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Waldenstrom macroglobulinaemia (WM), the predominant subtype of lymphoplasmacytic lymphoma with bone marrow involvement and serum IgM paraprotein, is a haematological condition commonly associated with renal parenchymal involvement. However, antineutrophil cytoplasmic antibody (ANCA)‐negative pauci‐immune crescentic glomerulonephritis (PICGN) in kidney infiltrated by lymphoma is very rare, with only two cases described in chronic lymphocytic leukaemia in English literature so far. We herein report the first patient with WM developing ANCA‐negative PICGN. He was a 76‐year‐old male who presented with elevated serum globulin level and bilateral groin lymph node enlargement, subsequently diagnosed to have WM after pathologic examination of the bone marrow and groin lymph node. One month later, he was found to have acute kidney injury and proteinuria. Renal biopsy confirmed the presence of parenchymal involvement by WM accompanied by PICGN; while ANCA testing was negative. He was treated with pulse methylprednisolone followed by oral prednisolone. In addition, six courses of intravenous rituximab and oral cyclophosphamide were given. There was significant improvement in both his renal and haematological conditions. The clinical course of this case suggested that ANCA‐negative PICGN may represent a paraneoplastic syndrome and a rare manifestation of WM‐associated renal lesion. Early kidney biopsy and prompt treatment may improve the outcome of patients. [ABSTRACT FROM AUTHOR]

Standard testing for disease evaluation in B-cell acute lymphoblastic leukemia (B-ALL) includes examination of the bone marrow and cerebrospinal fluid. Radiographic or functional imaging are indicated when clinical signs of non-CNS extramedullary disease are present but are not standard in the relapsed/refractory setting. We describe two cases of patients with relapsed/refractory BALL with prior exposure to blinatumomab and/or inotuzumab ozogamicin presenting for CAR-T cell treatment. Both patients were thought to only have minimal residual disease (MRD) at the pre-CAR disease assessment, with MRD of 6,648 (0.66%) and 100 (0.01%) cells per million cells, respectively, as measured by next-generation sequencing (NGS) in their bone marrows. Both patients for distinct reasons unrelated to non-CNS extra-medullary (EM) symptoms had PETMRIs prior to lymphodepletion and CAR T cell infusion. In both cases patients were found to have significant bulky subclinical EM disease that required changes in clinical management. In the newly-emergent era of antigen-targeted immunotherapy, it is foundational that incidence and relapse patterns following targeted therapy are well-understood. Herein we contribute to a growing body of literature addressing this fundamental clinical gap and highlight a future role for formal prospective imaging studies to better establish response, toxicity and relapse patterns following CAR-T cell therapy in EM B-ALL. [ABSTRACT FROM AUTHOR]

Background: Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation that results in an uncontrolled hyperinflammatory state. HLH is classified into two main categories: primary (familial) HLH and secondary (acquired) HLH. Secondary HLH can result from various underlying, including infection-associated hemophagocytic syndrome (IAHS) and macrophage activation syndrome (MAS) associated with rheumatologic disorders, among others. Epstein–Barr virus (EBV) often causes IAHS, but central nervous system (CNS) involvement is rare among systemic lupus erythematosus (SLE) patients. We report a case of EBV encephalitis associated with HLH in a patient with childhood-onset SLE. Case presentation: A 12-year-old girl had received a diagnosis of SLE 2 months before presentation. After a period of inactive disease on treatment, fever and seizures, with altered mental status and hallucinations, developed over several weeks. A complete blood cell count (CBC) revealed pancytopenia, accompanied by elevated levels of inflammatory markers: 86 mm/hr erythrocyte sedimentation rate, 8.9 mg/dl c-reactive protein, and 3,966 ng/mL of ferritin. The differential diagnosis included active neuropsychiatric SLE, CNS infection and neurological manifestations in secondary HLH, which could have represented either IAHS or MAS. Meropenem and acyclovir were initially administered for clinical acute encephalitis, followed by pulse methylprednisolone; however, the fever persisted, and another CBC revealed progressive cytopenia. A bone marrow study showed hypocellularity and active hemophagocytic activity, and intravenous immunoglobulin was additionally given due to the diagnosis of HLH. Cerebrospinal fluid (CSF) analysis showed 60/mm3 white blood cells (N 55%, L 45%), 141 mg/dL glucose (0.7 blood-CSF glucose ratio), < 4 mg/dL protein; results of Gram stain and bacterial culture were negative. The viral encephalitis panel from the CSF confirmed EBV infection. Bone marrow immunohistochemistry examination revealed increasing levels of CD8 + T-cell and equivocal positive results for EBV-encoded RNA in situ hybridization; therefore, HLH potentially associated with EBV was diagnosed. After treatment with IVIg, cyclosporin A, and prednisolone, the patient's symptoms gradually improved and she was eventually able to return to school. Conclusions: Our case highlights the importance of a thorough differential diagnosis, including EBV encephalitis associated with HLH, in patients with childhood SLE, particularly in cases of clinical deterioration occurs after initial treatment. [ABSTRACT FROM AUTHOR]

Background: Flower-shaped nuclei in plasma cells are rare in multiple myeloma. Case presentation: We report on an 88-year-old male who presented with a mass lesion in the clavicular region. A biopsy of the mass revealed an increase in mature plasma cells with round nuclei. In contrast, a bone marrow examination showed increased plasma cells with flower-shaped nuclei. The patient tested negative for human T-lymphotropic virus type-1 and was diagnosed with multiple myeloma. Conclusions: While multiple myeloma is known for intra-tumor heterogeneity, reports of morphological heterogeneity based on the site of tumor sampling are limited. In this case, the presence of plasma cells with flower-shaped nuclei enabled the identification of site-dependent morphological tumor heterogeneity. [ABSTRACT FROM AUTHOR]

This document is a letter published in the Blood Cancer Journal. The authors discuss the progression patterns of smoldering multiple myeloma (SMM), an asymptomatic plasma cell disorder that precedes multiple myeloma (MM). They highlight the importance of early treatment for high-risk SMM and the inclusion of biomarkers of malignancy in the diagnostic criteria for MM. The authors conducted a retrospective study of 447 SMM patients and found that bone lesions and anemia were the most common criteria for end-organ damage. They also emphasize the need for further diagnostic improvement to identify progressive patients before they develop end-organ damage. [Extracted from the article]

Objective: Rare coexistence of disease or pathology. Background: Simultaneous occurrence of chronic lymphocytic leukemia (CLL) and plasma cell myeloma (PCM) is an uncommon hematological condition, with most patients presenting in late adult life. When these diagnoses occur concurrently, it often poses diagnostic challenges to the pathologist, with other important differential diagnoses including lymphoplasmacytic lymphoma, marginal-zone lymphoma, and chronic lymphocytic leukemia with plasmacytoid differentiation. Ancillary studies are indispensable in arriving at a reliable diagnosis in this clinical scenario. Case Reports: We present 2 cases of simultaneous CLL and PCM that were diagnosed in our facility. The bone marrow in these patients showed increased plasma cells with a separate population of neoplastic lymphoid cells. Bone marrow examination and ancillary studies (immunohistochemistry, fluorescence in situ hybridization, and molecular studies) were performed in both cases to arrive at the diagnosis and rule out other important differential diagnoses. While the first patient was still being observed at the time of writing this report, and found to be clinically stable during his last clinic visit, the second patient succumbed to the disease as a result of gram-negative sepsis. Conclusions: CLL and PCM can occasionally co-exist, posing diagnostic challenges to the pathologist. Ancillary diagnostic techniques are important in making a correct diagnosis. Making an accurate diagnosis is vital as this will guide appropriate treatment strategies. Whenever these 2 conditions occur simultaneously, patients often succumb as a result of progression of PCM. [ABSTRACT FROM AUTHOR]

