Abstract: Background/Objectives: Oxidative stress and iron overload remodel erythrocyte mem-branes in β-thalassemia, but their systemic metabolic correlates are not well defined. We applied untargeted metabolomics to identify serum biomarkers reflecting these patho-physiological processes. Methods: Thirty-one adults with β-thalassemia [18 transfu-sion-dependent (TDT), 13 non-transfusion-dependent (NTD)] and 8 age/sex-matched healthy controls were studied. Fasting serum was profiled using untargeted UHPLC-Orbitrap MS. Multivariate modeling (SIMCA-P) and FDR-controlled univariate statistics identified discriminant features, followed by pathway enrichment analysis. Associations with clinical variables (chelation regimen, ferritin, cardiac MRI T2* and liver iron concentration) were examined. Results: A total of 183 metabolites were detected; versus controls, 124 were decreased, 54 increased, and 5 remained unchanged in patients. Key discriminants included lysophosphatidylcholines (LysoPC 18:1, 18:3), polyunsatu-rated fatty acid (PUFA)-bearing phosphatidylcholines (PC 20:4/18:0, PC 18:0/20:4), con-jugated bile acids (glycocholic acid, glycochenodeoxycholic acid, glycoursodeoxycholic acid), and bilirubin. Pathway analysis revealed significant enrichment (FDR-corrected) in linoleic acid metabolism (q = 0.024, impact = 1.000) and arachidonic acid metabolism (q = 0.022, impact = 0.433), with supportive nominal signals from glycerophospholipid (impact = 0.401) and porphyrin/heme (impact = 0.242) pathways. No significant metabolic dif-ferences were observed between TD and NTD patients. Conclusions: β-thalassemia serum metabolomics reflects oxidative membrane lipid remodeling with a prominent PLA₂/LysoPC–arachidonic axis and evidence of heme turnover and altered bile-acid signaling. These data propose a practical biomarker panel - LysoPCs, arachidonic ac-id-enriched PCs and conjugated bile acids - warranting targeted validation alongside conventional clinical parameters for disease monitoring and therapeutic assessment.

Abstract: Background: Chemotherapy induced thrombocytopenia (CIT) leads to bleeding complications, treatment delay or de intensification, and platelet transfusion requirement. Evidence suggests that thrombopoietin receptor agonists (TPO RAs) can restore platelet counts in this scenario. Avatrombopag (AVA) is an oral TPO RA whose efficacy in treating CIT in haematological malignancy has been barely addressed. Objectives: We aimed to evaluate AVA’s efficacy in improving platelet recovery and reducing transfusion requirement in haematological patients with CIT. Methods: In this retrospective observational study, haematological patients who developed CIT persisting for 3 weeks and were treated with AVA between November 2023 and December 2024 were recruited. Results: Twenty three patients were recruited. Nineteen (82.6%) responded to AVA, most within the first four weeks: ten (43.5%) and nine (39.1%) achieved platelet counts >30×109/L (partial response) and >100×109/L (complete response), respectively. Response was maintained after a median (interquartile range [IQR]) follow up of 47 (26–99) days from therapy initiation. Transfusions were significantly fewer than in the previous period: 0 (0–8) vs. 11 (2–15), p = 0.007. Once on treatment, 13 (56.5%) patients no longer required transfusion. No patient delayed or de intensified chemotherapy. No safety concerns were reported. Conclusions: AVA shows promise in safely reducing CIT associated transfusion needs in haematological malignancy.

Abstract:

