Search Results (1,316)

Background/Objectives: The differential diagnosis of classic Hodgkin lymphoma (CHL) versus anaplastic large cell lymphoma (ALCL) and other T-cell lymphomas (TCL) with Hodgkin-like features remains challenging in some cases, and may require TCR molecular testing with prolonged turnaround time. The limited literature has previously described PRAME (Preferentially Expressed Antigen in Melanoma) overexpression in Hodgkin cells and its absence in cutaneous T-cell lymphomas. The aim of this study was to examine the staining pattern of PRAME in CHL compared to the pattern in non-cutaneous ALCL and TCL. Methods: Twenty-four cases of CHL, 21 cases of ALK-negative ALCL, nine cases of ALK-positive ALCL and 11 cases of other TCL were stained for PRAME. Results: PRAME showed strong and diffuse (3+) expression in 80% of CHL cases while, in contrast, 0% of ALK-negative ALCL showed 3+ staining and 11% of ALK-positive ALCL showed 3+ staining. Non-ALCL TCL showed only 0 or 1+ staining. Conclusions: PRAME may be another helpful stain in the workup of CHL and its morphologic mimics. Full article

Background/Objectives: Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL) affect young women, with cure rates exceeding 80%. Treatment-related gonadal insufficiency is recognized for its impact on fertility, yet fertility preservation remains underutilized, and prospective data are limited. The aim of this study is to prospectively evaluate gonadal function in women ≤40 years old with lymphoma undergoing chemotherapy. Methods: Ovarian reserve and endocrine ovarian function were evaluated by sequential measurements of follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), progesterone, and estradiol at diagnosis, during, and after chemotherapy. Results: 81 female patients ≤40 years old were enrolled, including 53 with HL and 28 with NHL (16 with PMBCL). HL patients had significantly lower AMH values for their respective age group compared to all other diagnoses (p = 0.05), which was more striking for patients ≤30 years old (p = 0.039), indicating pre-existing reduced ovarian reserve in HL. In HL, both FSH and AMH levels indicate gonadal dysfunction for at least six months post-chemotherapy, with AMH serving as a more sensitive biomarker than FSH. For PMBCL patients treated with R-DA-EPOCH, AMH suppression was noticed, with no evidence of recovery up to 18 months post-treatment. At all time points, the PMBCL patients had significantly lower AMH values compared to the HL patients (AMH6: p = 0.03, AMH12 and AMH18: p = 0.05). AMH emerged as the most sensitive marker of ovarian damage, with pretreatment levels <7 pmol/L predicting impaired ovarian reserve in HL patients. Conclusions: For HL, the pretreatment cut-off of 7 pmol/L could discriminate patients with ovarian insufficiency post-treatment, whereas no statistically significant predictive association was identified in PMBCL. These findings require validation in larger cohorts. Full article

Ophelia syndrome is a rare paraneoplastic limbic encephalitis associated with classical Hodgkin lymphoma (cHL), most often with antibodies against metabotropic glutamate receptor 5 (mGluR5). We describe a 19-year-old man with newly diagnosed cHL who presented with generalised seizures, cognitive dysfunction, spastic paraparesis, cauda equina-related autonomic dysfunction, and a 35 × 31 mm haemorrhagic inflammatory lesion in the right temporal lobe. Brain biopsy showed dense intravascular and perivascular inflammatory infiltrates without neoplastic cells. Cerebrospinal fluid demonstrated pleocytosis and intrathecal IgG synthesis with type III oligoclonal bands. Serum and cerebrospinal fluid neuronal autoantibody panels were negative, but mGluR5 antibodies were not assessed. Cervical lymph node biopsy confirmed nodular sclerosis cHL, stage IIA. After exclusion of infectious encephalitis and central nervous system lymphoma, the presentation was considered most consistent with Ophelia-like paraneoplastic limbic encephalitis. ABVD chemotherapy was initiated, with rapid neurological improvement after the first cycle. Complete metabolic response was achieved after two cycles and sustained after six cycles. At 15-month follow-up, major neurological symptoms had not recurred, although bladder and bowel dysfunction persisted. This case highlights the importance of considering paraneoplastic limbic encephalitis in cHL despite negative standard neuronal antibody testing and of documenting whether mGluR5 antibodies were assessed. Full article