Introduction: Abiraterone and enzalutamide are two androgen receptor pathway inhibitors approved, among others, for the treatment of metastatic castration-resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based regimen. Although hematological effects, especially neutropenia, are one of the main complications of other oral antineoplastic drugs, these adverse effects are infrequent in the case of androgen receptor pathway inhibitors. Case report: We report the case of a patient diagnosed with metastatic castration-resistant prostate cancer who discontinued an androgen receptor pathway inhibitor due to drug-related grade 4 neutropenia. His control blood counts before enzalutamide starting were normal. After one month of treatment, he developed a grade 4 neutropenia, with complete neutrophil count recovery four weeks later. He underwent a bone marrow aspiration, which revealed normocelullar results, and enzalutamide was restarted. Three weeks later, the treatment was eventually discontinued due to neutropenia reappearance. Neutrophil count recovery was achieved one month later. Then, he started treatment with abiraterone, but two weeks later neutropenia reappeared. Abiraterone was withdrawn, and the patient recovered from neutropenia 2 weeks later. Management and outcomes: This case exposes not only the occurrence of rare toxicity of two individual drugs but also the description of a probable drug-class adverse event not reported before. The patient recovered from neutropenia after the androgen receptor pathway inhibitor was withdrawn, thereby supporting the diagnosis of probable drug-induced neutropenia. Discussion: There is scarce evidence in the literature concerning androgen receptor pathway inhibitor-related neutropenia. However, its life-threatening potential cannot be ignored, so healthcare professionals should be warned of the possibility of the occurrence of such adverse reactions. [ABSTRACT FROM AUTHOR]

Sideroblastic anaemias are a diverse group of congenital and acquired bone marrow failure disorders marked by the presence of ring sideroblasts, ineffective erythropoiesis, and systemic iron overload. Congenital Sideroblastic anaemia (CSA) is mainly caused by gene mutations associated with heme synthesis, iron-sulfur [Fe-S] cluster, and mitochondrial protein synthesis pathways. The most prevalent form of CSA is caused by mutations in the erythroid-specific -amino levulinate synthase (ALAS2) gene, which encodes the first enzyme in the heme synthesis pathway in red blood cells. The second most prevalent form of CSA is caused by a mutation in the Solute carrier family 25 member 38 (SLC25A38) gene, which codes for an erythroid-specific protein of the inner mitochondrial membrane. Additionally, 15–20 genes are altogether associated with CSA. In this study, we aim to identify the CSA patients, understand their genetics and establish genotype-phenotype correlation. We have identified fifteen cases of CSA using our targeted NGS (t-NGS) panel. The major clinical findings in our cohort were microcytic anaemia, ring sideroblasts, and dyserythropoiesis in the bone marrow. Currently, two patients are responsive to pyridoxine, while the rest are on blood transfusion support. We have identified ten variants in three different genes of CSA (ALAS2, SLC25A38 & HSPA9). Five patients harbour four hemizygous variants- p.Ala282Ser, p.Arg170Cys, p.Arg204Gln and exon 2 duplication in the ALAS2 gene. In seven patients, we have identified three homozygous mutations – p.Pro190Arg, p.Arg187Gln and p.Arg134Cys in the SLC25A38 gene. These mutations have been predominantly identified in the European population. Three patients revealed three heterozygous variants p. Thr463Ile, D326Tyr, and Arg284Trp in the HSPA9 gene. PyMoL was used to evaluate the functional effects of these variations and understand their effect on the structure of the protein. We believe that by combining a bone marrow examination with genetic sequencing, CSA patients can acquire a definitive diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies but is often associated with significant adverse events. As these events affect up to 80% of patients, they constitute a crucial problem to overcome. This review focuses on the monitoring process of CAR-T cell therapy including the monitoring of the persistence, activity, and phenotyping of the cells. The implementation of tools like flow cytometry and polymerase chain reaction provides insights into cellular responses, enabling the optimization of CAR-T cell therapy for more precise and personalized treatment and addressing the challenge of tumor relapse. Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment for relapsed/refractory B-cell lymphomas. Despite its success, this therapy is accompanied by a significant frequency of adverse events, including cytokine release syndrome (CRS), immune-effector-cell-associated neurotoxicity syndrome (ICANS), or cytopenias, reaching even up to 80% of patients following CAR-T cell therapy. CRS results from the uncontrolled overproduction of proinflammatory cytokines, which leads to symptoms such as fever, headache, hypoxia, or neurological complications. CAR-T cell detection is possible by the use of flow cytometry (FC) or quantitative polymerase chain reaction (qPCR) assays, the two primary techniques used for CAR-T evaluation in peripheral blood, bone marrow (BM), and cerebrospinal fluid (CSF). State-of-the-art imaging technologies play a crucial role in monitoring the distribution and persistence of CAR-T cells in clinical trials. Still, they can also be extended with the use of FC and digital PCR (dPCR). Monitoring the changes in cell populations during disease progression and treatment gives an important insight into how the response to CAR-T cell therapy develops on a cellular level. It can help improve the therapeutic design and optimize CAR-T cell therapy to make it more precise and personalized, which is crucial to overcoming the problem of tumor relapse. [ABSTRACT FROM AUTHOR]

Ghosal hematodiaphyseal dysplasia (GHDD) is an autosomal recessive disorder characterized by diaphyseal dysplasia of long bones, bone marrow fibrosis, and steroid-responsive anemia. Patients with this disease have a mutation in the thromboxane-AS1 (TBXAS1) gene located on chromosome 7q33.34. They present with short stature, varying grades of myelofibrosis, and, hence cytopenias. Patients with the above presentation were evaluated through clinical presentation, X-ray of long bones, bone marrow examinations, and confirmed by genetic testing. In this article, we present two cases: The first case is a 3-year-old boy who presented with progressive pallor and ecchymotic patches for a year. On investigation, he had bicytopenia and bone marrow fibrosis. His anemia was steroid responsive and was finally diagnosed as GHDD. The second case is a 20-month-old girl who presented with blood in stools, developmental delay, anemia, and increased intensity of long bones on X-ray. Since other investigations were normal, suspicion of GHDD was raised, and a genetic workup was conducted which suggested mutation in TBXAS1 gene, confirming the diagnosis of GHDD. Children with refractory anemia and cortical thickening on skeletogram should always be evaluated for dysplasias. Timely treatment with steroids reduces transfusion requirements and halts bone damage, thus leading to better growth and improved quality of life. [ABSTRACT FROM AUTHOR]

This letter to the editor discusses the successful treatment of a heavily pretreated patient with multiple myeloma and liver extramedullary disease using belantamab mafodotin (Belamaf). Extramedullary disease is a rare and aggressive form of multiple myeloma characterized by the presence of soft-tissue plasmacytomas. Belamaf is a first-in-class drug that targets B-cell maturation antigen (BCMA) and has shown promising results in clinical trials. The patient in this case study experienced complete resolution of liver lesions after treatment with Belamaf, although the drug has since been withdrawn from the market due to the results of a clinical trial. Ongoing clinical trials are investigating the use of Belamaf in combination with other drugs. [Extracted from the article]

The Myelodysplastic syndromes (MDS) are a heterogenous group of clonal bone marrow (BM) stem cell myeloid neoplasms, characterized by ineffective hematopoiesis that results in dysplasia in hematopoietic cells and peripheral cytopenias, especially anemia, and a propensity to leukemic transformation. The suspicion of MDS is raised by a typical but not specific clinical picture and routine laboratory findings, but the gold standard for MDS diagnosis is still BM examination with the presence of uni-or multi-lineage dysplasia and increased blast percentage, together with exclusion of other reasons. Cytogenetics is also an essential part of the diagnostic and prognostic processes. Flow cytometry and full genetic characterization are helpful but not mandatory for MDS diagnosis. This review summarizes the current steps of diagnostic approach for a patient suspected of having MDS. We also express our hopes that within the near future, non-invasive technologies, especially digital and peripheral blood genetics, will mature and be introduced into practice. [ABSTRACT FROM AUTHOR]

COVID-19 infection is still a mystery in terms of its long-term effect on health and its consequences on hematological disorders. Prior studies including ours have shown the abnormal changes in hematopoietic cells in COVID-19 patients. In this article, we are presenting 2 cases of pediatric B-lymphoblastic leukemia (B-ALL) with a previous history of COVID-19 infection. The first case describes a 22-month-old boy presenting with lymphadenopathy, neutropenia, and anemia with concurrent COVID-19 infection without any evidence of a hematolymphoid neoplasm as per bone marrow and lymph node biopsy. However, he presented after 2 months with bone marrow biopsy confirming B-ALL. The second case is that of a 4-year-old girl presenting with B-ALL who has had asymptomatic COVID-19 infection 5 months before this current presentation. Both the cases had complete resolution of COVID-19 infection during the time of presentation with acute leukemia. There were notably 2 rare findings along the course of the patients' illnesses. First, the unusual plasmacytosis in the marrow during active COVID-19 infection in the first patient and the second, is predilection of development of B-ALL following COVID-19. In both the cases the fluorescence in situ hybridization (FISH) studies showed pathologic alteration of the RUNX1 gene. Overall, there are no literature to support a causal association between acute B-ALL and COVID-19. The diagnosis of B-ALL in these patients after COVID-19 infection may be totally unrelated. However, if we consider Greaves proposed 2-hit model for childhood acute leukemia, that an infectious agent can precipitate development of B-ALL in a genetically susceptible individual. Alteration of the RUNX1 gene in both the patients, opens a door for further exploration of the "second-hit" hypothesis regarding an infectious agent precipitating development of B-ALL in a genetically susceptible individual. [ABSTRACT FROM AUTHOR]

