Received Bone Marrow Transplantation Research Articles

Analysis of Thalassemia Gene Mutation Types and Ethnic Distribution Characteristics in Hechi Area, Guangxi

To investigate the genotype, mutation type, and ethnic distribution characteristics of thalassemia in the population of Hechi area, Guangxi, and to provide a reference basis for prevention and control of thalassemia and eugenic counseling in the region. Gap-polymerase chain reaction (gap-PCR) and reverse dot blot (RDB) were used for genetic testing on suspected thalassemia persons, and the results were analyzed. Among 29 136 samples, a total of 17 016 (58.40%) positive samples for thalassemia genes were detected, with a higher detection rate in males than in females (χ2=49.917，P < 0.001). The detection rates of thalassemia genes were significant different among Zhuang, Han, Yao, Mulao, and Maonan ethnic groups (χ2=546.121, P < 0.001). The α-thalassemia genotypes were mainly --SEA /αα (16.67%), -α3.7/αα (8.90%), α CSα/αα (6.00%). Additionally, four rare genotypes were detected, including -- THAI/αα (47 cases), HKαα/αα (2 cases), --SEA /-α 21.9 (2 cases), and -- THAI/αCSα (1 case). The β-thalassemia genotypes were mainly β CD17/βN (7.49%), βCD41-42/βN (6.70%), βCD71-72/βN (0.44%). 108 cases of moderate and severe β-thalassemia were detected, of which 81 cases had a history of blood transfusion, the transfusion frequency of 60 cases was more than 10 times/year, and 10 cases received bone marrow transplantation. Thalassemia in Hechi area is predominantly deletion type --SEA /αα, the detection rate of thalassemia in ethnic minorities is higher than that in Han population. In this area, moderate and severe β-thalassemia have certain incidence, these patients mostly need regular blood transfusion and iron removal treatment, and very few patients have received bone marrow transplantation. This study provides a certain reference basis for prevention and control of thalassemia and eugenic counseling in the region.

A prospective study of all-trans retinoic acid plus venetoclax and azacitidine in newly diagnosed acute myeloid leukemia.

6545 Background: Over the decade, anthracycline and cytarabine-based intensive chemotherapy remains the standard of care for acute myeloid leukemia (AML) but is hampered by serious toxicities like myelosuppression, increased transfusion requirement and disappointing clinical outcomes among the so-called poor-prognosis AML subsets. BCL-2 inhibitor plus azacitidine (AZA) has become a preferred treatment for AML, but the remission rate and overall survival (OS) are suboptimal. Apart from hematologic toxicities, 70.0% of patients were RBC transfusion dependent and 58.6% were platelet transfusion dependent. At present, all-trans retinoic acid (ATRA) is used as a differentiation drug, and there is no combination regimen with BCL-2 inhibitor. This study aimed to assess the efficacy and safety of ATRA plus venetoclax and AZA for newly diagnosed AML. Methods: This study enrolled 35 patients (≥18 years) with newly diagnosed AML between 2022 and 2023. For induction, patients received AZA (75 mg/m²) from Day 1 to 7, venetoclax at a target dose of 400 mg/d from Day 2 to 10, and ATRA (45 mg/m²/d) from Day 12 to 28 of each 28-day cycle for up to 2 cycles or until disease progression. Patients who achieved complete remission (CR) after two cycles of induction therapy received bone marrow transplantation or consolidation at their own discretion. For consolidation, patients received ATRA (45 mg/m²/d) from Day 1 to 21 and AZA (75 mg/m²) from Day 1 to 7 of each 28-day cycle for up to 4 cycles or until disease progression. For maintenance, patients received ATRA (45 mg/m²/d) for 21 days per cycle plus AZA (75 mg/m²). Maintenance therapy was given every 3 months until disease progression and ATRA was provided during intermissions. The primary endpoint was the composite CR rate (CR and CR with incomplete hematologic recovery) at the end of cycle 1 of inductive therapy. Results: As of now, the composite CR rate reached 74% (26/35) and the objective response rate reached 91% (32/35). The composite CR was 73% (11/15) in the adverse risk group and 75% (15/20) in the favorable-intermediate risk group at the end of cycle 1. Thirty-three patients entered cycle 2. The cumulative composite CR rate reached 91%(30/33) after 2 cycles of induction therapy. The median event-free survival was 390 days, and the median OS was 573 days. Platelet transfusion independence occurred in 17% (6/35) patients in cycle 1 and 73% (24/33) in cycle 2. Furthermore, 20% (7/35) and 73% (24/33) patients were RBC transfusion independent in cycle 1 and 2, respectively. Any-grade infections occurred in 74% (26/35) patients, including 12 before admission. Conclusions: The treatment regimen achieved a high composite CR rate and was well tolerated, with reduced hematologic toxicities in cycle 2 of induction therapy. Both adverse risk and favorable-intermediate risk patients benefited from the regimen, which holds promise for treating AML in adult patients. Clinical trial information: NCT05654194 .

