Alexandar Tzankov

Flower-Win/Lose signaling underlies a tumor–host fitness conflict in ovarian cancer, in which tumor-derived exosomal Tu-stroma reduces the fitness of surrounding host cells, favoring tumor expansion within host tissues. High-grade serous carcinoma (HGSC), the most prevalent histotype of epithelial ovarian cancer and leading cause of ovarian-cancer-related mortality, arises from serous tubal intraepithelial carcinoma (STIC), a noninvasive precursor typically identifiable only by histopathologic examination of excised fallopian tube tissue. Here we evaluated Tu-stroma, a tumor-associated long noncoding RNA enriched in serum extracellular vesicles (EVs), as a circulating biomarker in STIC and early-stage HGSC, representing the earliest histopathologically defined phases of disease. Tu-stroma was quantified in serum EVs from 506 individuals with histologically normal adnexa, benign-adnexal lesions, isolated STIC and HGSC across International Federation of Gynecology and Obstetrics (FIGO) stages I–IV. Normalized EV Tu-stroma ΔC_T values were elevated in STIC (n = 43) and HGSC (n = 232) versus controls (n = 143) and benign-adnexal lesions (n = 88), including premenopausal women (controls = 57, benign = 34, STIC = 32, HGSC = 88). In paired receiver operating characteristic analyses, Tu-stroma showed higher discrimination than cancer antigen 125 (CA125) for STIC versus controls (area under the curve (AUC) = 0.99 versus 0.59, P < 0.001) and benign-adnexal masses (0.99 versus 0.31, P < 0.001), and for HGSC versus controls (AUC = 0.99 versus 0.96, P = 0.001) and benign-adnexal masses (0.98 versus 0.84, P < 0.001). Tu-stroma showed no systematic elevation across inflammatory or physiologic comparators (n = 116) or nonovarian malignancies (n = 160), each assessed against healthy controls (n = 100), supporting disease-context specificity. Modeled risk-enriched contexts yielded predictive values compatible with intended-use populations. These findings identify Tu-stroma as a candidate EV-RNA marker associated with pre-invasive and early HGSC biology. Prospective evaluation in consecutively enrolled real-world cohorts is required to validate diagnostic performance, predictive value and clinical utility.

Background: The COVID-19 pandemic has caused a broad range of respiratory complications. Among the spectrum of COVID-associated pulmonary conditions, severe bilateral pneumonitis that might progress to acute respiratory distress syndrome represents the most critical manifestation. A substantial proportion of survivors of severe COVID-19 continue to experience persistent respiratory symptoms and functional limitations. These findings are referred to as post-acute sequelae of COVID-19. Summary: These residual post-COVID lung abnormalities are mechanistically linked to the structural changes of acute lung injury, but also to persistent systemic inflammatory signatures, and are reflected in a range of histopathological patterns, including pulmonary fibrosis, hyperinflammation, angiopathic and immunothrombotic tissue responses. Key Messages: This review focuses on the current knowledge of the pathogenesis and pathophysiology of post-COVID lung disease. We also schematically delineate the broad spectrum of post-COVID lung disease and explain the underlying pathomechanisms.

Sequential lymphoid neoplasms are rare and diagnostically challenging, with a variable clonal relationship. Here we present the case of a 59-year-old woman with mediastinal grey zone lymphoma (MGZL), who, shortly after achieving complete remission, developed a subsequent cutaneous neoplasm. Comparative molecular studies were performed using high-throughput sequencing (HTS), which demonstrated that both neoplasms shared high-allele-frequency E P300 :p.P2333L and P TPRK :p.R532K variants. In addition, each neoplasm harboured private, mutually exclusive variants— NFK BIA :p.R245Sfs*39 and B TG2 :c.142+5G>C in the MGZL and JA K1 :p.Q562* and J A K1 :p.G1097D in the skin. Integrating the clinical course with HTS, we diagnosed lymphomatoid papulosis and excluded relapse of the MGZL. Interestingly, the shared variants were likely germline rather than clonal, suggesting they created a permissive background predisposing to two independent transforming events along the B- and T-cell lineages. Molecular studies may help to reveal the genetic basis of composite lymphomas and to resolve diagnostically discordant, complex presentations.

Microglia are regarded as self-maintaining brain parenchymal macrophages without contribution from adult hematopoiesis. While peripheral macrophage engraftment into the brain has been reported, the biological variables governing central nervous system (CNS) macrophage niche access remain unclear. We show that CNS macrophage engraftment depends on (1) the balance between tissue-resident macrophage (TRM) self-renewal, (2) the temporal alignment of niche opening with the availability of engraftment-competent cells and (3) proximity to the vacated niche, rather than prolonged niche vacancy. Fate mapping revealed that monocytes entering the subdural space undergo border-associated macrophage (BAM)-like differentiation, clonal expansion, and transpial migration into the parenchyma, whereas mature BAMs directly repopulate selectively vacated parenchymal niches. We further identified a parenchymal macrophage population with a peripheral BAM-like transcriptional program in aged and neurodegenerative human brains, challenging the dogma of MG-exclusivity. Together, these discoveries provide a predictive framework for understanding macrophage maintenance and replacement, and for developing macrophage-based cellular therapies.