Pancytopenia is an uncommon abnormality detected on a full blood count. Features of presentation tend to be non-specific, and are due to impaired functions of the cell lines involved. These can include fatigue, infection and bleeding. However, the aetiology of pancytopenia is extensive. This narrative review aims to provide a minimally invasive diagnostic algorithm for generalist clinicians to approach pancytopenia, including investigations into the underlying aetiology, and when a referral to the haematologist is warranted for further investigations such as bone marrow aspiration and trephine biopsy. [ABSTRACT FROM AUTHOR]

This study focuses on acute myeloid leukemia (AML), a condition with a 5-year survival rate below 30% despite various treatment options. Recent strides in targeted therapies have shown promise, leading to better outcomes with minimal toxicity. These advances underscore the importance of discovering new diagnostic and prognostic targets for AML. In this context, the authors investigated the expression of microRNA-106b-5p (miR-106b-5p), Rab10 mRNA, and Rab10 proteins in peripheral blood and bone marrow (BM) samples from both healthy individuals and AML patients at different stages of the disease (initial diagnosis, recurrence, and complete remission). This examination aimed to identify potential biomarkers for AML diagnosis, treatment, and prognosis. From June 2021 to December 2022, they collected 100 BM and peripheral blood samples. The relative expression of miR-106b-5p and Rab10 mRNA in the BM of AML patients was measured using Real-time polymerase chain reaction (qRT-PCR), while the relative expression of Rab10 protein in serum was determined using the ELISA method. The chromosomal karyotype of initially diagnosed patients was analyzed using the R tape. The qRT-PCR results revealed that the expression of miR-106b-5p and Rab10 mRNA were significantly higher in patients at initial diagnosis and recurrence compared with healthy individuals and those in complete remission (p < 0.001). They observed a significant reduction in the expression of miR-106b-5p, Rab10 mRNA, and Rab10 protein in the BM and peripheral blood of patients during complete remission (p < 0.05), as demonstrated by dynamic monitoring of five patients in the initial group. Furthermore, they found a close association between the expression of miR-106b-5p and the number of white blood cells at the initial diagnosis in AML patients (p < 0.05). Spearman correlation analysis revealed a positive correlation among miR-106b-5p, Rab10 mRNA, and Rab10 proteins (p < 0.05). The diagnostic potential of miR-106b-5p and Rab10 proteins was underscored by Receiver Operating Characteristic (ROC) curve analysis, which demonstrated their high accuracy in AML diagnosis (AUC: 0.944 and 0.853, respectively; p < 0.0001). Additionally, Kaplan–Meier survival analysis suggested that lower expression of these markers was associated with better prognoses (p < 0.05). In summary, their findings propose miR-106b-5p and Rab10 proteins as promising biomarkers for AML, offering insights for diagnosis, treatment, and prognosis. [ABSTRACT FROM AUTHOR]

Background Allogeneic hematopoietic stem cell transplant for myeloid neoplasms with increased fibrosis is uncommon; morphologic features posttransplant can be concerning for persistent disease. Methods In this retrospective study, we identified 22 patients transplanted for myeloproliferative neoplasms or chronic myelomonocytic leukemia with fibrosis at our institution, and reviewed slides from pretransplant and posttransplant bone marrow biopsies. Clinical features and results of molecular, chimerism, and cytogenetic studies were retrieved from the medical record. Results Pretransplant bone marrow biopsies commonly exhibited hypercellularity, atypical megakaryocytes, and reticulin fibrosis. At day 100, 36% of biopsies had reticulin grade >MF1 and 33% of those tested had positive molecular studies, with no significant associations between day 100 marrow characteristics and molecular profile or peripheral count recovery times. In the 1 year posttransplant biopsies (n = 12), 7 of 9 had negative molecular studies; of these, none had reticulin grade >MF1, 1 had trichrome 1+, 2 had atypical megakaryocytes, and 1 was hypercellular. Conclusions Supporting recent literature, our study indicates that persistent day 100 reticulin fibrosis/collagen deposition does not show an association with day 100 molecular status. Our study additionally provides data for 12 patients with 1 year posttransplant marrow biopsies, with the majority of those lacking either increased fibrosis or molecular evidence of persistent disease. [ABSTRACT FROM AUTHOR]

Objective: The prognostic factors and outcomes of Turkish children with newly diagnosed acute lymphoblastic leukemia (ALL), treated with the Modified St. Jude Total XV Protocol, which was adjusted by adding high-dose methylprednisolone (HDMP) before induction in the original protocol, were assessed in this study. Materials and Methods: The Modified St. Jude Total XV Protocol was administered to 183 newly diagnosed ALL patients, aged 1-18 years, between 1 January 2008 and 30 January 2016. HDMP was applied at doses of either 10 mg/kg/day (Group A) or 20 mg/kg/day (Group B) for 7 days before induction and then tapered over the next 7 days to 5 or 10 mg/kg/day, and continued at 2 mg/kg/day for 2 weeks during the induction phase. Absolute blast count (ABC) in peripheral blood and minimal residual disease (MRD) in bone marrow were assessed at the end of the initial 7-day HDMP treatment. MRD in the bone marrow was evaluated on day 15 and at the end of the induction period. The follow-up for these patients ended on 15 July 2019. Results: The 5-year event-free (EFS) and overall survival (OS) rates for all patients were 85.6±2.6% and 89.2±2.3%, respectively. The rate of good response to steroids (defined as ABC in peripheral blood of less than 1000/mm3 on day 7) was 88% and 97% of children achieved complete remission after induction. The survival rate and infection frequency did not show statistically significant differences between Group A and B. EFS and OS correlated with initial leukocyte count, age of 10-18 years at diagnosis, CD20 positivity at diagnosis, and gramnegative bacterial infection during remission induction. Conclusion: The remarkable response rates on days 7 and 15, along with the promising EFS and OS results in childhood ALL patients treated with the Modified St. Jude Total XV Protocol, highlight the early and substantial response effect of HDMP. At the onset of induction, shortterm HDMP can be initiated, preferably at 10 mg/kg/day for the first 7 days, to minimize potential side effects. [ABSTRACT FROM AUTHOR]

Babesiosis, as a vector-borne infectious disease, remains relatively rare and is prone to being overlooked and misdiagnosed. Therefore, understanding the epidemiological characteristics and clinical manifestations of babesiosis is crucial for the prompt detection and treatment of the disease. We reported a 63-year-old male patient presenting with spontaneous fever and chills. Laboratory investigations revealed erythrocytopenia, reduced hemoglobin levels, and increased reticulocytes and total bilirubin. Bone marrow examination indicated vigorous cell proliferation, a decreased granulocyte to red cell ratio, and predominant erythroid cell proliferation, with a higher prevalence of intermediate and late-stage juvenile granulocyte and erythroid cells. Initial treatment focused on hemophagocytic syndrome triggered by Epstein-Barr virus infection yielded unsatisfactory results, leading to secondary multiple pulmonary infections. Metagenomic next-generation sequencing (mNGS) of sputum samples pointed to hemolytic anemia induced by Babesia infection, which was subsequently confirmed through peripheral blood smear analysis. The patient responded well to prompt administration of atovaquone and azithromycin, with symptoms resolving and laboratory parameters normalizing. Hemolytic anemia resulting from babesiosis should be distinguished from hemophagocytic syndrome caused by Epstein-Barr virus and other hematologic conditions. mNGS represents an efficient technique for Babesia detection. [ABSTRACT FROM AUTHOR]