Background: Atrial fibrillation (AF) is independently associated with cognitive impairment and dementia through mechanisms extending far beyond traditional cardioembolic stroke risk. However, the relative contribution of distinct pathophysiological pathways and the efficacy of emerging therapeutic interventions for cognitive protection remain incompletely characterized. Objectives: This comprehensive review synthesizes current evidence on the epidemiology, pathophysiological mechanisms, therapeutic interventions (pharmacological, rhythm-control, and digital health), and research priorities addressing the AF–dementia relationship. Methods: A narrative review integrating evidence from observational studies, mechanistic research, randomized controlled trials, systematic reviews, and meta-analyses published through January 2026. Literature sources included MEDLINE/PubMed, major cardiology and neurology journals, and expert consensus statements. Searches used combinations of keywords: "atrial fibrillation," "cognitive decline," "dementia," "silent cerebral infarction," "cerebral hypoperfusion," "direct oral anticoagulants," "catheter ablation," and "digital health." Inclusion criteria encompassed studies examining the AF–cognition association, mechanistic pathways, therapeutic interventions with cognitive outcomes, and digital health technologies in AF management. Heterogeneous study designs prevented quantitative meta-analysis; qualitative synthesis focused on effect sizes, strength of evidence, and clinical implications. Results: Strong epidemiological evidence demonstrates that AF increases relative risk of dementia by 1.4–2.2 fold independently of clinical stroke, with silent cerebral infarction present in 25–40% of AF patients. Multiple interacting pathophysiological mechanisms account for AF-associated cognitive decline: cerebral microembolism (meta-analysis: OR 2.30 for silent infarction on MRI), chronic cerebral hypoperfusion (15–20% reduction in total cerebral blood flow in persistent AF), neuroinflammation, cerebral small vessel disease, and structural brain atrophy. Emerging therapeutic strategies offer complementary neuroprotective mechanisms: direct oral anticoagulants (DOACs)—particularly apixaban and rivaroxaban—reduce dementia risk by approximately 30% compared to warfarin (RR 0.69); rhythm control strategies and catheter ablation demonstrate dementia risk reduction (HR 0.52–0.69); and comprehensive digital health platforms implementing the ABC pathway reduce adverse cardiovascular events by 61% while optimizing adherence and enabling early AF detection. However, evidence-specific to cognitive endpoints remains limited, with the landmark BRAIN-AF trial showing no benefit of low-dose rivaroxaban in low-stroke-risk AF patients—suggesting that non-embolic mechanisms predominate in this population. Conclusions: AF represents a multifaceted threat to brain health requiring a paradigm shift from isolated stroke prevention toward comprehensive heart–brain health optimization. Integration of pharmacological neuroprotection (preferring DOACs), hemodynamic optimization (rhythm control in selected patients), cardiovascular risk factor management, and digital health technologies provides unprecedented opportunity for cognitive preservation. However, critical knowledge gaps persist regarding AF burden thresholds, the relative contribution of competing pathophysiological mechanisms, optimal anticoagulation strategies in low-risk populations, and the long-term cognitive benefits of emerging digital technologies. Prospective randomized clinical trials with cognitive impairment as a primary endpoint, serial neuroimaging, and diverse population representation are urgently needed to validate preventive strategies and refine therapeutic decision-making.

Abstract: Background and Clinical Significance: Diffuse Large B-Cell Lymphoma (DLBCL) is a morphologically and molecularly heterogeneous lymphoproliferative disorder that originates from a clonal B-cell ancestor, that can either arise de novo or transform from an indolent B-cell lymphoma. It represents 30% of adult lymphoma cases. Patients usually present with rapidly enlarging lymph nodes or mass(es) at a single site or multiple sites. Myofibroblastoma (MFB) is a benign mesenchymal tumor of the mammary stroma composed of fibroblasts and myofibroblasts. These entities do not often present concurrently. Case presentation: An 80-year-old man with a history of Diffuse Large B-Cell Lymphoma (DLBCL) IV-BS stage with a high-risk International Prognostic Index (IPI). The patient underwent treatment with R-CHOP regimen. In the post therapeutic evaluation, an 18F‐Fluorodeoxyglucose (18F-FDG) positron emission tomography with computed tomography (PET‐CT) scan revealed a nodular solid lesion with a faintly increase metabolic standardized uptake value (SUVmax) of 3 in the upper outer quadrant of his left breast. The patient has not presented symptoms or any complications since surgery (12 months) and remains in complete remission (CR). Conclusions: Given the potential diagnostic pitfall and therapeutic implications of MFB in the context of DLBCL, a conscientious evaluation by a multidisciplinary team (MDT) is highly recommended.