Examination of the bone marrow (BM) remains fundamental to the diagnosis, classification, prognostication, and monitoring of hematolymphoid and other disorders affecting blood cell production. Since publication of the International Council for Standardization in Haematology (ICSH) guideline in 2008, advances in diagnostic technologies, disease classification systems and laboratory reporting practices have significantly evolved. These developments necessitate a framework to support contemporary BM evaluation and reporting. This document, prepared by an international ICSH Working Party, provides updated guidance on the examination and reporting of BM specimens and is an extension and refinement of the 2008 ICSH guidelines. It outlines the appropriate application and integration of key diagnostic modalities, including morphological assessment of BM aspirate and trephine biopsy specimens, immunophenotypic analysis by flow cytometry and immunohistochemistry and molecular genetic testing. Central to this guidance is the principle of integrated reporting, whereby findings from all diagnostic modalities are synthesized within the clinical context and aligned with current international classification systems. The ICSH acknowledges the emergence of automated digital microscopy, computational decision support tools, and other technological innovations in BM analysis. These developments hold considerable promise, but whilst many remain under evaluation, specific guidance regarding their routine clinical implementation is beyond the scope of this document.

Within a prospective cohort of patients with immune dysregulation, we identified several individuals with chronically increased proportions of TCR γδ cells but normal peripheral lymphocyte counts. Among those, we identified one individual with a TCR γδ cell–specific heterozygous p.Y665F STAT5B gain-of-function mutation. Recurrent oral aphthous lesions, susceptibility to infection, arthralgia, and fatigue, were linked to relatively elevated numbers of γδ T cells expressing a Vγ9Vδ2 TCR, displaying hyperphosphorylation of STAT5 upon in vitro IL-2 stimulation. The TCR Vγ9Vδ2 cells exhibited enhanced proliferative response to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and dysregulated cytokine production. The TCR γδ cell transcriptome revealed the suppression of the default Th17 program, along with inhibition of RORC and MAF expression. The JAK inhibitor baricitinib improved clinical features of the observed immune dysregulation and reduced the frequency of peripheral TCR Vγ9Vδ2 cells. Thus, functionally altered TCR γδ cells may underlie chronic immune dysregulation of unknown molecular cause, demonstrated here to be amenable to tailored immune modulation.

SUMMARY: Microglia are regarded as self-maintaining brain parenchymal macrophages without contribution from adult hematopoiesis. Nevertheless, peripheral macrophage engraftment into the brain has been reported, but the biological variables governing central nervous system (CNS) macrophage niche access remain unclear. We show that CNS macrophage engraftment is determined by the balance between tissue-resident macrophage (TRM) self-renewal and the temporal alignment of niche opening with the availability of engraftment-competent cells and proximity to the vacated niche, rather than prolonged niche vacancy. Fate mapping revealed that monocytes entering the subdural space undergo border-associated macrophage (BAM)-like differentiation, clonal expansion, and transpial migration into the parenchyma, whereas mature BAMs directly repopulate selectively vacated parenchymal niches. We further identify a parenchymal macrophage population with a peripheral BAM-like transcriptional program in aged and neurodegenerative human brains, challenging the dogma of MG-exclusivity. Together, these findings establish a predictive framework for interpreting macrophage maintenance and replacement and for developing macrophage-based therapies.

The workshop on ‘Reactive and therapy induced BM changes linked to systemic infectious and non-infectious disorders including MAS/HLH’ of the 22nd meeting of the European Association for Haematopathology held in Dubrovnik, 2024, included 58 cases. These encompassed a broad range of infections, autoimmune disorders, malignancies and therapy-effects, or a combination of these factors, of which 28 had an associated Hemophagocytic Lymphohistiocytosis (HLH) / Macrophage Activation Syndrome (MAS). Histoplasmosis, the infection mostly associated with HLH, showed a wide variability of BM changes, with or without focal lesions. Leishmaniasis, less often associated with HLH, induced BM changes that mimic myelodysplastic syndrome. BM changes after COVID-19 infection included myeloid and megakaryocytic hypoplasia, erythroid hyperplasia, dyserythropoiesis, hemophagocytosis, and possibly ring granulomas. Other infectious causes included viruses (HHV-8, EBV, Parvovirus B19), mycobacterial infections, and human granulocytic anaplasmosis. HLH may arise in association with the full spectrum of EBV-related disorders, including acute infection, systemic chronic active EBV disease, viral reactivation, and EBV-associated malignancies. BM changes associated with autoimmune diseases included plasmacytosis, myeloid hyperplasia and hemophagocytosis, with or without meeting the criteria of MAS/HLH, the latter often triggered by a secondary infection or exacerbation of the disease. Haematologic malignancies (EBV-positive and negative) with HLH encompassed B-cell, T-/NK-cell, and myeloid neoplasms. In addition, the workshop included therapy-induced BM changes, such as differentiation syndrome, lenalidomide-associated B-ALL, therapy-related dysplasia, gelatinous transformation, CAR-T–induced BM hypoplasia, and CAR-T–associated HLH. Finally, the workshop demonstrated the presence of T-cell expansions in a variety of conditions, which should not be misinterpreted as T-cell malignancy.