Search Results (210)

CAR-T cell therapy has shown substantial efficacy in haematological malignancies, but its application to solid tumours remains limited by poor effector-cell infiltration, functional exhaustion, antigenic heterogeneity, and an immunosuppressive microenvironment. In this study, we develop a new spatiotemporal mathematical model of CAR-T therapy for solid tumours that integrates these resistance mechanisms within a single reaction–diffusion framework. The model is formulated as a system of partial differential equations describing functional and exhausted CAR-T cells, antigen-positive and antigen-low tumour subpopulations, and chemokine, immunosuppressive, and hypoxic fields. Steady-state analysis and finite-difference simulations showed that therapeutic outcome is governed by the interplay between CAR-T cell infiltration, exhaustion, and antigen escape. The model reproduces partial tumour regression followed by residual tumour persistence, therapy-driven enrichment of antigen-low cells, and reduced efficacy under stronger immunosuppressive and hypoxic conditions. In the combination therapy scenario considered here, repeated simulated CAR-T cell administration together with attenuation of the suppressive microenvironment improves tumour control. The proposed model provides a mechanistic basis for analysing resistance and for future optimisation studies of CAR-T therapy in solid tumours. Full article

Background: Tuberculosis (TB) remains a major global health threat, particularly in low- and middle-income countries, with TB infection (TBI) serving as the primary source of TB disease. While HIV infection has long been recognised as a major risk factor for TB progression, the rise of Non-Communicable Diseases (NCDs), which may exert immunosuppressive effects, further compounded by their treatment, contributes to increased TB susceptibility. This scoping review synthesises evidence from systematic reviews on medical and behavioural risk factors for TBI progression to TB disease, for both asymptomatic and symptomatic disease. Methods: A preliminary literature search was conducted on 11 January 2025, in PUBMED using the keywords “tuberculosis,” “asymptomatic or subclinical tuberculosis” “risk factors,” and “systematic review” followed by targeted reviews on the identified medical and behavioural risk factors for TB infection progression to TB disease. Results: A total of 25 systematic reviews were included. Medical risk factors for progression from TB infection to TB disease included diabetes mellitus (DM), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), undernutrition (including iron and vitamin D deficiency), cancer—particularly haematological malignancies—and immunosuppressive therapies (TNF-α inhibitors and glucocorticoids). Iron and vitamin D deficiency, particularly severe deficiency, is linked to increased TB risk, especially among people living with HIV. Behavioural risk factors, including tobacco, drug, and alcohol use, were also highlighted. Geographic variations in TB prevalence, diagnostic practices, and healthcare systems contributed to differences in risk estimates across reviews. No systematic reviews were identified that examined risk factors for asymptomatic TB. Conclusions: The convergence of TB with NCDs, compounded by immunosuppressive therapies, poses a public health challenge in high TB burden settings. Effective TB prevention requires targeted screening, along with enhanced management of these NCDs. Nutritional support, particularly screening and treatment of anaemia and vitamin D deficiency, may benefit individuals with TBI, comorbid NCDs, and HIV. A multidisciplinary approach, integrating behavioural interventions and tailored prevention strategies, is essential to achieving WHO’s End TB targets. Addressing the evidence gap on risk factors for asymptomatic TB is also critical to improve early detection and interrupt transmission. Full article