The purpose of this pilot randomized controlled trial was to analyze and compare the effects of advanced platelet-rich fibrin (A-PRF) and plasma rich in growth factors (PRGF), combined with deproteinized bovine bone mineral (DBBM), in bone regeneration outcomes in maxillary sinus augmentation (MSA) procedures. The maxillary sinuses of 15 patients were grafted with DBBM alone (control group), DBBM mixed with A-PRF (PRF group), or DBBM mixed with PRGF (PRGF group). After a 6-month healing period, bone core biopsy samples were collected prior to implant placement for histologic and histomorphometric analyses, evaluating the mean percentages of mineralized tissue (MT), remaining bone graft material (RBGM), and nonmineralized tissue (NMT). Mean MT was 20.33% ± 11.50% for the control group, 32.20% ± 7.29% for the PRF group, and 34.80% ± 6.83% for the PRGF group. Mean RBGM was 24.00% ± 7.94% for the control group, 26.00% ± 7.78% for the PRF group, and 15.80% ± 8.23% for the PRGF group. Mean NMT was 55.66% ± 7.77% for the control group, 41.40% ± 8.32% for the PRF group, and 49.60% ± 5.68% for the PRGF group. No statistically significant differences (P > .05) were seen across the three groups for MT, RBGM, and NT. These findings suggest that adding A-PRF and PRGF to DBBM does not enhance new bone formation outcomes in maxillary sinus augmentation procedures. None of the two platelet concentrates were superior to the other in any of the variables assessed. [ABSTRACT FROM AUTHOR]

Introduction: Mastocytosis is a rare hematologic neoplasm characterized by the abnormal proliferation and accumulation of mast cells in various tissues. Its clinical manifestations vary widely, ranging from cutaneous lesions to systemic involvement with potentially life threatening symptoms. Understanding the pathophysiology, diagnosis, and management of mastocytosis is crucial for improving patient outcomes. Aim of the Study: The aim of this study was to provide a comprehensive overview of mastocytosis, including its epidemiology, risk factors, pathophysiology, clinical manifestations, diagnostic approaches, and management strategies. By synthesizing current knowledge on mastocytosis, this study aims to enhance understanding of the disease and guide clinical practice. Description of the State of Knowledge: Mastocytosis is classified into cutaneous and systemic forms, with various subtypes based on clinical and histopathological features. Diagnosis relieson a combination of clinical suspicion, serum tryptase levels, histological examination of bone marrow biopsies, and genetic testing. Management strategies include symptomatic treatment, avoidance of triggers, and targeted therapies such as monoclonal antibodies and tyrosine kinase inhibitors. Advanced forms may require cytoreductive therapy or allogeneic hematopoietic stem cell transplantation (alloHSCT). Conclusions: Despite advancements in diagnosis and treatment, achieving lasting remission in mastocytosis remains challenging, especially in advanced cases. Further research into the molecular mechanisms underlying the disease and the development of novel therapeutic modalities are needed to improve patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Introduction: Knee osteoarthritis (KOA), a chronic degenerative disease, significantly impairs quality of life due to pain and mobility limitations. Traditional treatments focus on symptom management without addressing the underlying disease progression, leading to a growing interest in regenerative medicine approaches. Bone marrow aspirate concentrate (BMAC), rich in mesenchymal stem cells and growth factors, has shown potential for cartilage repair and symptom relief in KOA. Despite promising outcomes, the optimal BMAC dosage for knee OA treatment remains undetermined. This study aims to evaluate the clinical efficacy and safety of varying BMAC dosages in knee OA treatment. Methods: This prospective controlled dose–escalation study involved 75 patients with early-stage knee OA, categorized into three groups based on BMAC dosage administered 10 × 106 cells (low-dose group), 50 × 106 cells (medium-dose group), or 100 × 106 cells (high-dose group). All the patients underwent a single intra-articular injection of BMAC and were monitored over a year. The primary outcomes include Visual Analog Scale (VAS) for pain and the Knee Injury and Osteoarthritis Outcome Score (KOOS) for joint function recorded at baseline, 1, 3, 6, and 12 months post-intervention. Adverse events were also documented. Results: Significant clinical improvements in VAS and KOOS scores were noted across all groups at all time points compared to the baseline. However, these improvements did not significantly differ between dosage groups throughout the follow-up period. Adverse effects were minimal and primarily consisted of transient post-injection pain and effusion, with no dose-dependent increase in complications. Conclusion: BMAC treatment for knee OA is safe and demonstrates potential for significant pain relief and functional improvement, irrespective of the dosage administered within the tested range. The lack of significant differences among varying dosages suggests a plateau in therapeutic efficacy beyond a certain threshold. Further research is necessary on the long-term outcomes to optimize the dosing strategy. [ABSTRACT FROM AUTHOR]

Purpose: Osteochondritis dissecans (OCD) is a common cause of knee pain. Management for adult‐onset OCD (AOCD) usually involves surgery. Surgical treatments include palliative, reparative and reconstructive techniques. The aim of this systematic review and meta‐analysis is to evaluate the efficacy of reconstructive techniques for the treatment of OCD in skeletally mature knees. Methods: A systematic search was carried out on four databases up to November 2023 (Medline, Embase, Cochrane Library, Web of Science). The study was registered on international prospective register of systematic reviews and performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines. Clinical studies on skeletally mature patients were included, which utilised reconstructive techniques such as autologous chondrocyte implantation (ACI), matrix‐induced autologous chondrocyte implantation, osteochondral allograft transplantation surgery or bone marrow‐derived cellular transplantation. Demographical data, patient‐reported outcome measures and postoperative complications were recorded. Quantitative outcome measures that were comparable across studies were pooled for meta‐analysis. A random effects model was used. Heterogeneity was assessed using the I2 statistic and Cochran's Q test. Statistical significance was set at p < 0.05. Risk of bias was assessed using the risk of bias in non‐randomised studies ‐ of interventions tool for nonrandomised studies. Results: Sixteen studies were included with 458 OCD lesions in 432 patients. The average age was 24.9, and 62.6% were male. The mean follow‐up time was 61.5 months. At 36 months follow‐up, International Knee Documentation Committee (IKDC) subjective, Tegner and EuroQol‐visual analogue scale (EQ‐VAS) scores improved from 42.4 to 78.6 (standard mean difference [SMD]: 2.47; p < 0.001), 2.27–4.99 (SMD: 2.363; p = 0.002) and 30.4–57.5 (SMD: 2.390; p < 0.001), respectively. Overall complication rate was 8.9%. Smaller OCD lesion sizes resulted in a greater improvement in IKDC subjective (SMD: 2.64 vs. 2.01; p = 0.038), EQ‐VAS (SMD: 3.16 vs. 0.95; p = 0.046) and Tegner scores (SMD: 3.13 vs. 1.05; p = 0.007) and had a lower complication rate (p = 0.008). Males showed a larger improvement in IKDC subjective scores than females (SMD: 2.56 vs. 1.56; p = 0.029), while younger patients had a larger improvement in IKDC subjective scores (SMD: 2.71 vs. 2.12; p = 0.045) and fewer complications than older patients (p = 0.003). There were no significant differences between cohorts treated with ACI and those treated with non‐ACI reconstructive techniques. Publication bias was not detected (n.s.). Conclusion: Reconstructive techniques used to treat OCD in the skeletally mature knee resulted in significant improvements in clinical and functional outcomes, with a low overall complication rate. Since a younger age leads to a greater improvement in IKDC subjective score and a lower complication rate, surgical intervention should not be delayed, especially in AOCD lesions which are more likely to follow a progressive and unremitting clinical course. Level of Evidence: Level III. [ABSTRACT FROM AUTHOR]