P020 Clinical characteristics, disease trajectories and management of Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: a systematic review

Abstract Background/Aims VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory condition, characterised by somatic mutation of UBA1 gene. To date, no systematic literature review (SLR) has been undertaken to summarise the clinical manifestations, genotypes and treatment of VEXAS. We undertook a SLR to evaluate the multisystem characteristics and genotypes associated with VEXAS syndrome. Methods Articles discussing VEXAS syndrome, published 1946 until May 2023, were included. The protocol was registered in the PROSPERO database of systematic reviews (CRD42023407547). Medline, Embase and Cochrane Databases were searched. The research questions were: 1) What are the clinical characteristics of patients diagnosed with VEXAS? 2) What are the genotypes associated with VEXAS? 3) What are the effective treatments for VEXAS? Articles meeting inclusion criteria were examined by two authors at abstract and full paper stage. Information was extracted on: demographics, type and prevalence of clinical manifestations, genetic mutations, and treatment. Meta-analysis using a random effects model was used to determine pooled estimates of serum markers. Results From 214 articles, 64 were included, comprising 273 patients with VEXAS. 96.3% were male, with a mean age of 67.2 years (SD 6.8) at disease onset. Study cohorts were from: Europe (n = 25); North America (n = 18); South America (n = 1); Asia (n = 16); Australasia (n = 4). The most frequent diagnoses made prior to VEXAS were: relapsing polychondritis (n = 48); Sweet’s syndrome (n = 24); polyarteritis nodosa (n = 11); myelodysplastic syndrome (n = 10). Fever was reported in 195 cases (71.4%) and weight loss in 69 (25.3%). Most patients had pulmonary (n = 231; 84.6%), haematological (n = 228; 83.5%) dermatological (n = 217; 79.5%) and musculoskeletal (n = 138; 50.5%) involvement, although other organ manifestations of varying prevalence were also recorded. Pooled estimates of serological investigations were: ESR 101.3 mm/hr (SE 4.8; n = 246); CRP 144.2 mg/L (SE 14.1; n = 258); Hb 91.0 g/L (SE 3.2; n = 265); MCV 107.3 fL (SE 2.3; n = 265). The most commonly reported mutations were “c.122T&amp;gt;C pMET41Thr” (n = 71), “c.121A&amp;gt;G pMET41Val” (n = 35) and “c.121A&amp;gt;C pMet41Leu” (n = 33). Most patients received glucocorticoids (n = 133, 48.7%) followed by methotrexate (n = 55, 20.1%) and IL-6 inhibitors (n = 47, 17.2%). One patient underwent splenectomy; six received bone marrow transplants. Regarding mortality, 44 patients were reported to have died due to manifestations of VEXAS syndrome. Conclusion This is the first SLR to capture clinical manifestations, genetics and treatment of cases of VEXAS reported to date. Diagnosis remains clinically challenging, as evidenced by the multiple prior diagnoses ascribed to patients, most commonly relapsing polychondritis and Sweet’s syndrome. Most patients present with haematological disorders, fever, pulmonary and dermatological involvement. Reported mortality was consistent with genetic variants strongly associated with reduced survival rates. Genetics and treatment of VEXAS continue to be an active area of research. Future studies are needed to better understand these as well as optimize treatment for people with this rare condition. Disclosure K. Kouranloo: None. M. Dey: None. J. Almutawa: None. N. Myall: None. A. Nune: None.

Modulation of lipid profile by secretory phospholipase A2 group IIA: Verification with a transgenic mouse model

We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE−/− and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.