Circulating tumour DNA (ctDNA) assays are increasingly applied in haematological malignancies for non-invasive genotyping, quantitative response assessment, measurable residual disease (MRD) detection, and relapse surveillance, often complementing bone marrow-based testing and, in selected scenarios, potentially reducing its frequency. Yet, translating ctDNA results into comparable clinical decisions across laboratories, platforms, and time remains challenging because ctDNA measurements are influenced by the definition of the measurand (for example, variant allele fraction versus mutant molecules per mL), pre-analytical variables, end-to-end workflow losses, and lineage-specific confounders such as clonal haematopoiesis of indeterminate potential (CHIP), therapy-related clonal haematopoiesis, and compartmental disease (marrow, plasma, cerebrospinal fluid, extramedullary sites). This review proposes a harmonisation framework for haematological ctDNA based on three linked concepts—metrological traceability, which connects reported values to reference systems with stated uncertainty, commutability, which ensures that reference materials behave like patient specimens across diverse workflows and fit-for-purpose reference materials that support calibration, and quality control, external quality assessment, and cut-off setting for intended uses such as early molecular response in large B-cell lymphoma, molecular MRD in acute myeloid leukaemia, and deep response monitoring in multiple myeloma. This framework is accompanied by harmonised CHIP-aware reporting rules for settings without matched cellular DNA and practical change-control/bridging strategies to preserve clinical decision thresholds when platforms or bioinformatic pipelines evolve. Full article

Background: T-cell-engaging bispecific antibodies (TCEs) have transformed haematological malignancy treatment (blinatumomab > 40% complete remission), yet solid tumour efficacy remains limited (<15% response rates) due to antigen heterogeneity, immunosuppressive microenvironments, and T-cell dysfunction. Systematic molecular engineering, biomarker-driven patient selection, and rational tumour microenvironment modulation are now collectively transforming TCEs from experimental agents into an adaptable platform therapy for solid tumours. Methods: Review of 55 phase I–III trials of CD3-based TCEs in solid tumours, including tarlatamab (DLL3-targeted, small-cell lung cancer) and xaluritamig (STEAP1-targeted, prostate cancer). Analysis of next-generation engineering strategies and resistance mechanisms via genomic and immunohistochemical data. Result: Response rates now approach ~40% in selected settings, marking an inflection point. In extensive-stage small-cell lung cancer, tarlatamab achieved ~40% responses with definitive survival benefit (phase III HR 0.60, 95% CI 0.47–0.77; p < 0.001; median OS 13.6 months). In metastatic castration-resistant prostate cancer, xaluritamig produced ~41% responses in heavily pretreated patients. Step-up dosing reduced severe cytokine release syndrome to <1% (as low as 0.6% with teclistamab), enabling outpatient administration. Neurological adverse events require monitoring but are less frequent than with cellular therapies. Together these results mark a decisive transition from proof-of-concept to clinically validated platform therapy. Discussion: Three resistance mechanisms limit durability: (i) antigen heterogeneity (28–60% of progressors develop antigen-negative subclones); (ii) immunosuppressive microenvironments (stromal barriers, myeloid-derived suppressor cells, hypoxia); (iii) T-cell exhaustion (PD-1/TIM-3/LAG-3 co-expression). Conclusions: Next-generation TCE platforms integrating conditional activation, cytokine payloads, and checkpoint modulation—deployed with biomarker-guided selection and TME-modulating combinations—represent a transformative therapeutic strategy. With tarlatamab’s phase III survival benefit establishing clinical proof-of-concept, and pivotal trials underway for xaluritamig and next-generation agents, TCEs are positioned to become standard-of-care platform therapies in biomarker-defined solid tumours by 2028–2030. Full article

Adoptive immunotherapy using ex-vivo-amplified autologous αβ T cells has achieved notable success in the treatment of diverse cancer types. Pre-eminent among these developments has been the advent of chimeric antigen receptor (CAR) T cell therapy, which has revolutionised the treatment of selected haematological malignancies. However, autologous CAR T cell immunotherapy is poorly scalable and has demonstrated limited efficacy against solid tumours. Accordingly, there has been significant interest in alternative strategies that may bridge these gaps. The use of γδ T cells is an attractive alternative since they possess intrinsic anti-tumour activity and do not elicit graft versus host disease (GvHD) when employed as an allogeneic drug product. In this review, we evaluate the potential use of γδ T cells for cancer immunotherapy and how manufacturing and genetic engineering refinements can be used to potentiate this activity. We also summarise current clinical experience with CAR γδ T cell therapies and discuss the implications of these findings for the next generation of cellular immunotherapies. Full article