Background: Patients often consider bone marrow aspiration and biopsy to be one of the most painful medical procedures. The effectiveness of non‐pharmacological interventions to reduce pain during bone marrow aspiration and biopsy remains unclear. Aim: To synthesize existing evidence regarding the effectiveness of non‐pharmacological interventions in mitigating procedural pain among patients undergoing bone marrow aspiration and biopsy. Design: A systematic review and meta‐analysis of randomized controlled trials. Methods: Six electronic databases, including PubMed, EMBASE, CINAHL, PsycINFO, Cochrane Library and Web of Science were searched from inception to July 15, 2023. The risk of bias was assessed using the Cochrane Risk of Bias Tool Version 2.0. Meta‐analysis was conducted using STATA 16. The certainty of the evidence was assessed by the GRADE approach. Results: This meta‐analysis included 18 studies derived from 17 articles involving a total of 1017 participants. The pooled results revealed statistically significant pain reduction effects using distraction (SMD: −.845, 95% CI: −1.344 to −.346, p <.001), powered bone marrow biopsy system (SMD: −.266, 95% CI: −.529 to −.003, p =.048), and acupoint stimulation (SMD: −1.016, 95% CI: −1.995 to −.037, p =.042) among patients undergoing bone marrow aspiration and biopsy. However, the pooled results on hypnosis (SMD: −1.228, 95% CI: −4.091 to 1.515, p =.368) showed no significant impact on pain reduction. Additionally, the pooled results for distraction did not demonstrate a significant effect on operative anxiety (MD: −2.942, 95% CI: −7.650 to 1.767, p =.221). Conclusions: Distraction, powered bone marrow biopsy system and acupoint stimulation are effective in reducing pain among patients undergoing bone marrow aspiration and biopsy. Patient or Public Contribution: Not applicable. Relevance to Clinical Practice: This meta‐analysis highlights the effectiveness of distraction, powered bone marrow biopsy system and acupoint stimulation for reducing pain in patients undergoing bone marrow biopsy. Healthcare professionals should consider integrating these interventions into pain management practices for these patients. Registration: (PROSPERO): CRD42023422854. [ABSTRACT FROM AUTHOR]

Background: Transient erythroblastopenia of childhood (TEC) is an acquired, self-limited pure red cell aplasia that usually occurs in children 4 years old and younger. This clinical condition has been priorly described to be linked to numerous viral and immunologic mechanisms. COVID-19, caused by the coronavirus SARS-CoV-2, was initially discovered in China in December 2019. The disease quickly spread worldwide, resulting in pandemic. Case Presentation: This manuscript reports a new clinically relevant condition associated to COVID-19, describing a child with clinical and biochemical signs of Pure Red Blood cells aplasia and complete absence of erythroblasts at the bone marrow needle aspiration with signs of erythrophagocytosis, resembling morphological signs such as in hemophagocytic lymphohistiocytosis (HLH), temporally associated to SARS-CoV-2 infection. Conclusion: This report highlights a newly described continuum laboratory and clinical spectrum of immune/hematological dysregulations secondary to SARS-CoV-2. SARS-CoV‐2 infection-linked TEC has never been described in literature, but, according to our findings, should be considered in all the patients with transient erythroblastopenia without congenital red blood cell abnormalities and serology negative for major infections associated with TEC. This condition must be considered in the same spectrum of MIS-C and the inter-links among the two clinical manifestations, as well as a potential interdependence among them, should be considered in the future. [ABSTRACT FROM AUTHOR]

A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5- to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20–100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidence-based and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%–30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted. [ABSTRACT FROM AUTHOR]

Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes. MF presents in primary and secondary forms, with common symptoms including splenomegaly, anemia, and thrombocytopenia. Diagnostic criteria involve bone marrow examination and mutation studies. Current treatments are limited, with allogeneic stem cell transplant as the only curative option. Recent FDA approval of Momelotinib (MMB) offers new promise for MF patients with anemia. MMB, a JAK1/2 and ACVR1 inhibitor, effectively reduces spleen size, improves hemoglobin levels, and decreases transfusion dependency. The MOMENTUM trial compared MMB to danazol in JAK inhibitortreated MF patients with anemia, showing MMB's superior symptom relief and transfusion independence rates. Additionally, the SIMPLIFY-1 and SIMPLIFY-2 trials evaluated MMB in JAK inhibitor-naïve and experienced patients, respectively, confirming MMB's non-inferiority to ruxolitinib in spleen volume reduction and highlighting its benefits in transfusion requirements. MMB's unique dual inhibition mechanism addresses anemia by suppressing hepcidin production, thus enhancing erythropoiesis. These trials collectively suggest MMB as an effective treatment for MF, improving quality of life and offering a survival advantage for patients with anemia. Despite challenges, such as trial design limitations and adverse events, MMB represents a significant advancement in MF management, providing a new therapeutic option for a previously underserved patient population. [ABSTRACT FROM AUTHOR]

Background: Polycythemia Rubra Vera (PRV) is a myeloproliferative neoplasm characterized by uncontrolled red blood cell production. This study aimed to evaluate the applicability of the 2016 WHO diagnostic criteria for PRV in Sulaimaniyah City, Kurdistan Region, Iraq, focusing on the incidence of JAK2 mutations and their association with patient demographics and clinical features. Materials & Methods: A cross-sectional retrospective study was conducted on 100 PRV patients between February 2023 and February 2024 at Hiwa Hematology/Oncology Hospital and Shorsh Teaching Hospital. Patients were selected using a convenience sampling method, which involved including all eligible patients with available JAK2 mutation data and bone marrow examination results during the study period. Blood parameters, bone marrow examination, and JAK2 mutation status were analyzed. Statistical associations between JAK2 mutation status and age, gender, and clinical features (neutrophilia, thrombocytosis, splenomegaly) were assessed. Results: The mean age of the patients was 52.91 ± 16.76 years, with 51% older than 50 years. Males comprised 68% of the cohort. Among the patients, 47% were JAK2 mutation-positive, and 53% were JAK2-negative. JAK2- positive patients were significantly older (mean age 57.51 ±17.84 years) compared to JAK2-negative patients (mean age 48.83 ± 14.73 years; p=0.009). A significant association was found between JAK2 mutation status and gender (p=0.01), with a higher proportion of males among JAK2-negative patients. JAK2-positive patients showed higher incidences of neutrophilia (25.5% vs. 3.8%; p=0.002), thrombocytosis (46.8% vs. 13.2%; p<0.001), and splenomegaly (53.2% vs. 9.4%; p<0.001) compared to JAK2-negative patients. Conclusions: The study revealed that while the 2016 WHO criteria are generally effective for diagnosing PRV, the higher-than-expected proportion of JAK2-negative patients suggests the need for additional diagnostic considerations in this population. The significant associations between JAK2 mutation status and specific clinical features emphasize the heterogeneity of PRV presentations and the potential need for regional adaptations of the WHO criteria. [ABSTRACT FROM AUTHOR]

Objective: Conventional magnetic resonance imaging (MRI) uses T1-weighted and short-tau inversion recovery (STIR) sequences to characterize bone marrow in axial spondyloarthritis. However, quantification is restricted to estimating the extent of lesions because signal intensities are highly variable both within individuals and across patients and MRI scanners. This study evaluates the performance of quantitative T1 mapping for distinguishing different types of bone marrow lesions of the sacroiliac joints. Materials and methods: In this prospective study, 62 patients underwent computed tomography (CT) and MRI of the sacroiliac joints including T1, STIR, and T1 mapping. Bone marrow lesions were characterized by three readers and assigned to one of four groups: sclerosis, osteitis, fat lesions, and mixed marrow lesions. Relaxation times on T1 maps were compared using generalized estimating equations and receiver operating characteristics (ROC) analysis. Results: A total of 119 lesions were selected (sclerosis: 38, osteitis: 27, fat lesions: 40; mixed lesions: 14). T1 maps showed highly significant differences between the lesions with the lowest values for sclerosis (1516±220 ms), followed by osteitis (1909±75 ms), and fat lesions (2391±200 ms); p<0.001. T1 mapping differentiated lesions with areas under the ROC curve of 99% (sclerosis vs. osteitis) and 100% (other comparisons). Conclusion: T1 mapping allows accurate characterization of sclerosis, osteitis, and fat lesions at the sacroiliac joint but only for homogeneous, non-mixed lesions. Thus, further sequence development is needed before implementation in clinical routine. [ABSTRACT FROM AUTHOR]

Background/Aim: Diagnosing primary splenic malignant lymphoma (PSML) is challenging due to the nonspecific nature of splenomegaly, necessitating splenic biopsy for confirmation. However, performing partial splenic resection for diagnostic purposes is an elective procedure due to the risk of major hemorrhage. Despite the longstanding practice of splenectomy over the past few decades, it remains invasive and may result in severe early or late complications. Hence, we present laparoscopic partial splenectomy (LPS) in a patient suspicious of PSML for diagnostic purposes in this study. Case Report: An 81- year-old woman presented to our hospital with a one-month history of fever and dry cough. Atypical cells had been detected in her peripheral blood nine months ago. However, at that time, a bone marrow examination did not reveal any atypical cells. The laboratory tests revealed a soluble interleukin receptor-2 levels of 4,667 U/dl and atypical cells were also found in peripheral blood. Abdominal computed tomography showed splenomegaly without any other relevant findings. These findings are suspicious of PSML and LPS without vessel ligation was performed and a small fraction of the spleen from the inferior pole measuring 1.8×1.0 cm was resected. The operation lasted for 63 min with minimal estimated blood loss. Histopathological findings were compatible with the diagnosis of diffuse B-cell lymphoma. The postoperative clinical course was uneventful, and splenomegaly demonstrated improvement six months after the operation. Conclusion: LPS without vessel ligation for biopsy may be valuable for the diagnosis of malignant lymphoma, particularly when there are no swollen lymph nodes, as it offers a less invasive approach. [ABSTRACT FROM AUTHOR]