Background/Objectives: Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) provide quantitative assessments of metabolically active tumor burden; however, their prognostic value in Hodgkin lymphoma (HL) remains uncertain. This study evaluated the associations of baseline PET/CT-derived MTV and TLG with clinical disease characteristics, treatment response, progression-free survival (PFS), and overall survival (OS) in patients with classical HL. Methods: This retrospective single-center study included 105 adults diagnosed with classical HL between July 2020 and April 2023. Baseline PET/CT images were analyzed using LIFEx 7.1.0. Volumes of interest were delineated using a fixed threshold of 41% of SUVmax. Total MTV and TLG were calculated by summing the values of all FDG-avid lesions. Survival outcomes were evaluated using Kaplan–Meier analysis, the log-rank test, and Cox proportional hazards regression. Results: The median age was 33 years, and the median follow-up was 24 months. Higher MTV and TLG were significantly associated with advanced-stage disease, high International Prognostic Score, B symptoms, bulky disease, and extranodal involvement. Higher MTV was associated with a lower end-of-treatment response rate, whereas higher TLG was associated with lower interim and end-of-treatment response rates. Disease progression occurred in 19 patients, and 11 patients died. Compared with patients with MTV < 249, those with MTV ≥ 249 had numerically higher hazards of progression (HR = 2.18, 95% CI: 0.88–5.40; p = 0.09) and death (HR = 1.21, 95% CI: 0.37–3.96; p = 0.75). Compared with patients with TLG < 1252, those with TLG ≥ 1252 had a numerically higher hazard of progression (HR = 1.53, 95% CI: 0.61–3.86; p = 0.37) but a lower hazard of death (HR = 0.56, 95% CI: 0.17–1.85; p = 0.34). However, all confidence intervals included 1, and none of these differences reached statistical significance. Conclusions: Baseline MTV and TLG reflect disease burden and are associated with treatment response in classical HL. However, neither parameter was significantly associated with PFS or OS in this cohort. Their potential value as survival prognostic biomarkers requires confirmation in larger prospective studies with longer follow-up. Full article

Background/Objectives: Cutaneous T-cell lymphomas (CTCL), most commonly mycosis fungoides and Sézary syndrome, are rare non-Hodgkin lymphomas. Advanced disease responds poorly to current treatments, highlighting the need for new molecularly targeted therapies. WEE1 is a central regulator of the G2/M checkpoint and S-phase progression and has emerged as a therapeutic target in several malignancies, yet it has not been systematically explored in CTCL. Methods: We screened a library of more than 2200 kinase inhibitors in CTCL cell lines and selected adavosertib for further study. Its effects were tested in four CTCL lines; primary keratinocytes and fibroblasts; patient-derived malignant CD4⁺ T cells and healthy donor CD4⁺ T cells; and a MyLa xenograft model, using viability, apoptosis, cell-cycle, Western blot, and phospho-protein array assays. Results: Adavosertib reduced viability at submicromolar IC₅₀ values (0.26–0.56 µM) across all four CTCL lines while largely sparing primary skin cells and was more active in malignant than in healthy donor CD4⁺ T cells. It induced apoptosis and cell-line-specific S-phase and/or G2/M accumulation, lowered WEE1 and phospho-CDK1 (Tyr15), and increased phospho-H2A.X. A phospho-protein array showed activation of checkpoint and stress signalling. In a preliminary xenograft experiment, adavosertib slowed MyLa tumour growth. Conclusions: These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease. Full article