Background/Objectives: Thrombocytopenia subsequent to antineoplastic therapies 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 thrombocytopenia in haematological malignancy has been barely addressed. We aimed to evaluate AVA’s efficacy in improving platelet recovery and reducing transfusion requirement in haematological patients with thrombocytopenia. Methods: In this retrospective observational study, haematological patients who developed thrombocytopenia 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 4 weeks: 10 (43.5%) and 9 (39.1%) achieved platelet counts ≥ 30 × 10⁹/L (partial response) and ≥100 × 10⁹/L (complete response), respectively. Response was always maintained for 30 days after AVA withdrawal. Transfusions were significantly fewer than in the previous period: 0 (0–8) vs. 11 (2–15), median (interquartile range [IQR]), 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 thrombocytopenia-associated transfusion needs in haematological malignancy. Full article

Objective: This study aimed to investigate erythrocyte morphological alterations in hematological malignancies, with particular emphasis on structural differences among leukemia subtypes and anemia. Materials and Methods: Peripheral blood samples were obtained from 60 patients, including individuals with anemia (n = 10), acute lymphoblastic leukemia (ALL, n = 15), acute myeloid leukemia (AML, n = 15), chronic lymphocytic leukemia (CLL, n = 15), and chronic myeloid leukemia (CML, n = 5), as well as 10 healthy controls. Erythrocyte morphology was evaluated using light microscopy and scanning electron microscopy. Morphological abnormalities, including loss of biconcavity, poikilocytosis, echinocyte transformation, burr cells, and stomatocytes, were assessed in accordance with International Council for Standardization in Haematology (ICSH)-based morphological definitions. Results: Distinct erythrocyte morphological alterations were observed across disease groups. AML cases demonstrated pronounced central depression-like or perforation-like structures and hypochromasia. Lymphoid malignancies, particularly ALL and CLL, exhibited increased echinocyte formation, whereas chronic leukemias showed a higher prevalence of stomatocytes and cup-shaped cells. Quantitative scoring indicated that loss of biconcavity was most prominent in anemia, followed by AML, CML, ALL, and CLL. Poikilocytosis was most frequent in anemia, followed by ALL, CLL, AML, and CML. Conclusions: The findings indicate that erythrocyte shape alterations are more heterogeneous and prominent in lymphoid leukemias, whereas myeloid leukemias exhibit distinct ultrastructural membrane abnormalities. Although studies focusing on erythrocyte morphology in leukemia remain limited, the present results provide a foundational morphological reference dataset that may support the development and validation of artificial intelligence-based diagnostic approaches. Further studies involving larger cohorts and expanded imaging analyses are warranted to improve diagnostic accuracy and translational applicability. Full article

Background: SARS-CoV-2 vaccination is crucial for protecting against severe COVID-19 disease; however, patients with haematological malignancies (HM) respond poorly to vaccination due to immunosuppression driven by chemotherapy, targeted cell depletion, and immune dysregulation. We sought to define novel biomarkers that predict effective vaccination in patients with HM. Methods: HM patients and healthy controls received SARS-CoV-2 vaccines and were followed for six months post-vaccination. Virus-specific humoral and cellular immune responses were analysed in serum and whole blood pre- and post-vaccination, and serum proteomics was analysed pre-vaccination to identify potential biomarkers for vaccine response. Results: HM patients displayed delayed antibody seroconversion, and 37.5% failed to seroconvert. Baseline proteomic and cellular immune profiles revealed that T-cell-associated chemokines CXCL13 and CRTAM were differentially expressed, with decreased levels seen in vaccine non-responders. Vaccine response was also associated with a reduced frequency of circulating monocytes, greater numbers of B-cells, and a trend toward greater numbers of CD4+ helper cell phenotypes, including T peripheral helper cells pre-vaccination. In vitro generation of COVID-19-specific T-cells from a subset of participants trended towards increased cytotoxic CD4+ and CD8+ T-cell activity in seroconverters and dysfunctional COVID-19-specific T-cell responses in non-seroconverters. Conclusions: These results suggest that HM patients have impaired T-cell immunity, and non-responders may be identified by low levels of serum CXCL13 and CRTAM. This allows for the identification of at-risk patients who would benefit from alternative COVID-19 prophylaxis strategies. Full article