Abstract:

Background: We sought to analyze the geographic distribution of HFE p.C282Y (homeostatic iron regulator c.845G>A; rs1800562) allele frequencies in Iberia. Methods: We analyzed published population/control cohorts of 50 or more subjects in mainland Spain and mainland Portugal and determined whether or not the p.C282Y genotypes in each cohort deviated from Hardy-Weinberg equilibrium (HWE) proportions. We defined combined p.C282Y allele frequencies from Spain and Portugal as representative of Iberia. We computed linear regressions (Pearson’s correlations) of allele frequencies vs. latitudes and longitudes of cohort recruitment sites, defined significant regressions as allele frequency gradients, and mapped regional allele frequencies. Results: There were 33 Iberian cohorts: 24 Spanish (12,082 subjects; 10 autonomous communities) and 9 Portuguese (1024 subjects; five administrative regions). p.C282Y genotypes in one of 33 cohorts (3.0%) deviated significantly from HWE proportions. Aggregate allele frequency in Iberia was 0.0291 (762/26,212) [95% confidence interval: 0.0271, 0.0312]. The correlation of allele frequencies vs. latitudes in Iberia was significant (r₃₃ = 0.4129; p = 0.0152). The correlation of allele frequencies vs. longitudes was not significant (r₃₃ = -0.0118; p = 0.9552). The range of 15 regional allele frequencies in Iberia was 0.0068 (Murcia) to 0.5000 (Galicia). Frequencies were highest in regions adjacent to the north and northwest coasts (Cantabria, Galicia, Norte) and lowest in the south (Algarve, Murcia). Conclusions: There is a significant decreasing linear north-to-south gradient of HFE p.C282Y allele frequencies in Iberia. p.C282Y allele frequencies are highest in regions adjacent to the north and northwest coasts.

Abstract:

Background: Platelet concentrates (PCs) are vital for treating hematologic disorders and thrombocytopenia, yet their short shelf life (3–5 days) is limited by platelet storage lesion (PSL)-a process involving biochemical and structural deterioration that reduces post-transfusion efficacy. This study aimed to characterize alterations in platelet surface receptors and RNA content during storage to better understand PSL mechanisms. Methods: Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were prepared from healthy donors and stored PCs. Flow cytometry was used to assess the expression of GPIbα, GPVI, Integrin αIIbβ3, and CD9. Thiazole orange (TO) staining evaluated RNA content to distinguish young from aged platelets, while soluble GPVI (sGPVI) levels were quantified by ELISA. Data were analyzed using one-way ANOVA and Student’s t-test (P < 0.05). Results: Baseline receptor profiles were established from fresh donor platelets. Stored PCs showed a progressive decline in GPIbα and GPVI expression from day 6, with significant reductions by day 11 (P < 0.05). αIIbβ3 expression decreased early (day 6) and stabilized thereafter, whereas CD9 remained unchanged. TO staining indicated a gradual loss of RNA-rich platelets, signifying aging. ELISA revealed increased sGPVI levels from day 6 to day 14, inversely correlating with surface GPVI loss. Conclusion: Prolonged storage leads to receptor degradation and platelet senescence, notably affecting GPIbα, GPVI, and αIIbβ3. Elevated sGPVI levels and reduced RNA content reflect progressive PSL. Flow cytometry and ELISA offer reliable monitoring tools, and sGPVI may serve as a biomarker for platelet quality during storage.

Abstract: Congenital erythropoietic porphyria (CEP), also known as Günther disease, is a rare autosomal recessive porphyria caused by deficiency of uroporphyrinogen III synthase, leading to accumulation of phototoxic type I porphyrins. CEP classically presents in infancy with severe photosensitivity, blistering, scarring, and hemolytic anemia; however, significant phenotypic variability has increasingly been recognized. We report 32-year-old women diagnosed with CEP in early infancy who demonstrated persistently and profoundly elevated erythrocyte porphyrin levels over more than a decade yet followed a relatively non-mutilating clinical course. Genetic testing identified a low penetrance intronic UROS variant typically associated with erythropoietic protoporphyria, underscoring diagnostic challenges and genotype-phenotype discordance. The patient experienced marked improvement in photosensitivity and burning pain after initiation of afamelanotide, without need for transfusion therapy or stem cell transplantation. This case highlights the heterogeneity of CEP, the importance of long-term biochemical follow up, and the potential role of afamelanotide in improving quality of life for selected patients with CEP.