Pyogenic spondylitis after Corynebacterium striatum blood stream infection following allogeneic hematopoietic stem cell transplantation for malignant lymphoma

Patient 1 was a 70-year-old woman with refractory diffuse large B-cell lymphoma who received allogeneic peripheral blood stem cell transplantation from an HLA-haploidentical related donor. Upper back pain appeared on day63, and Th8-Th9 pyogenic spondylitis was diagnosed based on magnetic resonance imaging (MRI). Blood culture on day14 identified Corynebacterium striatum as the causative bacteria of blood stream infection (BSI). The pyogenic spondylitis resolved after treatment with daptomycin for 2 months. Patient 2 was a 65-year-old man with relapsed angioimmunoblastic T-cell lymphoma who received bone marrow transplantation from an HLA-DR single-antigen-mismatched unrelated donor. Lower back pain appeared on day30, and L4-L5 pyogenic spondylitis was diagnosed based on MRI. Blood culture was negative. Daptomycin and clindamycin were selected for treatment based on the drug susceptibility of bacteria that had caused pre-engraftment BSI (Escherichia coli on day3 and Corynebacterium striatum on day9), and the pyogenic spondylitis resolved after 6 months of this treatment. Pyogenic spondylitis should be considered in the differential diagnosis of back pain accompanied by BSI before engraftment in allogeneic hematopoietic stem cell transplant recipients.

Clinical characteristics, disease trajectories and management of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: a systematic review.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly discovered autoinflammatory condition characterised by somatic mutation of the UBA1 gene. The syndrome leads to multi-system inflammation affecting predominantly the skin, lungs and bone marrow. We undertook a systematic review of the multisystem features and genotypes observed in VEXAS syndrome. Articles discussing VEXAS syndrome were included. Medline, Embase and Cochrane databases were searched. Information was extracted on: demographics, type and prevalence of clinical manifestations, genetic mutations and treatment. Meta-analysis using a random effects model was used to determine pooled estimates of serum markers. From 303 articles, 90 were included, comprising 394 patients with VEXAS. 99.2% were male, with a mean age of 67.1 years (SD 8.5) at disease onset. The most frequent diagnoses made prior to VEXAS were: relapsing polychondritis (n = 59); Sweet's syndrome (n = 24); polyarteritis nodosa (n = 11); and myelodysplastic syndrome (n = 10). Fever was reported in 270 cases (68.5%) and weight loss in 79 (20.1%). Most patients had haematological (n = 342; 86.8%), dermatological (n = 321; 81.5%), pulmonary (n = 297; 75.4%%) and musculoskeletal (n = 172; 43.7%) involvement, although other organ manifestations of varying prevalence were also recorded. The most commonly reported mutations were "c.122T > C pMET41Thr" (n = 124), "c.121A > G pMET41Val" (n = 62) and "c.121A > C pMet41Leu" (n = 52). Most patients received glucocorticoids (n = 240; 60.9%) followed by methotrexate (n = 82; 20.8%) and IL-6 inhibitors (n = 61, 15.4%). One patient underwent splenectomy; 24 received bone marrow transplants. VEXAS syndrome is a rare disorder affecting predominantly middle-aged men. This is the first systematic review to capture clinical manifestations, genetics and treatment of reported cases. Further studies are needed to optimise treatment and subsequently reduce morbidity and mortality.

Hyperleukocytosis Does Not Present a Worse Prognosis in Acute Myeloid Leukemia (Non-APL) with Favorable Risk According to ELN-2022 Criteria: A Retrospective Study