Introduction: Classification of haematological malignancies has evolved over centuries from multiple morphology-based classifications to a single consensus classification, the World Health Organisation (WHO) classification of tumours in 2001, which included clinical history and immunophenotype. The next two decades saw a revised WHO classification, incorporating immunophenotyping, cytogenetics, molecular genetics, morphology, and clinical features. In 2022, the WHO classification of Haematolymphoid Tumours fifth edition (WHO-HAEM5) and International Consensus Classification (ICC) integrated advanced genetic technologies. Navigating two classifications has caused uncertainty for pathologists and clinicians globally. However, there is added concern for low and middle income countries (LMICs), where diagnostic disparities compared to high income countries (HICs) already exist. The incorporation of advanced and costly genetic testing will likely widen this gap. This disparity and diagnostic evolution are the focus of this review. Methods: A literature search was performed for articles reporting on historical evolution of haematological malignancy diagnosis, diagnostic challenges for haematology in LMICs, haematological classification systems, overall survival, and laboratory turn-around times was performed using three scholarly databases; and a Google search was made for historic portions of this review. Ninety-two publications were included. Results: This narrative review describes the diagnostic and genetic evolution of haematological malignancies, and highlights disparities of laboratory diagnostics between LMICs and HICs. Conclusions: The existing disparities in diagnostic haematology between LMICs and HICs will likely widen due to the emphasis on advanced genetic testing in the WHO-HAEM5 and ICC. Advocacy for consistent accessibility and affordability of haematology diagnostics in LMICs is needed. Full article

Immune checkpoint proteins including PD-1, CTLA-4, LAG-3, TIM-3, and TIGIT regulate T-cell functions, which are essential for anti-tumor immunity. Over-expression of these immune checkpoint proteins leads to T-cell exhaustion and a significant impairment of anti-tumor immunity. Rejuvenation of effector T-cell function with immune checkpoint inhibitors (ICI) restores anti-tumor immunity, which translates into clinical efficacy in the frontline and salvage treatment of various hematological malignancies. Efficacy of ICIs is highest in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and NK/T-cell lymphomas, and modest in immune-privileged-site lymphomas and cutaneous T-cell lymphoma. However, in myeloid malignancies and multiple myeloma, the efficacy of ICIs remains doubtful. In addition to being used as single agents, ICIs have also been combined with other ICIs; as well as chemotherapy, antibody drug conjugates, and epigenetic agents (histone deacetylase inhibitors and hypomethylating agents). More innovative strategies include the use of ICIs in the context of allogeneic haematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. This review synthesizes current evidence for the use of ICI in different haematological malignancies, and highlights future directions toward biomarker-driven, rationally designed therapeutic combinations. Full article

Background: Preserving fertility in young women with cancer is crucial for comprehensive care. Based on GBD 2023 estimates, approximately 1000 women aged 15–39 are diagnosed with haematological malignancies annually in Italy. Guidelines recommend timely fertility preservation (FP) counselling for all at-risk patients, yet real-world access data remain limited. Methods: This multicentre, retrospective observational study analysed FP counselling for women aged 15–39 with haematological malignancies from 2015 to 2023. Counselling data were extracted from the Italian Assisted Reproductive Technology Registry (IARTR). This data collection system, known as PreFerIta, was developed within a project supported by the Italian Ministry of Health to collect data on Fertility Preservation (FP) treatments in oncology patients and/or those at risk of iatrogenic infertility, provided in seven specialised ART centres across Italy. The PreFerIta database includes data on both oocyte cryopreservation and ovarian tissue cryopreservation. Annual visits were related to the estimated regional incidence of new haematological malignancies (GBD 2023). Counselling-to-incidence ratios, absolute/relative gaps, and 95% confidence intervals (CIs) were calculated. Results: From 2015 to 2023, an estimated 4473 new haematological malignancies occurred in the catchment regions. Concurrently, 1200 FP counselling visits were recorded. While incidence modestly declined, counselling activity remained high. The counselling-to-incidence ratio increased from 17.33% in 2015 to 31.92% in 2018, stabilising between 26% and 31% thereafter (30.98% in 2023). The relative counselling gap decreased from 82.67% to 69.02%. These ratios represent lower-bound estimates of access to specialised oncofertility consultations. Conclusions: In this Italian network, approximately one in four to one in three incident haematological malignancies in young women were associated with specialised FP counselling. This reflects a substantial integration of oncofertility services into haematology care, highlighting opportunities to further strengthen referral pathways and achieve full guideline concordance. Full article