Background: Immunotherapy and targeted therapy have gained ground over conventional chemotherapy in treating various cancers. While pulmonary toxicity associated with these agents is rare, it represents a significant factor in both mortality and morbidity and may influence the overall success of cancer treatment. This case series report adds to the emerging evidence of cancer therapy-induced pneumonitis features and corticotherapy outcomes. Patients and methods: This single-center, retrospective case series analyzed 12 consecutive cases of patients undergoing immunotherapy (four receiving nivolumab, four receiving pembrolizumab) or targeted therapy (three receiving obinutuzumab, one receiving abemaciclib) for cancer (seven with lung cancer, three with non-Hodgkin lymphoma, one with breast cancer, one with renal cancer) who developed pneumonitis during their follow-up. Results: The interval from oncological treatment initiation to pneumonitis onset ranged from 6 to 48 months (median = 18.5), and in four patients it occurred after discontinuation of oncologic therapy. In most patients, the diagnosis was established with high probability based only on the clinical presentation, radiologic pattern, and concomitant oncologic therapy. Bronchoscopy with bronchoalveolar lavage analysis was performed in eight of the 12 patients, particularly when onset followed treatment discontinuation. The main symptom was dyspnea (10/12 cases), and three of 12 patients had respiratory failure (SpO₂ ≤ 88%). The CTCAE severity grades were: one mild, seven moderate, three severe, and one life-threatening. The CT scan showed different patterns (7 OP, 4 NSIP-like, and 1 HP). Eleven patients received oral methylprednisolone (0.40 to 0.82 mg/kg) for 5 to 16 weeks. Two patients continued oncologic treatment, and six discontinued. Pneumonitis improved or resolved in 11 of the 12 patients; one patient deteriorated after reintroduction of immunotherapy and subsequently died from cancer-related complications. Conclusions: Immunotherapy- and targeted therapy-induced pneumonitis can express various features and severities, and prompt recognition and diagnosis based on clinical, radiologic and contextual elements are mandatory. In this small, heterogeneous series the individualized corticosteroid regimens used were followed by favorable outcomes. Our observations suggest that, in selected clinically improving patients, follow-up may rely only on clinical assessment and chest X-ray, and extensive tests may be reserved for non-responsive cases. Full article

Diffuse large B-cell lymphoma (DLBCL), the most prevalent subtype of non-Hodgkin lymphoma (NHL), is an aggressive and fairly heterogeneous group with diverse clinical, pathological, and molecular features. Despite the success of first-line immunochemotherapy, relapsed or treatment-resistant forms remain a clinical challenge. Consequently, minimally invasive markers are needed to predict refractoriness. Recently, circulating microRNAs (miRNAs) have emerged as highly stable, promising biomarkers. MiRNAs such as miR-21, miR-155, miR-222-3p, and the miR-17~92 cluster act as oncogenes that promote tumor survival, while others, such as miR-34, miR-181a, miR-144, miR-101, miR-10a, and miR-320, act as tumor suppressors. Despite multiple recent publications that have correlated dysregulated miRNAs with diagnostic and prognostic importance, the clinical translation has not been fully addressed. Overall, this review provides an updated perspective on the potential of miRNAs in DLBCL and outlines key challenges and future directions for their integration into precision oncology, as miRNAs can remodel the clinical management of DLBCL by enabling earlier diagnosis, improved prognostication, and personalized treatment approaches. Full article

Chronic hepatitis C virus (HCV) infection is an established risk factor for B-cell lymphoproliferative disorders and represents a paradigmatic model of infection-driven lymphomagenesis. Although direct-acting antivirals have markedly reduced the burden of HCV-related disease, HCV-associated lymphomas continue to occur. Moreover, HCV screening remains incomplete in some geographical areas and healthcare settings, leaving a substantial proportion of infected individuals unaware of their status. This narrative review integrates current evidence on the mechanisms linking chronic HCV infection to mixed cryoglobulinemia and overt B-cell non-Hodgkin lymphoma. HCV lymphotropism and persistent antigenic stimulation could initially promote the selection and expansion of autoreactive B-cell clones, while mixed cryoglobulinemia represents the most informative pre-lymphomatous risk condition. Cytokine-mediated survival signals, particularly those involving B-cell activating factor, reinforce clonal persistence and cooperate with host genetic susceptibility, impaired apoptotic control, and activation-induced cytidine deaminase-mediated genomic instability. The progressive acquisition of somatic driver mutations, copy-number alterations, and epigenetic and transcriptomic changes may enable selected clones to escape functional anergy and become increasingly independent of the original viral stimulus that, in turn, represents an initial trigger of the lymphoproliferative process. Recurrent abnormalities converge on NF-κB, NOTCH, chromatin-regulatory, apoptotic, and cell-cycle pathways, although HCV-associated lymphomas remain molecularly heterogeneous. Emerging microRNA profiles further contribute to the molecular characterization of the transition from chronic infection and cryoglobulinemia to lymphoma. Despite the availability of highly effective antiviral therapies, HCV-associated lymphomagenesis remains clinically relevant and continues to provide an especially informative model for understanding how chronic viral infection can drive human cancer development. Full article