Introduction: Acute myeloid leukemia (AML) with hyperleukocytosis, characterized by a white blood cell count ≥100,000/µL, is usually considered a subtype associated with poor prognosis. For AML patients with hyperleukocytosis, more aggressive treatment approaches, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), are commonly considered. However, when favorable-risk AML accompanies hyperleukocytosis, it is unclear whether the risk level needs to be redefined. There is also no universally accepted treatment strategy for this subtype. We conducted a retrospective, single-center study to investigate the impact of hyperleukocytosis on the response and prognosis of favorable-risk AML according to ELN-2022 risk classification. Method: We retrospectively enrolled 217 favorable-risk AML patients, excluding acute promyelocytic leukemia (APL), treated at Zhejiang University School of Medicine's First Affiliated Hospital from October 1st, 2021, to April 30th, 2023. Some of them have been treated in other hospitals. The diagnosis, risk classification, and response evaluation were determined according to ELN-2022 criteria. Patients were divided into two groups: the hyperleukocytosis group (white blood cell count ≥100,000/µL) and the non-hyperleukocytosis group (white blood cell count &amp;lt;100,000/µL). We compare these two groups on the response rate after the induction chemotherapy, the median overall survival (mOS), and median disease-free survival (mDFS), then evaluate different treatments and other prognostic factors associated with outcomes. Statistical analyses were carried out using SPSS 24.0. The Kaplan-Meier method and log-rank test were used to assess and compare the survival outcomes. Univariate Cox proportional hazards regression was used to determine associated risk factors for overall survival. A two-tailed P value &amp;lt;0.05 was considered statistically significant. Result: Totally 217 patients were enrolled. To balance the impact factors, 12 patients who received high-dose cytarabine were excluded from the non-hyperleukocytosis group. The cohort ready for analysis had 45 patients in the hyperleukocytosis group and 160 patients in the non-hyperleukocytosis group. Two groups had no significant differences in age; gender, FAB classification; platelet counts and hemoglobin level at initial diagnosis; co-existing intermediate/high-risk mutations according to 2022 ELN risk stratification; treated with high-dose cytarabine, or receiving bone marrow transplantation (all P＞0.05). The median follow-up time was 29.5 months, and 154 patients were still alive at the study endpoint. There were no significant differences in the composite complete remission (CRc) rates (73.3% vs. 79.3%, P= 0.389), mOS (65.0m vs. 56.0m, P= 0.574), and mDFS (54.0m vs. 35.0m, P= 0.855) between two groups. With high-dose cytarabine (2.0-3.0 g/m2 q12h X 3 days for at least three courses) as consolidation chemotherapy, the two groups had no significant difference in mOS (Not reached vs. Not reached, P=0.143) and mDFS (21.0m vs. 35.0, P= 0.352). In order to understand the impact of allo-HSCT on the hyperleukocytosis group, we divided this group into the allo-HSCT subgroup and the non-HSCT subgroup. After balancing on age, gender, presence of high-risk mutations, and MRD negativity after the first remission (all P&amp;gt;0.05), the mOS in the allo-HSCT subgroup (n=16) was significantly longer than the non-HSCT subgroup (n=16) (Not reached vs. 46.0m, P= 0.007). However, the mDFS had no significant difference between the two sub-groups (63.0m vs. 43.0m, P= 0.341). The univariate Cox proportional hazards regression analysis revealed that only age had a significant impact ( P= 0.01), all other factors had no significant effects, including hyperleukocytosis, gender, hemoglobin level, platelet count, intermediate/high-risk mutations, or bone marrow transplantation. Conclusion: In favorable-risk AML, hyperleukocytosis does not lead to an adverse prognosis. Received high-dose cytarabine as a consolidation therapy, favorable-risk AML patients with hyperleukocytosis do not have worse OS or DFS than those without hyperleukocytosis. Allo-HSCT may bring longer OS for hyperleukocytosis patients at favorable risk but may not bring longer DFS. Our results suggest favorable-risk AML patients with hyperleukocytosis can be managed equally as non-hyperleukocytosis patients.

Machine Learning and Artificial Intelligence Techniques for Detecting Driver Drowsiness

The number of vehicles on the road rises in tandem with the development of vehicle manufacture. With the rapid growth of automobiles, the number of road accidents appears to be steadily increasing. Accidents are a typical occurrence in our daily lives. Road accidents are the top cause of death from injuries worldwide in the top 10. It now forms an amazingly important part of the global burden of illness. An estimated 1.2 million people are killed in accidents every year, and an estimated 50 million are injured while receiving bone marrow transplants in leading countries. Drowsiness, along with fatigue of drivers, are some of the major causes of road accidents. Every year, we see an increase in death numbers worldwide. This study also looks into automatically detecting driver drowsiness with AI, visuals, and CNN. The Driver Drowsiness System works on the concept of Multi-Layer Feed Forward Network, especially on Convolutional Neural Networks (CNN). CNN was developed with the help of around 7000 images of eyes in both drowsiness and non-drowsiness states with different facial architectures. These images were split into training (80 percent of images) and testing (20 percent of images) datasets. The images under the training dataset are given as the input for the network for training purposes. Backpropagation algorithms and optimizers are used to reduce the loss as much as possible. We created an algorithm for detecting, tracking, and analysing motor and visual effects to measure ROI.

Impact of HLA-mismatched unrelated transplantation in patients with adult T-cell leukemia/lymphoma.