Background: Childhood cancer is the leading cause of natural death among children in high-income countries, despite treatment improvements. The Spanish Registry of Childhood Tumours (RETI-SEHOP) systematically records all cases treated within the network of SEHOP units. Using RETI-SEHOP data, we evaluated survival trends to assess progress in patient care, both overall and by tumour. Methods: A total of 20,534 childhood cancer cases (0–14 years) were recorded across the period 1999–2021. The 1-, 3-, and 5-year overall survival (OS) were estimated using the Kaplan–Meier method, applying the cohort approach for 1999–2018 and the period approach for 2019–2022. OS by age and sex was analysed in the recent 2009–2018 incidence cohort. Age-adjusted OS time trends were examined using joinpoint Cox models for 1999–2022. Results: For all tumours combined, 5-year OS increased from 75.4% to 84.6% between 1999–2003 and 2019–2022. While positive trends were identified for all haematological malignancies examined, a more varied scenario was evident for solid tumours, as ependymomas improved fastest (1.51 points annually), and sarcomas, except for rhabdomyosarcoma, remained stagnant. Conclusions: Our results reflect a period characterised by a combination of new therapeutic developments, improved diagnostics, and more refined risk stratification, which has ultimately led to a reduction in disease-related mortality. Full article

Background: Parasitic skin-related conditions represent a frequent and evolving challenge in human dermatology, as they often mimic other dermatoses, and are increasingly complicated by therapeutic resistance. With this study, we aimed to provide a practical, clinician-oriented overview of our experience, contextualising it within the current literature. Materials and Methods: We conducted a retrospective, single-centre observational study, reporting a case series of 88 patients diagnosed with parasitic or arthropod-related skin infestations at the San Raffaele Hospital Dermatology Unit (Milan) between 2019 and 2024, and integrated a concise narrative review of contemporary evidence on diagnosis, non-invasive imaging and management. For each case, we documented clinical presentation, dermoscopic or reflectance confocal microscopy (RCM) findings, and treatment response. Non-invasive tools (dermoscopy, videodermoscopy, RCM) were used when appropriate. Results: The spectrum of conditions included flea bites, bed bug bites, cutaneous larva migrans, subcutaneous dirofilariasis, Dermanyssus gallinae dermatitis, pediculosis, tick bites (including Lyme disease), myiasis, scabies, and cutaneous leishmaniasis. One case of eosinophilic dermatosis of haematologic malignancy was also considered due to its possible association with arthropod bites. Non-invasive imaging was critical in confirming suspected infestations, particularly in ambiguous cases or when invasive testing was not feasible. Several cases highlighted suspected therapeutic resistance: a paediatric pediculosis and three adult scabies cases required systemic therapy after standard regimens failed, raising concerns over putative resistance to permethrin and pyrethroids. In dirofilariasis, the persistence of filarial elements visualised by RCM justified the extension of antiparasitic therapy despite prior surgical removal. Conclusions: Our findings underline that accurate diagnosis, early intervention, and tailored treatment remain essential for the effective management of cutaneous infestations. The observed vast spectrum of isolated parasites reflects broader health and ecological dynamics, including zoonotic transmission, international mobility, and changing environmental conditions. At the same time, diagnostic delays, inappropriate treatments, and neglected parasitic diseases continue to pose significant risks. To address these challenges, clinicians should remain alert to atypical presentations, and consider a multidisciplinary approach including the consultation with parasitologists and veterinarians, as well as the incorporation of high-resolution imaging and alternative therapeutic strategies into their routine practice. Full article