Objective: This study aims to elucidate the clinical features observed in cases of pediatric acute myeloid leukemia (AML) initially presenting with cardiac tamponade and to share treatment experiences. Materials and methods: Five pediatric patients were initially diagnosed with AML accompanied by cardiac myeloid sarcoma (MS). The diagnosis was established by examining our hospital records and reviewing pertinent literature from 1990 to July 2023, accessible through MEDLINE/PubMed. We comprehensively assessed the clinical characteristics and treatment modalities employed for these patients. Result: Five pediatric patients presented with acute symptoms, including shortness of breath, malaise, cough, and fever, leading to their hospitalization. Physical examination revealed irritability, hypoxia, tachypnea, tachycardia, and hypotension. Initial detection utilized chest X-ray or echocardiogram, leading to subsequent diagnoses based on pericardial effusion and/or bone marrow examination. Two patients received chemotherapy at the time of initial diagnosis, one with cytarabine and etoposide, and the other with cytarabine and cladribine. Post-treatment, their bone marrow achieved remission, and over a 2.5-year follow-up, their cardiac function remained favorable. Unfortunately, the remaining three patients succumbed within two weeks after diagnosis, either due to receiving alternative drugs or without undergoing chemotherapy. Conclusion: This is the first and largest case series of pediatric AML patients with cardiac MS, manifesting initially with cardiac tamponade. It highlights the rarity and high mortality associated with this condition. The critical factors for reducing mortality include identifying clinical manifestations, conducting thorough physical examinations, performing echocardiography promptly, initiating early and timely pericardial drainage, and avoiding cardiotoxic chemotherapy medications. [ABSTRACT FROM AUTHOR]

Aim: This study was conducted to determine the effect of music on the pain, anxiety, and comfort levels of patients who underwent bone marrow aspiration and biopsy. Methods: This study was conducted on patients with hematological malignancies. Music was used with the intervention group. Patients' pain, anxiety, and comfort levels were measured. In addition, qualitative data were obtained through in-depth interviews with patients. Results: A significant difference (p < 0.05) was found between the experimental and control groups regarding pain, comfort and anxiety levels following the application of music. It was found that there was a negative correlation between comfort and pain (r=-0.442 p < 0.001) and between comfort and anxiety (r=-0.544 p < 0.001). As a result of qualitative interviews, patients mentioned the relaxing effect of music and the reduction of anxiety and pain levels. They also stated that music can be utilized as an alternative method. Conclusion: According to the results of the present study, music reduced the pain and anxiety levels of the patients in bone marrow aspiration and biopsy and increased their comfort levels. We can say that music can be used in the clinic as a non-pharmacological method for pain, anxiety and comfort. Clinical Trials Number: NCT05895357 (Date:08/06/2023). [ABSTRACT FROM AUTHOR]

Introduction: A previously published web‐based App using Gradient‐boosted models (GBMs) of eight laboratory parameters was established by Oster et al. to facilitate diagnosis or exclusion of myelodysplastic syndromes (MDS) in patients. Methods: To validate their algorithm, we compared 175 anemic patients with MDS diagnosis from our German MDS Registry with 1378 non‐MDS anemic patients who consulted various specialties in the Düsseldorf university hospital. Results: Based on hemoglobin level, leukocyte and platelet count, mean corpuscular volume, absolute neutrophil count, absolute monocyte count, glucose and creatinine, plus the patients' gender and age, we could not reproduce a high negative predictive value (NPV), but confirmed a useful specificity of 90.9% and a positive predictive value (PPV) of 77.1%. 1192 of 1378 controls were correctly categorized as "probably not MDS (pnMDS)" patients. A total of 65 patients were wrongly classified as "probable MDS (pMDS)," of whom 48 had alternative explanations for their altered laboratory results. In a second analysis, we included 29 patients with chronic myelomonocytic leukemia (CMML) resulting in only one label as possible MDS, suggesting that highly proliferative bone marrow disorders are correctly excluded. Conclusion: The possibility of reliably excluding MDS from differential diagnosis based on peripheral blood lab work appears to be attractive for patients and physicians alike while the confirmation of MDS diagnosis still requires a bone marrow biopsy. [ABSTRACT FROM AUTHOR]

Introduction: This study aims to evaluate the effectiveness and reliability of the utilization for clinical reporting of the evaluation of digital images of bone marrow aspirates by morphologists and their comparability with the classic microscopic morphological evaluation. Methods: We scanned 180 consecutive bone marrow needle aspirates smears using the "Metafer4 VSlide" whole slide imaging (WSI) digital scanning system. We evaluated the statistical comparability and the risk of bias of the microscopic readings with those performed on the screen on the digitized medullary images. Results: The evaluation of cellularity on the screen was equivalent, with a higher frequency of "normal" than the analysis of digital preparations. The means and medians of the percentage values obtained on the different cell populations with the microscopic and digital reading were comparable as the main categories are concerned, with an average difference equal to 0 for the neutrophilic and eosinophilic granulocytic series, at −0.2% for the total myeloid cells, at 1.2% for the erythroid series, at −0.4% for the lymphocytes and at −0.4% for the blasts. Dysplastic features were consistently identified in 69/71 cell lineages. Conclusion: Our study demonstrated that screen evaluation of digitized bone marrow needle aspirates provides quantitative and qualitative results comparable to traditional microscopic analysis of the corresponding slide smears. Digital images offer significant benefits in reducing the workload of experienced operators, reproducibility and sharing of observations, and image preservation. Even in routine diagnostic activities, their use does not alter the quality of the results obtained in evaluating bone marrow needle aspirates. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cadmium (Cd) is a highly toxic and widespread environmental oxidative stressor that causes a myriad of health problems, including osteoporosis and bone damage. Although nuclear factor erythroid 2-related factor 2 (NRF2) and its Cap ‘n’ Collar and basic region Leucine Zipper (CNC-bZIP) family member nuclear factor erythroid 2-related factor 1 (NRF1) coordinate various stress responses by regulating the transcription of a variety of antioxidant and cytoprotective genes, they play distinct roles in bone metabolism and remodeling. However, the precise roles of both transcription factors in bone loss induced by prolonged Cd exposure remain unclear. OBJECTIVES: We aimed to understand the molecular mechanisms underlying Cd-induced bone loss, focusing mainly on the roles of NRF2 and NRF1 in osteoclastogenesis provoked by Cd. METHODS: Male wild-type (WT), global Nrf2-knockout (Nrf2-/-) and myeloid-specific Nrf2 knockout [Nrf2(M)-KO] mice were administered Cd (50 or 100 ppm) via drinking water for 8 or 16 wk, followed by micro-computed tomography, histological analyses, and plasma biochemical testing. Osteoclastogenesis was evaluated using bone marrow-derived osteoclast progenitor cells (BM-OPCs) and RAW 264.7 cells in the presence of Cd (10 or 20 nM) with a combination of genetic and chemical modulations targeting NRF2 and NRF1. RESULTS: Compared with relevant control mice, global Nrf2-/- or Nrf2(M)-KO mice showed exacerbated bone loss and augmented osteoclast activity following exposure to 100 ppm Cd in drinking water for up to 16 wk. In vitro osteoclastogenic analyses suggested that Nrf2-deficient BM-OPCs and RAW 264.7 cells responded more robustly to low levels of Cd (up to 20 nM) with regard to osteoclast differentiation compared with WT cells. Further mechanistic studies supported a compensatory up-regulation of long isoform of NRF1 (L-NRF1) and subsequent induction of nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 1 (NFATc1) as the key molecular events in the Nrf2 deficiency-worsened and Cd-provoked osteoclastogenesis. L-Nrf1 silenced (via lentiviral means) Nrf2-knockdown (KD) RAW cells exposed to Cd showed dramatically different NFATc1 and subsequent osteoclastogenesis outcomes compared with the cells of Nrf2-KD alone exposed to Cd, suggesting a mitigating effect of the Nrf1 silencing. In addition, suppression of reactive oxygen species by exogenous antioxidants N-acetyl-L-cysteine (2 mM) and mitoquinone mesylate (MitoQ; 0.2 μM) mitigated the L-NRF1-associated effects on NFATc1-driven osteoclastogenesis outcomes in Cd-exposed Nrf2-KD cells. CONCLUSIONS: This in vivo and in vitro study supported the authors’ hypothesis that Cd exposure caused bone loss, in which NRF2 and L-NRF1 responded to Cd and osteoclastogenic stimuli in a cooperative, but contradictive, manner to coordinate Nfatc1 expression, osteoclastogenesis and thus bone homeostasis. Our study suggests a novel strategy targeting NRF2 and L-NRF1 to prevent and treat the bone toxicity of Cd. [ABSTRACT FROM AUTHOR]