This Japanese nationwide retrospective study investigated the impact of HLA-mismatched unrelated transplantation for adult T-cell leukemia-lymphoma (ATL) patients who received transplantation between 2000 and 2018. We compared 6/6 antigen-matched related donor (MRD), 8/8 allele-matched unrelated donor (8/8MUD), and 1 allele-mismatched unrelated donor (7/8MMUD) in the graft-versus-host direction. We included 1191 patients; 449 (37.7%) were in the MRD group, 466 (39.1%) in the 8/8MUD group, and 276 (23.7%) in the 7/8MMUD group. In the 7/8MMUD group, 97.5% of patients received bone marrow transplantation, and no patients received post-transplant cyclophosphamide. The cumulative incidences of non-relapse mortality (NRM) and relapse at 4 years, and the probabilities of overall survival at 4 years in the MRD group were 24.7%, 44.4%, 37.5%, in the 8/8MUD group were 27.2%, 38.2%, and 37.9%, and in the 7/8MMUD group were 34.0%, 34.4%, and 35.3%, respectively. The 7/8MMUD group had a higher risk of NRM (hazard ratio (HR) 1.50 [95% CI, 1.13-1.98; P = 0.005]) and a lower risk of relapse (HR 0.68 [95% CI, 0.53-0.87; P = 0.003]) than the MRD group. The donor type was not a significant risk factor for overall mortality. These data suggest that 7/8MMUD is an acceptable alternative donor when an HLA-matched donor is unavailable.

Impact of Early Intervention for STAT3 Dominant-Negative Disease

IntroductionSTAT3 dominant negative disease (STAT3 DN) is characterized by elevated IgE, recurrent skin and lung infections, skeletal, connective tissue, and vascular abnormalities. Early genetic diagnosis, especially with familial disease, allows for early intervention, which may impact natural history through minimizing infectious complications. MethodsWe retrospectively reviewed medical records of 18 STAT3 DN pediatric patients born after 2007, when STAT3 genetic testing was available. Clinical features, laboratory results, infections and treatments were compared between those with STAT3 DN family history and probands. ResultsOur cohort included 8 patients with STAT3 DN diagnosed by family history (median age 9 years; range 4–14) and 10 probands (median age 13 years, range 5–14). For those with family history, one was diagnosed in utero, six by 6 months of age, and one at 2 years. Probands were diagnosed at a median age of 2 years (range 1–6 years). STAT3 mutation domains were similar between groups. Those with family history started antiseptic washes at a mean of 2.4 months and prophylactic antibiotics at 0.4 years, whereas probands initiated antiseptics at 4.5 years and prophylactic antibiotics at 3 years. Compared to probands, patients with STAT3 DN diagnosed by family history had significantly (p < 0.05) reduced rates of hospitalizations (mean 0.6 vs 6.2 times), bacterial pneumonias (13% vs 90%), >4 skin abscesses (25% vs 90%), other serious infections (0% vs 40%), recurrent ear infections and/or tympanostomy tube placement (0% vs 60%), and severe eczema (13% vs 60%). Significant differences were not seen in parenchymal lung abnormalities (13% vs 50%, p = 0.09) and non-immunologic features, such as fractures and joint hyperextensibility. Mean peak serum IgE and absolute eosinophil counts (AEC) were comparable (IgE 6,865 vs 13,317 IU/mL; AEC 1,023 vs 1,182 cells/uL in family history vs probands). Those with family history received less advanced therapies than probands, specifically immunoglobulin replacement (13% vs 60%), antifungals (25% vs 60%), and lung surgery (0% vs 40%). One proband received bone marrow transplantation. ConclusionEarly diagnosis and intervention positively impacts disease course and management with markedly reduced rates of infectious complications, which may decrease future morbidity and mortality in this vulnerable patient population.

Omenn Syndrome Caused by A Novel Mutation of the DCLRE1C Gene: Case Report and Review of Literature

We report a case of Omenn syndrome due to a novel mutation of the gene DCLRE1C(Artemis). He was referred to our hospital with a complaint of protracted diarrhea, erythematoexfoliative rash, urinary tract infection, pneumonia, and failure to thrive. He was 2 months old. At the first sight, the diagnoses of Omenn syndrome, graft versus host disease (GVHD), Netherton syndrome, and Atopic dermatitis came to mind. Laboratory evaluation showed lymphopenia, eosinophilia, high IgE, and whole-exome sequencing revealed a mutation of the DCLRE1C gene. After obtaining blood samples, he received broad-spectrum antibiotics, antifungals, antiviral, prophylaxis for pneumocystis Jirovecii pneumonia, and Intravenous immunoglobulin. He expired owing to delayed referral and overwhelming sepsis before receiving bone marrow transplantation. In every neonate infant presenting with erythematoexfoliative skin rash, refractory infection, and lymphopenia, Omenn syndrome should be considered.