The chorioallantoic membrane (CAM) is a well-vascularised extra-embryonic membrane that supports avian embryonic development and can be used as an implantation site for xenograft models of various cancers. CAM tumour research models are powerful and versatile, offering a rapid, cost-effective and ethical complement to mouse xenograft studies. Their capacity for real-time observation of tumour growth, angiogenesis and metastasis within an immunocompetent living organism is particularly compelling. While CAM models have been extensively utilised for investigating solid cancers, such as breast, lung and pancreatic, their potential for haematological malignancy research remains comparatively underexplored. This review examines the relevance, advantages and translational potential of avian CAM models in studying blood cancers. Their applications across three primary categories are discussed—leukaemias, lymphomas and myelomas—highlighting experimental approaches that replicate aspects of human disease progression and therapeutic responsiveness. Moreover, the review evaluates species-specific considerations relevant to model fidelity, including evolutionary distance and functional parallels between avian and human haematopoiesis. These comparisons underscore both the opportunities and limitations for utilising CAM models in haematologic malignancy research. For their potential to investigate mechanisms of cancer development and treatment in simple but immunocompetent in vivo settings, we propose that CAM tumour models offer high value as a bridge between in vitro and mammalian in vivo studies for haematology translational research. Full article

Background/Objectives: Colorectal cancer (CRC) is one of the most common malignancies worldwide, with systemic inflammation increasingly recognised as a determinant of disease progression. This study aimed to establish a taxonomy-based classification of patients with newly diagnosed primary CRC using systemic inflammatory, haematological, and anthropometric markers, and to evaluate its association with tumour stage. Methods: A total of 229 patients (111 women, 118 men) undergoing surgery for primary CRC were included. Blood samples were analysed for haemoglobin, leukocytes, neutrophils, lymphocytes, platelets, C-reactive protein (CRP), and carcinoembryonic antigen (CEA). Anthropometric data were collected. Taxonomic clustering and ordinal logistic regression were used to explore associations with TNM and Astler–Coller classifications. Results: Men had higher neutrophil and leukocyte counts, elevated CEA concentrations (132.8 vs. 81.3 ng/mL), and higher NLR values (4.74 vs. 4.23) compared with women. Logistic regression confirmed that platelet count (OR 1.003; p = 0.004), PLR (OR 1.003; p = 0.003), and CEA (OR 1.03; p < 0.001) were positively associated with advanced TNM stage, while haemoglobin was inversely correlated (OR 0.88; p = 0.045). Among 84 clustering models, two taxonomies were the most clinically informative: Taxonomy I (BMI, neutrophils, platelets) and Taxonomy II (age, lymphocytes, platelets), both significantly associated with T, N, M, overall TNM stage, and Astler–Coller grade. Taxonomy I identified three patient groups. Type 3 represented the poorest phenotype, characterised by low BMI and haemoglobin, high platelets, elevated CEA and PLR, and predominance of TNM IIIC tumours, consistent with a cachectic–inflammatory profile. Type 1 displayed higher BMI, lower inflammation, and earlier-stage disease. Type 2 was characterized by elevated neutrophils and leukocytes. Taxonomy II distinguished four groups, with Type 2 demonstrating the most favourable profile (high haemoglobin and lymphocytes, low NLR and PLR, early TNM stage). Conclusions: Systemic inflammatory markers, haemoglobin, platelets, and CEA strongly predict CRC advancement. The proposed taxonomy provides clinically meaningful stratification of CRC patients and may support personalised risk assessment. This accessible approach may facilitate early identification of high-risk individuals, although validation in prospective studies is required. Full article