Abstract: Acute myeloid leukemia (AML) continues to pose significant therapeutic challenges, with high relapse rates driven largely by leukemic stem cells (LSCs), a rare, therapy-resistant population with self-renewal capacity, niche adaptation, and the ability to re-initiate disease. In this state-of-the-art review, we synthesize recent advances in LSC biology, addressing (i) how LSCs differ functionally and phenotypically from normal hemato-poietic stem cells, (ii) practical approaches for LSC quantification using multiparameter flow cytometry and LSC-enriched marker panels, (iii) the metabolic and epigenetic programs that enable LSC persistence under chemotherapy and contribute to measurable residual disease, and (iv) current therapeutic strategies targeting LSC eradication, in-cluding antibody-based therapies, apoptosis and metabolic inhibitors, and emerging epigenetic agents. We also examine the key translational barriers, particularly antigen overlap with normal progenitors, microenvironmental protection, and the need for assay harmonization, and propose a practical framework for integrating LSC assessment into risk stratification and therapeutic development.

Abstract: Background/Objectives: Sickle Cell Disease (SCD) is a rare hemoglobinopathy in Portugal, where epidemiological data remain limited. National newborn screening has revealed a higher-than-expected incidence, particularly in urban areas, underscoring the importance of understanding acute care utilization. Vaso-occlusive crises (VOC) frequently lead to emergency department (ED) attendance; however, no prior studies have characterized SCD care in Portuguese EDs. This study aimed to describe patterns of emergency care use, clinical presentation, and outcomes in a Portuguese hospital, and to contextualize these findings within international standards. Methods: This retrospective observational study reviewed SCD-related emergency visits to the ED of a district hospital from January 2021 to December 2023. Patients aged ≥18 years with SS, Sβ, or SC genotypes were included. Data collected included demographics, triage category, presenting complaints, pain scores, waiting times, treatments administered, diagnostic investigations, ED length of stay (LOS), disposition and 72-hour revisit rates. Descriptive and bivariate analyses were performed, with significance defined as p < 0.05. Results: A total of 264 ED episodes from 93 unique patients (mean age 30 years; 61% male) were identified, with a mean of 2.8 visits per patient over three years. Limb pain (31%) and back pain (28%) were the most common presenting complaints, and 83% of patients reported severe pain at triage. Most episodes were classified as very urgent (65.2%) or urgent (27.3%), yet the mean time to physician assessment was 58 minutes. The mean ED LOS was 13 hours, substantially longer than reported internationally, and 45.8% of visits resulted in hospital admission. Laboratory testing was performed in 91% of episodes and imaging in 39%. Analgesia was administered in 98% of visits, with frequent use of multimodal regimens; however, pethidine was used in 28% of episodes despite guideline recommendations discouraging its use. The 72-hour revisit rate was low (~4%), with six return visits requiring readmission. Conclusions: SCD patients in Portugal frequently present to the ED with high-acuity VOC requiring intensive evaluation and analgesia. ED LOS substantially exceeded international benchmarks, likely reflecting structural factors such as overcrowding, boarding delays and absence of dedicated acute pain pathways. The persistence of outdated opioid practices further highlights opportunities for quality improvement. These findings emphasize the need for locally adapted, guideline-concordant ED pathways to optimize the acute management of SCD and improve patient outcomes.

Abstract:

b-thalassemia and sickle cell disease are two inherited hematological diseases due to defective hemoglobin synthesis or to the production of hemoglobin with altered properties. These two conditions have prolonged survival with modern support therapies, albeit life-long, complex, expensive and resources-consuming. Studies carried out in the last three decades have shown that allogeneic hematopoietic stem cell transplantation (allo-HSCT) and gene therapy may offer a curative approach for these diseases. Allo-HSCT should be performed early in life to reduce disease-related complications like irreversible tissue damage due to iron overload in patients with transfusion-dependent b-thalassemia (TDT) and systemic vasculopathy in patients with sickle cell disease (SCD). HSCTs from a matched-sibling donor or a matched-unrelated donor represent the best therapeutic option; however, haplo-identical HSCT in both TDT and SCD is now increasingly performed as a valuable and viable option for a larger number of these patients. An alternative curative strategy is based on gene therapy. These curative approaches, particularly those of gene therapy, are available only in a part of the world. Gene therapy diffusion is strongly limited by its high technological and infrastructure requirements and its very high cost. Criteria must be defined for the optimal selection of TDT and SCD patients for allo-HSCT or gene therapy.

