-03). Having both CHIP and autosomal mCA was associated with a nominally increased risk of VTE (OR 1.76; 95% CI 1.02-3.06, P= 0.04). Otherwise, non- JAK2 CHIP , ASXL1 CHIP , TET2 CHIP , DNMT3A CHIP were not associated with increased prevalent VTE, regardless of clone size. Incident VTE and CHIP: CHIP was modestly associated with incident VTE with a hazard ratio of 1.15 (1.03-1.28; P=0.01), and CHIP with a larger clone size (VAF &amp;gt; 10%) was associated with a hazard ratio of 1.22 (95% CI 1.08-1.39; P= 0.001) (Figure 2). Consistent with our analysis of prevalent VTE, JAK2-CHIP and JAK2-CHIP with LOH 9p were strongly associated with incident VTE with hazard ratios of 3.76 (95% CI 1.79-7.9, P= 0.0004) and 4.89 (95% CI 1.84-13.04; P=0.0015). Other associations, including overall CHIP, CHIP with VAF &amp;gt;10%, CHIP together with autosomal mCA, autosomal mCA, non- JAK2 CHIP, TET2 CHIP with VAF &amp;gt;10%, showed modest increased hazard ratios between 1 and 2. Conclusions: In this study of risk of thrombosis in the UK Biobank, CHIP was not significantly associated with prevalent VTE and was modestly associated incident VTE. Among CHIP genotypes analyzed, only JAK2 mutations were significantly associated with both prevalent and incident VTE risk (OR 7.49 and HR 3.76, respectively). JAK2-mutant CHIP may be an undetected contributor to cases of VTE and may have therapeutic implications.

Patterns of prescription opioid use and opioid-related harms among adult patients with hematologic malignancies.

Treatment advances for hematologic malignancies (HM) have dramatically improved life expectancy, necessitating greater focus on long-term cancer pain management. This study explored real-world patterns of opioid use among patients with HM. This retrospective cohort study identified adults diagnosed with HM from January 1, 2013 through December 31, 2019 using the Truven MarketScan Commercial Claims and Encounters database. Across several HM types, we described rates of high-risk opioid use (based on Pharmacy Quality Alliance measures) and opioid-related harms, including incident opioid use disorder (OUD) diagnoses and opioid-related hospitalizations or emergency department (ED) visits. We used multivariable Cox regression to generate adjusted hazard ratios and 95% confidence intervals comparing the risk of opioid-related harms between patients with versus without high-risk opioid use. Our sample included 43,190 patients with HM. Median age at HM diagnosis was 54 years (interquartile range = 44-60). Most patients (61.9%) were diagnosed with lymphoma. Approximately half (49.2%) had an opioid dispensed in the follow-up period. Among all patients, 20.0% met criteria for high-risk opioid use, 0.9% had an OUD diagnosis, and 0.3% experienced an opioid-related hospitalization/ED visit in follow-up. High-risk opioid use increased the risk of an OUD diagnosis by 3.3 times (p < 0.0001) and an opioid-related hospitalization/ED visit 4.2 times (p < 0.0001). High-risk opioid use was prevalent among patients with HM and significantly increased the risk of opioid-related harms. However, rates of opioid-related harms were low. These findings highlight the importance of continually monitoring pain and opioid use throughout HM survivorship to provide safe, effective HM pain management.

Cancer Predisposition Genetic Testing Among Children with Hematologic Malignancies

Introduction: There is growing recognition of germline cancer predisposition syndromes (CPS) that increase risk of hematologic malignancies including leukemias, lymphomas, bone marrow failure syndromes and myeloproliferative diseases. Somatic (tumor) testing can identify potential germline variants based on multiple factors including variant allele fraction, sequence characteristics, and other findings; however, subsequent germline testing is required to characterize the lesion. Paired tumor and germline testing (T/N testing) is more accurate to diagnose CPS and may mitigate loss to follow-up, reduce time to CPS diagnosis, and possibly alleviate unnecessary anxiety due to suspected but ultimately disproved germline conditions. Previously, our center performed tumor-only diagnostic testing for patients with newly diagnosed hematologic malignancies. In 2020 we transitioned to paired T/N testing for all new hematologic malignancy diagnoses with patient/caregiver consent. Here we report the frequency of CPS diagnoses suggested by tumor-only testing and subsequently confirmed with germline testing, as well as CPS diagnoses identified from the outset by T/N testing. Methods: Data was automatically abstracted from the Children's Hospital of Philadelphia (CHOP) Diagnostic Genomics Database (FileMaker and Nexus) for 1057 pediatric, adolescent, and young adult patients who underwent testing with the CHOP Comprehensive Hematologic Malignancy panel between 2016 and 2023. This panel interrogates 117 genes for single nucleotide variants, insertions, deletions, and copy number variants. Of those tested, 932 patients underwent tumor-only testing, and 125 patients underwent paired T/N testing. Characteristics of patients with possible pre-established genetic syndromes (e.g. Trisomy 21) were cross-checked via manual chart review. Results: Schematic representation of patient testing is summarized in Figure 1. Among 932 patients who underwent tumor-only testing, 98 were identified to have potential or previously established germline pathogenic variants. Of these, 9 had known genetic syndromes and 8 had non-cancer related genetic diagnoses (e.g. Usher syndrome). Of the 81 patients with a suspected CPS, 26 were referred from an outside hospital with unavailable follow-up data. Among suspected germline patients from our center (n=55), 34 (62%) did not undergo confirmatory testing. Of the 21 (38%) who underwent confirmatory testing, 2 (10%) were diagnosed with a CPS. For patients with T/N testing, 16 of 125 (7%) were identified to have germline conditions; 8 were pre-established diagnoses and 4 were non-cancer related genetic diagnoses. Thus, 4 (3%) of patients with T/N testing were newly diagnosed with a CPS. New CPS diagnoses included: ETV6 thrombocytopenia and leukemia predisposition syndrome, CBL syndrome, GATA2 MDS/AML predisposition syndrome, Noonan syndrome, and CEBPA AML predisposition syndrome. Conclusion: At our center, 62% of patients with suspected germline conditions on tumor-only testing had no follow up testing documented in the available medical record. These data suggest that paired T/N testing at the time of hematologic malignancy diagnosis assists in mitigating loss-to-follow up for patients with possible CPS. Additionally, T/N testing may streamline result interpretation, reduce time to diagnosis, aid in treatment decisions, and guide cascade testing for potentially affected family members. When possible, genetic testing decisions and results should be discussed with a trained genetic counselor. Over time, increasing utilization of paired T/N testing may also enhance understanding of CPS-associated genes that increase risk of hematologic malignancies.