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Bone marrow biopsy (BMB) is a well-established diagnostic tool for various hematological, oncological, and other medical conditions. However, treatment options for geriatric patients (pts) facing these diseases are often constrained. In this single-center, retrospective analysis we assessed the diagnostic value of BMB in geriatric pts aged ≥ 85 years and examined its impact on therapeutic decisions. We examined 156 BMB procedures in 129 pts, extracting data from the electronic patient records and applying descriptive statistical methods. Nearly half of the primary diagnostic procedures (26; 44.1%) resulted in a modification of the initially suspected diagnosis. Notably, 15 (25.4%) of these procedures, led to changes in both the diagnosis and planned interventional treatment. Among the 15 follow-up procedures (36.6%), disease progression was initially suspected based on symptoms, but BMB results excluded such progression. In lymphoma staging biopsies, only 2 (3.6%) prompted a change in therapeutic intervention. Importantly, no BMB-related complications, such as bleeding, infection or nerve damage, were reported. Median survival after BMB was 16.1 months across all pts, yet it varied based on the diagnosis and comorbidity score. The survival of pts with a change in therapy based on BMB results did not significantly differ from those who did not undergo a therapy change. In conclusion, BMB proved to be generally safe and beneficial in this geriatric cancer patient cohort beyond the age of 85 years. However, the advantages of lymphoma staging in this patient population warrant further consideration., (© 2024. The Author(s).)

Bone marrow (BM) fibrosis in myeloproliferative neoplasms (MPNs) is associated with a poor prognosis. The development of myelofibrosis and differentiation of mesenchymal stromal cells to profibrotic myofibroblasts depends on macrophages. Here, we compared macrophage frequencies in BM biopsies of MPN patients and controls (patients with non-neoplastic processes), including primary myelofibrosis (PMF, n = 18), essential thrombocythemia (ET, n = 14), polycythemia vera (PV, n = 12), and Philadelphia chromosome-positive chronic myeloid leukemia (CML, n = 9). In PMF, CD68-positive macrophages were greatly increased compared to CML (p = 0.017) and control BM (p < 0.001). Similar findings were observed by CD163 staining (PMF vs. CML: p = 0.017; PMF vs. control: p < 0.001). Moreover, CD68-positive macrophages were increased in PV compared with ET (p = 0.009) and reactive cases (p < 0.001). PMF had higher frequencies of macrophages than PV (CD68: p < 0.001; CD163: p < 0.001) and ET (CD68: p < 0.001; CD163: p < 0.001). CD163 and CD68 were often co-expressed in macrophages with stellate morphology in Philadelphia chromosome-negative MPN, resulting in a sponge-like reticular network that may be a key regulator of unbalanced hematopoiesis in the BM space and may explain differences in cellularity and clinical course.

Kindlin-3 (K3)-mediated integrin adhesion controls homing and bone marrow (BM) retention of normal hematopoietic cells. However, the role of K3 in leukemic stem cell (LSC) retention and growth in the remodeled tumor-promoting BM is unclear. We report that loss of K3 in a mouse model of chronic myeloid leukemia (CML) triggers the release of LSCs from the BM into the circulation and impairs their retention, proliferation, and survival in secondary organs, which curbs CML development, progression, and metastatic dissemination. We found de novo expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) on CML-LSCs but not normal hematopoietic stem cells and this enabled us to specifically deplete K3 with a CTLA-4-binding RNA aptamer linked to a K3-siRNA (small interfering RNA) in CTLA-4 + LSCs in vivo, which mobilized LSCs in the BM, induced disease remission, and prolonged survival of mice with CML. Thus, disrupting interactions of LSCs with the BM environment is a promising strategy to halt the disease-inducing and relapse potential of LSCs., Competing Interests: The authors declare no competing interest.

Hematopoietic stem and progenitor cell (HSPC) functions are regulated by a specialized microenvironment in the bone marrow - the hematopoietic stem cell niche - of which the extracellular matrix (ECM) is an integral component. We describe here the localization of ECM molecules, in particular the laminin α4, α3 and α5 containing isoforms in the bone marrow. Laminin 421 (composed of laminin α4, β2, γ1 chains) is identified as a major component of the bone marrow ECM, occurring abundantly surrounding venous sinuses and in a specialized reticular fiber network of the intersinusoidal spaces of murine bone marrow (BM) in close association with HSPC. Bone marrow from Lama4 -/- mice is significantly less efficient in reconstituting the hematopoietic system of irradiated wildtype (WT) recipients in competitive bone marrow transplantation assays and shows reduced colony formation in vitro. This is partially due to retention of Lin - c-kit + Sca-1 + CD48 - long-term and short-term hematopoietic stem cells (LT-HSC/ST-HSC) in the G0 phase of the cell cycle in Lama4 -/- bone marrow and hence a more quiescent phenotype. In addition, the extravasation of WT BM cells into Lama4 -/- bone marrow is impaired, influencing the recirculation of HSPC. Our data suggest that these effects are mediated by a compensatory expression of laminin α5 containing isoforms (laminin 521/522) in Lama4 -/- bone marrow. Collectively, these intrinsic and extrinsic effects lead to reduced HSPC numbers in Lama4 -/- bone marrow and reduced hematopoietic potential., (Copyright © 2018 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.)