Background: Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia with a favorable prognosis. Hemorrhagic manifestations in APL at presentation are usually due to thrombocytopenia, consumptive coagulopathy, and fibrinolysis. Central nervous system (CNS) hemorrhage carries a risk for CNS relapse and early death in APL patients. Case Presentation: A 23-year-old male presented with sudden bilateral visual loss and headache. The ocular examination revealed a massive exudative retinal detachment in the right eye and bilateral dense vitreous hemorrhage. APL diagnosis was confirmed through peripheral blood and bone marrow examination, along with cytogenetic and molecular testing. The patient received 7+3 induction chemotherapy combined with All-trans-retinoic acid. After achieving complete remission, he underwent pars plana vitrectomy and silicone oil injection in the right eye. Intrathecal chemotherapy was considered for CNS prophylaxis after induction. Later, he had a medullary relapse which was managed with salvage therapy and autologous stem cell transplantation. Conclusion: Although APL has a favorable prognosis, its management can be complicated. It may present with retinal detachment or intraocular hemorrhage. Managing intraocular and intracranial hemorrhage is challenging due to the risks of hemorrhage and coagulopathy. This complexity is further heightened by poor visual prognosis, high risk of CNS infiltration, and potential for medullary relapse. [ABSTRACT FROM AUTHOR]

Severe hypercalcemia associated with vitamin D intoxication or malignancy in children is a rare and life-threatening condition. There is little published experience with Zoledronic acid (ZA) in the treatment of pediatric severe hypercalcemia. Here, we present two pediatric cases of severe hypercalcemia, one due to vitamin D intoxication and the second to malignancy, in which ZA was used as the first-line bisphosphonate in the treatment. While both cases responded well to a single dose of ZA, the second case experienced hypocalcemia requiring calcium treatment after ZA infusion. Our report shows that ZA may be an effective option in the treatment of severe pediatric hypercalcemia, although patients should be followed closely after infusion due to the risk of hypocalcemia. We provide additional published evidence for the effectiveness of ZA in correcting severe pediatric hypercalcemia and hope this will encourage future studies with larger numbers of patients. [ABSTRACT FROM AUTHOR]

Introduction: Hodgkin lymphoma (HL) is one of the pediatric and adult cancers, with the treatment of chemotherapy alone or combined with radiotherapy. Objectives: We aimed to evaluate the consequences and outcomes of the treatment with or without radiotherapy in a retrospective study. Patients and Methods: We carried out a cross-sectional retrospective study by referring and reviewing records for all patients admitted to Motahari hospital with HL diagnosis from 1995 to 2016. The Ann Arbor staging system classified the staging of disease. Results: Totally, 35 patients enrolled in our study that 54.3% were female, and 45.7% were male patients. The mean age of patients was 10.08±6.38 years. 10 (28.6%) cases classified in stage 1, 13 (37.1%) case in stage 2, 9 (25.7%) cases in stage 3, and 3 (8.6%) cases in stage 4. 30 patients (85.7%) were treated by chemotherapy and 5 (14.3%) patients with chemotherapy and radiation combination. In our study, the overall survival was 97.1% of patients treated with chemotherapy alone, and one patient died due to drug side effects. That is comparable with other studies that treated patients with chemotherapy and radiotherapy. Conclusion: According to our findings, chemotherapy without radiotherapy as initial treatment in HL would have similar results to concomitant radiotherapy and chemotherapy, so considering the cost and harms of radiotherapy, we suggest a limitation of radiotherapy to patients with resistant diseases that do not respond to chemotherapy solo-protocols. [ABSTRACT FROM AUTHOR]

The Myelodysplastic syndromes (MDS) are a heterogenous group of clonal bone marrow (BM) stem cell myeloid neoplasms, characterized by ineffective hematopoiesis that results in dysplasia in hematopoietic cells and peripheral cytopenias, especially anemia, and a propensity to leukemic transformation. The suspicion of MDS is raised by a typical but not specific clinical picture and routine laboratory findings, but the gold standard for MDS diagnosis is still BM examination with the presence of uni-or multi-lineage dysplasia and increased blast percentage, together with exclusion of other reasons. Cytogenetics is also an essential part of the diagnostic and prognostic processes. Flow cytometry and full genetic characterization are helpful but not mandatory for MDS diagnosis. This review summarizes the current steps of diagnostic approach for a patient suspected of having MDS. We also express our hopes that within the near future, non-invasive technologies, especially digital and peripheral blood genetics, will mature and be introduced into practice.

The article discusses the prediction of therapy-related myeloid neoplasms after CAR-T cell therapy using the Clonal Haematopoiesis Risk Score (CHRS). The study analyzed patients treated with CAR-T cells and found that those with clonal haematopoiesis had a higher risk of developing myeloid neoplasms. The research highlights the importance of assessing CHRS before CAR-T therapy to identify individuals at higher risk of early secondary myeloid neoplasms. [Extracted from the article]

A 46-year-old male patient presented with inflammatory diseases over more than 3 years. The patient suffered from recurrent pleuritis, polychondritis, orbital phlegmon, fever, and skin lesions. A bone marrow puncture added myelodysplastic syndrome to the patient's history. A focused cytomorphological reinvestigation of the archived bone marrow aspirate smears detected significant vacuolization of erythroid and myeloid precursor cells. Target sequencing revealed the UBA1 (p.Met41Thr) hotspot mutation that established the diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. [ABSTRACT FROM AUTHOR]

Purpose: To compare the diagnostic value of 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) and bone marrow biopsy and aspiration (BMBA) for evaluating bone marrow metastases (BMM) in newly diagnosed pediatric Ewing sarcoma (ES). Material and methods: To assess the diagnostic accuracy of 18F-FDG PET/CT against BMBA for marrow infiltration in ES patients, a retrospective analysis encompassed 103 ES patients from the Children's Hospital of Chongqing Medical University, spanning nine years, who underwent both 18F-FDG PET/CT and BMBA at the point of diagnosis. Results: The median age of this study was 9.3(15 days to 17.1 years), 52(50.5%) patients were male. Among the cohort, 8 subjects received a BMM diagnosis via marrow cytology or histopathology, concomitant with positive 18F-FDG PET/CT findings. An additional 4 patients were identified with BMM solely through 18FFDG PET/CT. No cytologically or histologically positive BMM were found in PET/CT-negative patients. Therefore, within this selected sample group, the 18F-FDG PET/CT imaging technique exhibited sensitivity of 100% and specificity of 95.8%. The five-year overall survival rate decreased from 57.5% among the entire cohort of patients to a mere 30% for individuals suffering from BMM. Conclusion: Given these findings, the prevailing reliance on BMBA warrants reevaluation when 18F-FDG PET/CT is available, potentially heralding a shift towards less invasive diagnostic modalities in the management of ES. [ABSTRACT FROM AUTHOR]