Abstract:

Background/Objectives: Multiple myeloma (MM) is characterized by complex interactions between tumor plasma cells and the tumor microenvironment, in which immune escape mechanisms play a key role. Non-classical major histocompatibility complex (MHC) molecules HLA-E and HLA-G are receptors capable of suppressing the activity of NK cells and T lymphocytes. However, their expression on immune cells in oncology, particularly in MM, remains poorly understood. Methods: Peripheral blood mononuclear cells from patients with MM and healthy controls were used as study material. HLA-E and HLA-G expression on T lymphocytes and monocytes was analyzed using flow cytometry. Results: MM was shown to be associated with increased expression of non-classical molecule HLA-E by T lymphocytes and monocytes, as well as an increased proportion of cells with phenotype HLA-E+HLA-DR+ among cells. Conclusions: Our study demonstrates that non-classical HLA-E molecule are actively expressed on immune cells in multiple myeloma, which may serve as a mechanism for tumor immune evasion. These data support further exploration of HLA-E as potential target for MM immunotherapy.

Abstract:

Background: Perianal infections (PIs) are a serious threat in patients with acute myeloid leukemia (AML). While CPX-351 is designed to reduce gastrointestinal toxicity, its impact on the incidence of PIs is unknown. This study aims to evaluate the incidence and characteristics of PIs in a cohort of CPX-351-treated AML patients. Methods: We enrolled 22 adult patients diagnosed with secondary AML receiving CPX-351 between May 2020 and July 2025 at Policlinico Tor Vergata Hospital. Statistical analysis used descriptive statistics and univariate analysis. Results: The incidence of PIs in the cohort was 31.8%. Microbiological cultures from the lesions commonly yielded Klebsiella pneumoniae and Enterococcus species. The development of a PI was associated with a significantly longer hospital stay (mean, 49.6 vs. 37.7 days; p = 0.034). A trend was noted between the presence of PIs and mucositis (p = 0.05) and positive rectal swabs (p = 0.09), with two patients (28.5%) having a positive pre-infection swab for Klebsiella pneumoniae. Surgical intervention was guided by patient pain levels and hematological criteria. Surgical patients had significantly higher pain levels and a platelet count greater than 20 x 10^9/L. All patients were alive at 30 days, with low rates of septic shock (14.2%, n=1) and no infection-related mortality or recurrence. Conclusions: Despite CPX-351′s known reduced gastrointestinal toxicity, our study showed a significantly higher incidence of PIs compared to literature data. While the outcomes were favorable, PIs led to prolonged hospitalization. Routine rectal swab surveillance could be a valuable tool for risk stratification and preemptive strategies.

Abstract: Background: Sickle cell disease (SCD) is the most common hemoglobin disorder in the world. Africa has the highest burden of SCD, accounting for up to 75% of the 300,000 annual births of individuals with SCD worldwide. In Tanzania, 11,000 – 14,000 babies are born with SCD each year. Despite treatment advancement, pain is still an attributable cause of admissions among patients with SCD. However, data is still lacking regarding the adequacy of pain control in patients with SCD in Tanzania. Objective: This study aimed to determine factors affecting pain control among patients with SCD presenting with painful events at Mwananyamala Regional Referral Hospital (MRRH) and Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania. Methodology: This was a cross-sectional study conducted at MRRH and MNH which are tertiary referral hospitals in Dar es Salaam, Tanzania. Patients with SCD aged 8 years and above who presented at the hospitals with painful events (from August 2022 to February 2023) were enrolled into the study. A structured questionnaire was used to collect data on participants' socio-demographic characteristics and clinical parameters. The adequacy of pain control was assessed using the WHO Pain Management Index. Multivariable binary logistic regression was used to determine factors associated with pain control. Differences were considered statistically significant when the p-value was < 0.05. Results: A total of 390 patients with SCD were analysed with mean age (± SD) of 15 (± 6) years. Most patients were recruited from outpatient clinics (88.2%). The male-to-female ratio was 1:1, the majority of patients had less than three pain episodes per year (77.9%), and most patients presented to the hospital with mild pain (64.6%) and were on Hydroxyurea (62.3%). Furthermore, one-third of patients had inadequate pain control. Factors associated with inadequate pain control included receiving initial pain management in other health facilities (adjusted odds ratio [aOR] and 95% confidence interval [CI] = 2.5 (1.5- 4.5), p=0.001), presenting to the hospital with moderate pain (aOR = 2.2, 95% CI [1.3-3.8], p=0.006), and presenting to the hospital with a fever (aOR = 3.8, 95% CI [1.1 – 13.9], p=0.04). Having severe pain and receiving initial treatment at MRRH or MNH seemed to be protective factors (aOR = 0.33, 95% CI [0.11- 0.97], p=0.04, and aOR = 0.29, 95% CI [0.14 -0.61], p=0.001, respectively). Conclusion: A considerable proportion of patients with SCD receive sub-optimal pain control. Receiving initial pain management from other healthcare facilities, presenting to the hospital with moderate pain, and having a fever were associated with inadequate pain control. Further research is warranted to elucidate ways of optimising the management of pain in patients with SCD in Tanzania.