Effect of the COVID-19 pandemic on allogeneic stem cell transplantation in Japan.

The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018-December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.

The Prevalence of Early Toxoplasmosis after Bone Marrow Transplantation Using PCR: A Study in Iranian Patients.

In immuno-compromised organ transplant recipients, toxoplasmosis can be caused by either an infected graft or a latent infection, during which transformation from a chronic state to an active infection (reactivation) is observed. PCR is an accurate and sensitive molecular method widely used in medical sciences, especially in diagnostic procedures. The aim of this study was to determine the prevalence of early toxoplasmosis infection in bone marrow transplant patients by PCR. The blood samples of 50 patients with hematological disorders who had received bone marrow transplants were collected using a standard phlebotomy technique. To evaluate antitoxoplasma antibodies, we utilized the enzyme-linked immunosorbent assay (ELISA) method using a specific commercial kit (Akon) based on the manufacturer's instructions. Genomic DNA extracted from toxoplasma tachyzoite was used as the template for PCR. 22 (44%) patients were women, and 28 (56%) were men. There were no significant differences in the distribution of genders and age groups in patients with various cancers. Antitoxoplasma IgG was positive in 39 patients, while none of them were IgM positive. According to PCR results, 5 patients were positive for toxoplasmosis. All of the PCR-positive cases (2 with AML, 2 with HL, and 1 with AA) had successful engraftment at 40 days post-transplantation. Because of the higher efficacy of PCR in the diagnosis of toxoplasmosis, using this method along with other routine diagnostic modalities in this condition is recommended. PCR-based techniques can also be utilized to periodically determine parasite load in blood after transplantation.

Reduced Antibodies and Innate Cytokine Changes in SARS-CoV-2 BNT162b2 mRNA Vaccinated Transplant Patients With Hematological Malignancies.

Immunocompromised individuals including patients with hematological malignancies constitute a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. A patient cohort who had received bone marrow transplantation or CAR-T cells was studied following a 2-dose BNT162b2 mRNA vaccination and compared to healthy vaccine recipients. Anti-Spike antibody and systemic innate responses were compared in the two vaccine cohorts. The patients had significantly lower SARS-CoV-2 Spike antibodies to the Wuhan strain, with proportional lower cross-recognition of Beta, Delta, and Omicron Spike-RBD proteins. Both cohorts neutralized the wildtype WA1 and Delta but not Omicron. Vaccination elicited an innate cytokine signature featuring IFN-γ, IL-15 and IP-10/CXCL10, but most patients showed a diminished systemic cytokine response. In patients who failed to develop antibodies, the innate systemic response was dominated by IL-8 and MIP-1α with significant attenuation in the IFN-γ, IL-15 and IP-10/CXCL10 signature response. Changes in IFN-γ and IP-10/CXCL10 at priming vaccination and IFN-γ, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral and reduced innate cytokine responses to vaccination compared to naïve vaccine recipients. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies.

A compilation of fecal microbiome shotgun metagenomics from hematopoietic cell transplantation patients

Hospitalized patients receiving hematopoietic cell transplants provide a unique opportunity to study the human gut microbiome. We previously compiled a large-scale longitudinal dataset of fecal microbiota and associated metadata, but we had limited that analysis to taxonomic composition of bacteria from 16S rRNA gene sequencing. Here we augment those data with shotgun metagenomics. The compilation amounts to a nested subset of 395 samples compiled from different studies at Memorial Sloan Kettering. Shotgun metagenomics describes the microbiome at the functional level, particularly in antimicrobial resistances and virulence factors. We provide accession numbers that link each sample to the paired-end sequencing files deposited in a public repository, which can be directly accessed by the online services of PATRIC to be analyzed without the users having to download or transfer the files. Then, we show how shotgun sequencing enables the assembly of genomes from metagenomic data. The new data, combined with the metadata published previously, enables new functional studies of the microbiomes of patients with cancer receiving bone marrow transplantation.