An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the normal range. An erythrocytosis can be classified as primary or secondary and congenital or acquired. The commonest primary acquired disorder is polycythemia vera. The diagnostic criteria for PV have evolved over time and this is the main diagnosis managed in hematology clinics. There are a variety of rare congenital causes both primary and secondary. In particular in young patients and/or those with a family history a congenital cause is suspected. There remains a larger cohort with acquired erythrocytosis mainly with non‐hematological pathology. In order to explore for a cause of erythrocytosis, measurement of the erythropoietin level is a first step. A low erythropoietin level indicates a primary cause and a normal or elevated level indicates a secondary etiology. Further investigation is then dictated by initial findings and includes mutational testing with PCR and NGS for those in whom a congenital cause is suspected. Following this possibly bone marrow biopsy, scans, and further investigation as indicated by history and initial findings. Investigation is directed toward the identification of those with a hematological disorder which would be best managed following guidelines in hematology clinics and referral elsewhere in those for whom there are non‐hematological reasons for the elevated hemoglobin. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the outcomes (relapse and mortality rate) and response of the bone marrow in early stages after combination chemotherapy in patients with T-cell Acute Lymphoblastic Leukemia (T-ALL). Methods: A descriptive cross-sectional study was conducted at King Fahad Medical City, from January 2021 to December 2022, to evaluate bone marrow findings at the time of diagnosis and post-chemotherapy in 26 patients diagnosed with T-ALL. The study included all patients diagnosed with T-ALL of any age group during the study period. The patients' bone marrows were examined at 0 days of treatment (diagnosis work-up), followed by examination at day 15 post induction therapy, and day 30 after treatment. Results: In this study, 26 cases of T-lymphoblastic leukemia were analyzed. The mean age at diagnosis was 15.69±14.28 years, and eight cases had central nervous system involvement. The majority of cases (88.5%) were positive for Cytoplasmic-CD3 and CD7. Positive findings by fluorescence in situ hybridization (FISH) were: T cell receptor (TCR) a/õ in 6 (23.1%) of the patients, CDNK2A/CEP9 in five (19.2%), and TRCB in one (3.8%). Examination of the bone marrow on day 15 revealed a decrease in blasts to <1% in nine patients, and to <1% in 19 patients on day 30 post-therapy. Relapse was recorded in five (19.23%) patients. Three (11.53%) patients did not survive during treatment, of which two were <10 years old. The relapse rate for T-ALL was 19.23%, with an overall survival rate of about 64%. The overall mortality rate was 11.53%. Conclusion: The relapse rate for T-ALL in our study was approximately 19%, but the mortality rate was 11.5%. A substantial decrease in blast percentages was observed, suggesting a favorable initial reaction of the bone marrow to the combined chemotherapy. This suggests that the use of aggressive and more effective chemotherapy has led to better outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: In recent years, artificial intelligence has been used increasingly in medical practice. Technological progress has made it possible to digitize the slides of histological preparations, allowing the use of image processing and AI technologies in surgical pathology. This potentially reduces variability and improves the uniformity of some histological evaluations, such as cellularity assessment in bone marrow biopsies, which is traditionally performed visually by expert human observers, resulting in inter-observer and intra-observer variability. In this work, we developed an accurate AI-based tool for the automated quantification of cellularity in BMB histology and compared its performances with cellularity estimates from five expert hematopathologists. Our results showed the robustness of our model across users and two different scanners for digitized image generation. The cellularity assessment in bone marrow biopsies (BMBs) for the diagnosis of Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs) is a key diagnostic feature and is usually performed by the human eyes through an optical microscope with consequent inter-observer and intra-observer variability. Thus, the use of an automated tool may reduce variability, improving the uniformity of the evaluation. The aim of this work is to develop an accurate AI-based tool for the automated quantification of cellularity in BMB histology. A total of 55 BMB histological slides, diagnosed as Ph- MPN between January 2018 and June 2023 from the archives of the Pathology Unit of University "Luigi Vanvitelli" in Naples (Italy), were scanned on Ventana DP200 or Epredia P1000 and exported as whole-slide images (WSIs). Fifteen BMBs were randomly selected to obtain a training set of AI-based tools. An expert pathologist and a trained resident performed annotations of hematopoietic tissue and adipose tissue, and annotations were exported as.tiff images and.png labels with two colors (black for hematopoietic tissue and yellow for adipose tissue). Subsequently, we developed a semantic segmentation model for hematopoietic tissue and adipose tissue. The remaining 40 BMBs were used for model verification. The performance of our model was compared with an evaluation of the cellularity of five expert hematopathologists and three trainees; we obtained an optimal concordance between our model and the expert pathologists' evaluation, with poorer concordance for trainees. There were no significant differences in cellularity assessments between two different scanners. [ABSTRACT FROM AUTHOR]

This letter to the editor discusses the case of a 47-year-old woman with relapsed/refractory hairy cell leukemia (cHCL) who achieved complete remission (CR) following treatment with the bispecific antibody mosunetuzumab. The patient had previously undergone various treatments, including cladribine, pentostatin, rituximab, vemurafenib, and moxetumomab pasudotox, but experienced relapse or insufficient response. Mosunetuzumab therapy resulted in hematologic CR for at least nine months, with negative measurable residual disease (MRD) based on blood tests. The use of bispecific antibodies in the treatment of cHCL shows promise and warrants further investigation. [Extracted from the article]

Histoplasmosis is a rare airborne fungal infection that is soil-based and is mostly documented in Human Immunodeficiency Virus (HIV)-positive patients. It is common in people living near valley regions. Hereby, authors report three cases of Asian women from different regions of Southern Rajasthan who died due to delayed diagnosis of histoplasmosis within a few days of admission. They all had complaints of fatigue and fever for one month. One presented with decreased urine output and pancytopenia, while the others had complaints of prolonged fever with pancytopenia and fatigue. In all three cases, bone marrow examination was done, and they shared the same diagnosis - disseminated histoplasmosis. It was further confirmed by special stains and microbiological investigations. Authors also reviewed recent articles based on South Asian region histoplasmosis case reports and found three case presentations with the same clinical presentation and outcomes. Treatment was started, but patients deteriorated and died within 10 days of admission. Delay in the diagnosis of histoplasmosis leads to the death of patients. Therefore, histoplasmosis should be considered as a differential diagnosis for prolonged fever with pancytopenia and chronic infections. [ABSTRACT FROM AUTHOR]

Background: Pancytopenia is a hematological condition which occurs commonly and etiology varies according to different geographic location. Finding out specific etiology is important for appropriate management. Aims and Objectives: The present study was undertaken to describe etiological factors which leads to pancytopenia in "Central Clinical Laboratory (CCL), Department of Pathology, P.D.U Medical College & Hospital, Rajkot". Materials and methods: A prospective study was conducted for a period of six months between September 2023 to February 2024 in which 220 patients were included. After acquiring clinical history, complete blood count including peripheral smears was done. Afterward, bone marrow aspiration was performed and microscopically examined in selected cases. Results: Among 220 patients studied, 134(60.09%) were males and 86 (39.09%) were females. Mean age was 38 years. The most common cause of pancytopenia was found to be megaloblastic anemia in 68 patients (30.90%) followed by thalassemia in 26 patients (11%). Other common causes included alcoholic liver disease in 20 patients (9.10%) and acute myeloid leukemia in 16 patients (7.27%), severe sepsis in 16 patients (7.27%). Conclusion: Megaloblastic anemia was found to be the most common cause of pancytopenia in this study. Identifying of etiologies of pancytopenia can be helpful in defining diagnostic and therapeutic strategies, which contributes toward the better management of patients. [ABSTRACT FROM AUTHOR]

The recently approved BCL2 inhibitor venetoclax (VEN) has achieved promising outcomes in new and relapsed/refractory (R/R) acute myeloid leukemia (AML). Although its use is not well established in R/R AML with extramedullary disease (EMD), some reports have shown promising outcomes. We retrospectively analyzed 11 patients of R/R AML with EMD (with (n = 4) or without (n = 7) concurrent marrow involvement), who were treated with VEN plus decitabine (n = 9) or low-dose cytarabine (n = 2) between May 2020 and October 2020 in Seoul St. Mary's Hospital. The median number of prior treatment lines was 3 (1–6), and most (n = 9, 81.8%) had multiple sites of EMD. Nine patients (81.8%) received concurrent therapy for extramedullary (EM) involvement sites with radiotherapy (RT) (n = 4), surgery (n = 1), and both of them (n = 4). Among 11 patients, 4 patients (36.4%) had either marrow or EM responses to VEN combination; EM response was seen in 1 patient (9.1%, partial response) who had received concurrent RT (25 Gy, 10 fx) during the 1st cycle of VEN combination, and other 3 patients showed marrow response without EM response. After median follow-up of 27.0 months, the median overall survival was estimated to be 5.4 months. To conclude, VEN combination regimens have shown only modest efficacy in EM recurrence of AML with little impact on eliciting EM response. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7–15 days) and five days (interquartile range, 3.75–9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases (P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39 IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH. [ABSTRACT FROM AUTHOR]