Abstract: The search for new therapeutic principles is essential for treating relapsed/refractory (r/r) acute myeloid leukemia (AML). Novel principles include genome-agnostic differentiation induction, controlling AML-triggering inflammation, potentiating the immune response and 'normalizing' AML metabolism. This review summarizes data from a phase I study (10 patients, pts) and three case reports (7pts) on the treatment of r/r AML by reprogramming AML hallmarks using APA, low dose azacitidine, pioglitazone (PPARα/γ agonist) and all-trans retinoic acid. APA reprograms the r/r AML phenotype in patients with clinically and molecularly/genetically unfavorable risk profiles (17pts, 16 refractory, one relapsed) in a genome-agnostic manner, restoring the plasticity of AML hallmarks, thereby improving immune surveillance, attenuating inflammation-triggered promotion of AML and distant microbial inflammation (healing of fungal pneumonia during induction of complete remission (CR) with APA), while normalizing leukemia metabolism (restoring phagocytosis and ROS production in leukemic neutrophils). APA induces complete remission (CR) in 10pts (59%), with only modest hematotoxicity following CR induction. This allows treatment to be carried out in an outpatient setting, including for elderly and comorbid patients. Triple transcriptional modulation, facilitated by epigenetic modelling with azacitidine, targets reprogramming of non-oncogene addiction networks in AML, re-establishing functionally active, closely interrelated myeloid hallmarks and AML cell death genome-agnostically.

Abstract: Background/Objectives: Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) is a fatal hyperinflammatory syndrome. Non-Hodgkin lymphoma (NHL) is the established primary trigger, while Hodgkin lymphoma (HL) is considered a rare cause. This exploratory study aimed to characterize the features of LA-HLH in a predominantly Hispanic patient population to generate novel pathophysiological hypotheses. Methods: We conducted a retrospective, multicenter analysis of adult patients diagnosed with HLH between 2000 and 2024. Using HLH-2004 criteria, we identified a final cohort of 20 patients with LA-HLH for analysis. Results: In our cohort (70% Hispanic, reflecting the catchment populations of the partic-ipating centers), the most common underlying malignancy was HL (60%), contradicting established literature. Stratification by HIV status suggested two distinct profiles: the HIV-negative group (n=13) was younger and driven almost exclusively by HL (85%), whereas the HIV-positive group (n=7) was older, driven by NHL (86%), and presented with more extreme hyperferritinemia and higher soluble IL-2 receptor (sIL-2R) levels. The overall mortality rate was 57.9%. Conclusions: The unexpected predominance of HL-driven HLH in this cohort suggests a need to re-evaluate the differential diagnosis in specific demographic contexts. Our findings are hypothesis-generating and suggest differing clinicopathological patterns by HIV status and lymphoma subtype; further studies are required to determine whether distinct biological pathways underlie these patterns. Given the retrospective nature and limited sample size, further multicenter studies with uniform laboratory testing and molecular profiling are required to clarify potential biological heterogeneity among LA-HLH presentations.