Etiologies of hearing loss in Fanconi Anemia

ObjectivesWe aim to describe types of hearing loss associated with Fanconi anemia patients who underwent a bone marrow transplant (BMT) to identify possible etiologies of hearing loss. Additionally, we hope to investigate hearing loss early in life as a potential predictor of needing a BMT surgery. Fanconi anemia is a rare autosomal recessive disease that is the most common inherited bone marrow failure syndrome, characterized by bone marrow failure and multiple congenital anomalies, including hearing loss. This is the largest study to date reviewing types of hearing loss in patients with Fanconi anemia, specifically in those who have undergone BMTs. MethodsA retrospective chart review of patients diagnosed with Fanconi anemia at a single institution, tertiary, referral-based children's hospital with a bone marrow transplant team specializing in Fanconi anemia was conducted from 4/19/1976 to 10/19/2015. History, physical examination, audiometry, and imaging findings were reviewed in patients with and without history of bone marrow transplant. Patient hearing levels, as measured by pure tone audiometry at 500 Hz, 1, 2, and 4 kHz, were evaluated. Patients were grouped by transplant status and results and were assessed to determine type and degree of hearing loss. Statistical analysis was performed to compare the likelihood of bone marrow transplant procedures in Fanconi anemia patients with normal and abnormal hearing. ResultsThere were 252 patients with Fanconi anemia identified via diagnosis search in institutional electronic medical records using CPT codes and cross referencing with the Fanconi Anemia database, 58 of whom had available audiometric data. Of the 58 Fanconi anemia patients with available audiograms, 21 (36%) had abnormal audiograms; 37 patients had normal audiograms. Twenty out of 21 (95%) patients who had abnormal audiograms had undergone bone marrow transplants. Thirty-one of 37 (84%) patients with normal audiograms had received bone marrow transplants. Statistical analysis showed that patients with hearing loss were more likely to require a BMT in the future (OR = 3.87, p = 0.05). Of the patients with abnormal audiograms and a bone marrow transplant (n = 20), 14 (70%) had conductive hearing loss, 5 (25%) had mixed hearing loss, and 1 patient (5%) had sensorineural hearing loss. 13 of 20 patients (65%) had bilateral hearing loss and eight of 20 (40%) had unilateral hearing loss. Of those patients with conductive hearing loss (n = 15), the most common etiologies were Eustachian tube dysfunction (47%), external auditory canal stenosis (33%), and abnormal middle ear anatomy (13%). ConclusionsHearing loss is a common finding in Fanconi anemia patients who have undergone BMTs with conductive hearing loss being the most common audiologic manifestation in our cohort of patients. This demonstrates the necessity of frequent hearing screenings in this population and close collaboration with audiology throughout patient care. Our study indicates that hearing status early in life may be a predictor of needing a bone marrow transplant in the future. Further studies should explore the long-term impact of BMT surgery on hearing status.

Influence of Body Mass Index, Cancer Type and Treatment on Long-Term Metabolic and Liver Outcomes in Childhood Cancer Survivors.

In the last decade, the survival of subjects affected by cancer in childhood has significantly improved. The increased lifespan of childhood cancer survivors (CCS) led to a greater risk for long-term, therapy-related morbidity. To identify the clinical predictors of metabolic adverse outcomes in CCS (average off-therapy period: 12 years), we recruited 126 survivors of different childhood cancers (86.5% hematological cancers) who received at least anticancer chemotherapy, consecutively approached during their annual oncohematological outpatient visit. At examination, anthropometric measures and cancer-related history were collected. Moreover, a fasting venous sample was carried out for measuring fasting plasma glucose and insulin, glycated hemoglobin, lipid panel, and transaminases. We calculated the indexes of insulin resistance (HOMA-IR, McAuley, and QUICKI) and secretion (HOMA-β), liver steatosis (Hepatic Steatosis Index) and fibrosis (FIB-4 and NAFLD fibrosis score), and visceral fat dysfunction (Visceral Adiposity Index). More than one-third of the subjects (37.3%) did not have normal weight, with 11.1% of them affected by obesity. At recruitment, obese subjects were at significantly higher risk for impaired fasting glucose, metabolic syndrome, visceral adipose dysfunction, and liver steatosis/fibrosis. Subjects who received bone marrow transplantation were prone to insulin resistance, while survivors of lymphoma presented a visceral adipose dysfunction These results suggest a carefully metabolic monitoring of CCS, particularly in subgroups at higher risk, to early detect these conditions, promptly begin therapeutic interventions, and mitigate the dysmetabolic-related health burden.

Serum proteomics screening intercellular adhesion molecule-2 improves intermediate-risk stratification in acute myeloid leukemia.