Summary: Dyskeratosis Congenita (DKC) is a systemic disorder caused by mutations resulting in impaired telomere maintenance. Clinical features include bone marrow failure and an increased risk of developing hematological malignancies. There are conflicting data whether androgen derivatives (AD) can elongate telomeres in vivo and whether AD treatment enhances the risk of gaining myelodysplastic syndrome‐related mutations. Seven TERC or TERT‐mutated DKC patients underwent AD treatment. All patients revealed hematological response. Telomere length of lymphocytes and granulocytes increased significantly and no MDS‐related mutations were detected. Pending longer follow‐up, treatment with AD seems to represent an efficient and safe therapy for DKC patients. [ABSTRACT FROM AUTHOR]

Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex–quantitative polymerase chain reaction (MM–qPCR) and fluorescence in situ hybridization (flow‐FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM–qPCR and flow‐FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next‐generation sequencing and in 16 patients, mutations in DKC‐relevant genes were identified. Whole leukocyte TL of patients measured by MM–qPCR was found to be moderately correlated with lymphocyte TL measured by flow‐FISH (r² = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM–qPCR (29%) was significantly lower compared with flow‐FISH (58%). These results suggest that MM–qPCR of peripheral blood cells is inferior to flow‐FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false‐positive results. [ABSTRACT FROM AUTHOR]

We evaluated pazopanib (800 mg orally QD) in patients not eligible for intensive treatment with relapsed/refractory AML or at initial diagnosis. Patients receiving pazopanib for > 14 days were analyzed for safety, tolerability, and efficacy. Co-primary endpoints were cumulative response rate and reduction of bone marrow microvessel density. Twenty patients (median age 76 years, range 52-86) were treated. Fifteen had relapsed/refractory and five had newly diagnosed AML. Median ECOG performance status was 1 (range 1-3). Four patients had adverse, 15 intermediate, and 1 patient favorable cytogenetic/molecular risk (ELN 2010 criteria). The safety profile of pazopanib was as reported. The most common adverse events of any grade were gastrointestinal. Two patients achieved PR (blast reduction > 50%), 14 stable disease (SD), and 4 progressive disease. Median PFS was 65 days (95% CI 29-105). After the end of the study, 1 CRi and 1 CRp occurred on demethylating agents, and 1 CR upon alloSCT. In these patients, SD and improved general condition on pazopanib allowed therapy escalation. Median OS for the overall study population was 191 days (95% CI 87-435) and 1-year survival was 35%. There was no significant change in microvessel density. Clinical trial information: NCT01361334. [ABSTRACT FROM AUTHOR]

We characterized bone marrow stromal cells (BMSC) from patients with pre-fibrotic myeloproliferative neoplasms (MPN). MPN-BMSC showed decreased capacity to stimulate the proliferation of colony-forming units of normal hematopoietic stem and progenitor cells and displayed increased matrix remodelling (in particular fibronectin deposition) compared to control BMSC. This finding was confirmed in pre-fibrotic MPN bone marrow biopsies in a tissue microarray (n = 34), which stained positive for fibronectin in the absence of reticulin as a standard myelofibrosis marker. Fibronectin expression correlated significantly with reduced haemoglobin levels in MPN-patients (p = 0.007; R2 = 0.42). Our data show significant cellintrinsic alterations in MPN-MSC and suggest that Fibronectin expression might be applicable as a biomarker for the identification of early myelofibrotic transformation in reticulin-negative MPN. [ABSTRACT FROM AUTHOR]

Determines the effects of chemotherapy on the treatment of small cell lung cancers and B-cell lymphoma. Use of computed tomography in determining enlarged lymph nodes; Description of adenocarcinomas of the stomach; Infiltration of the bone marrow by lymphoma.

Background: The JAK inhibitor (JAKi) ruxolitinib is standard treatment for myelofibrosis (MF), but some patients are unresponsive. Pre-clinical and clinical data suggest that addition of a Hedgehog pathway inhibitor (HPI) to ruxolitinib might improve response. Vismodegib is an HPI approved for treatment of locally advanced and metastatic basal cell carcinoma. The MYLIE study assessed the safety and efficacy of combining ruxolitinib with vismodegib in ruxolitinib-naive patients with MF and characterized the pharmacokinetics (PK) of vismodegib in this setting. Methods: In this phase Ib study, ten patients with intermediate- or high-risk primary or secondary MF received open-label vismodegib (150 mg/day orally) and ruxolitinib (15 or 20 mg orally twice daily, depending on baseline platelet count) for up to 48 weeks, or until withdrawal or discontinuation. PK samples were collected throughout the study for comparison with other patient populations. Efficacy outcomes at week 24 included spleen response (≥ 35% reduction in volume by imaging) and improvement in bone marrow fibrosis by central and investigator assessment, symptom response (≥ 50% reduction in Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom score), and anemia response (per International Working Group for Myeloproliferative Neoplasms Research and Treatment revised response criteria). Results: As of November 17, 2017, eight patients had completed 48 weeks of treatment with vismodegib and ruxolitinib; two discontinued treatment early. At week 24 (± 1 week), three patients experienced a spleen response by central review and no patients showed a 1-grade improvement in bone marrow fibrosis by central review. Five patients experienced symptom response at week 24, and no patients experienced an anemia response. The most common adverse events were muscle spasm (100% of patients), alopecia (70%), dysgeusia (50%), thrombocytopenia (50%), and nausea (40%); these events were predominantly grade 1/2. Three patients experienced a total of six serious adverse events. Conclusions: The combination of vismodegib and ruxolitinib was tolerable and no new safety signals were seen, but there was no evidence that the addition of vismodegib to ruxolitinib improved any of the efficacy outcome measures assessed. Further evaluation of this combination will not be pursued. Trial registration: ClinicalTrials.gov, NCT02593760. Registered November 2, 2015. [ABSTRACT FROM AUTHOR]

Mast cells have been implicated as mediators of bone marrow fibrosis and pruritus in myeloproliferative neoplasms (MPNs) with JAK2V617F or calreticulin mutations. We hypothesize that potent KIT inhibitors, already in clinical use for systemic mastocytosis, have therapeutic potential for the treatment of MPNs by directly targeting mast cells. [ABSTRACT FROM AUTHOR]