Abstract: Transcriptomic analyses of public datasets (TCGA and GTEx) revealed that both CD74 and Cathepsin L (CTSL) are significantly overexpressed in diffuse large B-cell lymphoma (DLBCL) compared to normal tissues, and their expression levels are highly correlated (Spearman R = 0.64, p = 3×1046). Kaplan–Meier analysis showed that elevated expression of both genes is associated with reduced disease-free survival (DFS), defining a high-risk CD74+/CTSL+ DLBCL subgroup. This is the first study demonstrating coordinated overexpression of CD74 and CTSL, and proposing their dual targeting via antibody–drug conjugates (ADCs) to improve outcomes in relapsed or refractory DLBCL. Cysteine cathepsins, a family of proteases, are upregulated in many cancers, facilitating tumor invasion and metastasis. Cathepsins are overexpressed and play key roles in DLBCL progression. GB111-NH₂, a potent broad-spectrum cathepsin inhibitor, significantly reduced cathepsin activity in lymphoma cell lines and patient samples. GB111-NH₂ treatment increased apoptosis and caspase-3 activation in DLBCL patient cells and chronic lymphocytic leukemia (CLL) mononuclear cells. Here, we developed a modified cathepsin inhibitor, M-GB, containing a maleimide linker for site-specific antibody conjugation. While M-GB alone has poor cell permeability, when conjugated to an antibody, it forms an ADC (M-GB-ADC) that selectively induces lymphoma cell death. M-GB-ADC demonstrated high specificity for CD74-expressing lymphoma cells while exhibiting minimal toxicity to non-target cells. Our findings highlight the potential of M-GB–ADC as a targeted therapy for overcoming rituximab resistance and treatment failure in DLBCL. This strategy enhances therapeutic efficacy and provides a treatment option by directing a cathepsin inhibitor payload specifically to malignant B cells.

Abstract: Background: Over the past century, numerous pharmacological regimens have been developed for multiple myeloma (MM), yet relapse remains inevitable. Although these regimens prolong overall survival (OS), repetitive treatment cycles and cumulative toxicity progressively impair quality of life (QoL). This study aimed to compare conventional stepwise therapies with CAR-T cell therapy in terms of QoL, toxicity, cost, and ethical value.Methods: Kaplan-Meier survival curves were analyzed to estimate overall (OS) and progression-free survival (PFS). Based on these durations, treatment costs were calculated. A simple and transparent utility-based model was developed to enable clinicians, researchers, and health policy authorities to easily estimate quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICER).Results: Among heavily pretreated patients, CAR-T therapy approximately doubled OS and PFS compared with other late-line regimens and provided markedly better quality of life with lower overall treatment burden. While daratumumab-based combinations improved survival and patient well-being, they were associated with very high treatment costs (~USD 1 million per patient). Carfilzomib-based regimens remained essential for managing high-risk disease despite their expense. In contrast, VMP represented a practical and accessible option, especially for transplant-ineligible or resource-limited patients.Conclusion: CAR-T therapy provided significant improvements in survival and quality of life compared with conventional regimens among patients who had received three or more prior lines of therapy. Its earlier use appears promising. However, the limited availability of CAR-T across only a few countries raises ethical concerns regarding treatment accessibility. Contrary to common assumptions, CAR-T can be less expensive than many traditional therapies, though its single-payment structure poses barriers for patients with limited financial means. Further analyses are needed to refine toxicity management and optimize its broader clinical application in multiple myeloma.

Abstract: Background: Despite advances in frontline therapy, most patients with relapsed or refractory multiple myeloma (RRMM) eventually progress, and optimal sequencing of monoclonal antibody–based regimens remains uncertain. Daratumumab and elotuzumab, each combined with lenalidomide and dexamethasone (SOC), have demonstrated overall survival (OS) benefits in randomized controlled trials. However, no head-to-head comparison exists. This study indirectly compared these regimens using reconstructed individual patient data (IPD) derived from published Kaplan–Meier curves. Materials and Methods: A literature search identified randomized trials evaluating daratumumab-SOC or elotuzumab-SOC versus SOC alone. Digitized OS curves from POLLUX and ELOQUENT-2 were processed using the IPDfromKM artificial-intelligence algorithm to reconstruct patient-level datasets. After assessing heterogeneity between SOC arms, pooled control data were used to conduct indirect comparisons. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression. Results: Reconstructed HRs closely matched published trial estimates for daratumumab (0.787 vs 0.73) and elotuzumab (0.845 vs 0.82). SOC arms differed significantly between trials, with POLLUX controls demonstrating better outcomes than ELOQUENT-2 controls. In the indirect comparison using pooled SOC outcomes from the two trials, daratumumab-SOC significantly improved OS versus SOC alone (HR 0.64; 95% CI 0.52–0.78), while elotuzumab-SOC did not (HR 1.08; 95% CI 0.91–1.29). The head-to-head indirect comparison favored daratumumab over elotuzumab (HR 0.59; 95% CI 0.45–0.77). Conclusions: AI-assisted reconstruction of IPD enabled an indirect comparison of daratumumab- and elotuzumab-based triple regimens in RRMM. Results suggest superior OS for daratumumab-SOC compared with elotuzumab-SOC, supporting daratumumab as the preferred monoclonal antibody partner to lenalidomide-dexamethasone when selecting third-agent therapy for RRMM.