The clinical risk classification of acute myelocytic leukemia (AML) is largely based on cytogenetic and molecular genetic detection. However, the optimal treatment for intermediate-risk AML patients remains uncertain. Further refinement and improvement of prognostic stratification are therefore necessary. The aim of this study was to identify serum protein biomarkers to refine risk stratification in AML patients. This study is a retrospective study. Label-free proteomics was used to identify the differential abundance of serum proteins in AML patients. Transcriptomic data were combined to identify key altered markers that could indicate the risk rank of AML patients. The survival status was assessed by Kaplan-Meier and multivariate Cox regression analyses. We delineated serum protein expression in a population of AML patients. Many biological processes were influenced by the identified differentially expressed proteins. Association analysis of transcriptome data showed that intercellular adhesion molecule-2 (ICAM2) had a higher survival prediction value in the intermediate-risk AML group. ICAM2 was detrimental for intermediate-risk AML, regardless of whether patients received bone marrow transplantation. ICAM2 well distinguishes the intermediate group of patients, whose probability of survival is comparable to that of patients with the ELN-2017 according to the reference classification. In addition, newly established stratified clinical features were associated with leukemia stem cell scores. The inclusion of ICAM2 expression into the AML risk classification according to ELN-2017 was a good way to transfer patients from three to two groups. Thus, providing more information for clinical decision-making to improve intermediate-risk stratification in AML patients.

Frequency of Infectious Agents After Bone Marrow Transplantation in Various Regions of Iran (2001 - 2017): A Systematic Review

Context: Infections are a major cause of disease and mortality in transplant recipients. Despite the studies conducted in Iran, no comprehensive and general research is available in this area. The present study aimed to determine the frequency of infectious agents in patients after bone marrow transplantation in Iran. Method: In this systematic review, relevant studies were selected based on type and objective, and data were collected from the articles published in Iran regarding the frequency of infectious agents after bone marrow transplantation in different regions of Iran. The studies were collected using systematic search methods. Results: In total, 11 studies were identified regarding infectious agents after bone marrow transplantation. Six studies were conducted in Tehran, three studies were performed in Shiraz, and Mashhad and Semnan provinces were the locations of two separate studies. Most of the case studies identified viral agents (54.5%; n = 6), followed by fungal infectious agents (27.3%; n = 3) and bacterial agents (18.2%; n = 2). Gram-positive bacteria (bacterial agents), cytomegalovirus (viral agents), and Candida and Aspergillus (fungi) had the highest frequency after bone marrow transplantation. Conclusions: According to the results, viral, fungal, and bacterial infectious agents were respectively most frequent in patients receiving bone marrow transplants. Gram-positive bacteria (bacterial agents), cytomegalovirus (viral agents), and Candida and Aspergillus (fungi) had the highest frequency after bone marrow transplantation.

Prognostic factors of pediatric hematopoietic stem cell transplantation recipients admitted to the pediatric intensive care unit.

BackgroundPediatric patients who received hematopoietic stem cell transplantation (HSCT) tend to have high morbidity and mortality. While, the prognostic factors of adult patients received bone marrow transplantation were already known, there is little known in pediatric pateints. This study aimed to identify the prognostic factor for pediatric intensive care unit (PICU) mortality of critically ill pediatric patients with HSCT.MethodsRetrospectively reviewed that the medical records of patients who received HSCT and admitted to PICU between January 2010 and December 2019. Mortality was defined a patient who expired within 28 days.ResultsA total of 131 patients were included. There were 63 boys (48.1%) and median age was 11 years (interquartile range, 4–15 years). The most common HSCT type was haploidentical (38.9%) and respiratory failure (44.3%) was the most common reason for PICU admission. Twenty-eight–day mortality was 22.1% (29/131). In comparison between survivors and non-survivors, the number of HSCTs received, sepsis, oncological pediatric risk of mortality-III (OPRISM-III), pediatric risk of mortality-III (PRISM-III), pediatric Sequential Organ Failure Assessment (pSOFA), serum lactate, B-type natriuretic peptide (BNP) and use of mechanical ventilator (MV) and vasoactive inotropics were significant predictors (P<0.05 for all variables). In multivariate logistic regression, the number of HSCTs received, use of MV, OPRISM-III, PRISM-III and pSOFA were independent risk factors of PICU mortality. Moreover, three scoring systems were significant prognostic factors of 28-day mortality.ConclusionsThe number of HSCTs received and use of MV were more accurate predictors in pediatric patients received HSCT.