Abstract: Background/Objectives: Mechanisms underlying treatment resistance in hematopoietic malignancies such as acute lymphoblastic leukemia (ALL) include: 1) enhanced activity of anticancer drug efflux mechanisms (MRP1); 2) suppressed activity of anticancer drug influx mechanisms (ENT-1); 3) enhanced drug detoxification activity (AKR1B10, AKR1C3, CYP3A4); 4) influence of the tumor microenvironment (GRP94) etc. We conducted this study to comprehensively and clinically examine treatment resistance due primarily to a decrease in the tumor intracellular anticancer drug concentrations. Methods: The subjects were 19 ALL patients who underwent initial induction therapy with alternating Hyper CVAD/MA therapy. Antibodies against 23 types of treatment resistance-associated proteins were used for immunohistochemical analysis of tumor specimens obtained from the patients, and correlations between the results of immunohistochemistry and the overall survival (OS) were retrospectively analyzed using the Kaplan-Meier method. Results: Based on the patterns of expression of the enzymes involved in treatment resistance, we classified the patients (Urayasu classification for ALL, which we believe would be very useful for accurately stratifying patients with ALL according to the predicted prognosis), as follows: Good prognosis group; n =1, 5%: AKR1B1(+)/AKR1B10(-), 5-year overall survival (OS), 100%; Intermediate prognosis -1 group; n= 9, 5%: AKR1B1(-)/AKR1B10(-) plus MRP1(-), 5-year OS, 68%; Intermediate-2 prognosis group; n = 6.3%: AKR1B1(-)/AKR1B10(-) plus MRP1(+), median survival, 17 months, 5-year OS, 20%; Poor prognosis group; n = 3, 16%: AKR1B1(-)/AKR1B10(+), median survival, 18 months, 5-year OS, 0%. n=2. Conclusions: The Urayasu classification for ALL is considered as being reliable for predicting the prognosis of patients with ALL after the initial Hyper CVAD/MA remission induction therapy.

Abstract:

Objectives: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, and consolidation with autologous hematopoietic stem cell transplantation (HSCT) in AML patients represents an alternative therapeutic option in the absence of related or unrelated donors, in the elderly or in patients with good or standard risk. In this retrospective analysis, the data were evaluated from a total of 47 AML patients who underwent autologous hematopoietic stem cell transplantation between November 2012 and March 2023 at the Bone Marrow Transplantation Unit of Medicalpark Izmir Hospital. The present study also investigates the factors affecting overall survival (OS) and progression-free survival (PFS). Methods: This study is a retrospective evaluation of the data obtained from 47 patients with AML who underwent an autologous HSCT. Results: 24 patients were female, and 23 patients were male. The median age at diagnosis was 39 years (range: 18-68 y). The mean OS from diagnosis to the last follow-up or death was 26 months (4-116 months), and the PFS was 20 months (3-69 months). An assessment of the factors that influenced OS and PFS showed no significant association of NPM positivity, gender, risk group, response to first-line chemotherapy, transplantation at CR (Complete remission) 1 or CR2, LDH (lactade dehidrogenase) , CD34 count, and the day of neutrophil engraftment with OS or PFS. In patients with FLT3(fms benzeri tirozin kinaz 3) positivity, OS was significantly shorter (p < 0.05), while PFS was not significantly different (p=0.21). Conclusions: Consolidation with auto-HSCT in AML patients can be preferred in subjects with good or intermediate 1 risk category according to ELN (European leukemia net )criteria, or in subjects with intermediate 2 or poor-risk category who have no related or unrelated donor.