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose-limiting toxicity in child, adolescent, and young adult (CAYA) oncology populations. Despite its clinical impact, objective biomarkers for early detection and monitoring remain limited. Neurofilament light chain (NfL), a marker of axonal injury, has emerged as a potential circulating biomarker of CIPN in adults and potentially for CAYAs. This pilot study evaluates the association between NfL and patient-reported CIPN severity in CAYAs. Methods: We conducted a prospective pilot study of 26 patients with acute lymphoblastic leukemia or lymphoma. CIPN was assessed using FACT-GOG/NTx scores. Linear mixed-effects models evaluated associations between NfL and neuropathy over time, adjusting for age and time from baseline. Logistic mixed models assessed the relationship between NfL and clinically significant neuropathy (FACT-GOG/NTx ≤ 40). Results: NfL was significantly associated with worsening neuropathy. A 50-unit increase in NfL corresponded to a 1.1-point decrease in FACT-GOG/NTx score (p < 0.001). Each doubling of NfL was associated with a 0.61-point decrease in FACT-GOG/NTx (p < 0.001). Higher NfL levels increased odds of neuropathy (OR 4.62, p < 0.001). Associations were strongest in leukemia patients and not observed in Hodgkin lymphoma when separately analyzed. Conclusions: This pilot study demonstrates that circulating NfL correlates with patient-reported neuropathy severity, supporting its role as a potential biomarker for CIPN in CAYAs. Differences between leukemia and lymphoma cohorts may reflect treatment-specific neurotoxicity patterns and should be validated in larger prospective studies. Limitations include small sample size, heterogeneity, and limited power for subgroup analyses. If validated, NfL could be incorporated into routine toxicity monitoring to identify patients at highest risk for progressive CIPN, enabling earlier supportive care interventions, referral to rehabilitation services, or enrollment in biomarker-guided prevention and treatment trials before irreversible nerve injury occurs. Full article

Background/Objectives: Lymphomas are the third most common pediatric malignancy, with non-Hodgkin lymphoma (NHL) comprising around 7% of childhood cancers. Environmental exposures have been linked to its etiology. Particulate matter (PM) prenatal exposure is increasingly scrutinized for potential effects on early-life carcinogenesis. We investigated whether exposure during pregnancy to PM_2.5 and PM₁₀ was associated with childhood NHL incidence. Methods: A population-based case–control study was conducted in Spain (2009–2016), including 3,682,038 children < 15 years. Incident NHL cases (n = 289) were identified through the Spanish Childhood Tumor Registry. Prenatal PM_2.5 and PM₁₀ exposures were estimated using a random forest model. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Exposures were modeled continuously and categorically by tertiles (low, medium, or high exposure) to assess nonlinearity; trimester-specific analyses were also explored. Results: In the analysis with the continuous exposure, higher prenatal PM_2.5 was associated with increased odds of NHL, and PM₁₀ showed smaller associations. With categorical variables, medium and high-level exposure to PM_2.5 showed an association with higher NHL incidence, especially in the third trimester. High-level exposure to PM₁₀ during the first and second trimesters was linked to a higher NHL incidence in children under five years. Conclusions: Maternal PM_2.5 and PM₁₀ exposure during pregnancy could be associated with childhood NHL incidence, with stronger associations among children diagnosed before age 5. These findings warrant replication and mechanistic investigation. Full article

Background: Late-onset neutropenia (LON) and hypogammaglobulinemia are recognized sequelae of rituximab therapy in B-cell non-Hodgkin lymphoma, and both may leave patients vulnerable to infection once treatment has ended. Methods: Fifty-three patients with newly diagnosed, unfavorable diffuse large B-cell lymphoma (DLBCL) who entered remission on dose-adjusted (DA) R-EPOCH immunochemotherapy were retrospectively evaluated. Neutropenia (absolute neutrophil count < 1.5 × 10⁹/L, CTCAE-graded), hypogammaglobulinemia and infections were registered at treatment completion and 6 and 12 months later. Results: All laboratory parameters changed significantly over time. Most reached their nadir at the end of treatment, whereas the absolute neutrophil count alone reached its lowest value later, at 6 months. Neutropenia, largely mild to moderate, affected 17.6% of patients at treatment completion, 22.4% at 6 months and 7.9% at 12 months. Neutropenia at 6 months was a new event, with no overlap with end-of-treatment neutropenia, and was mostly transient. Hypogammaglobulinemia (IgG < 5 g/L) occurred in 33.3%, 16.7% and 20.0%, respectively; median IgG declined to a nadir at the end of treatment and recovered thereafter, although the deficit tended to persist in the same patients. Post-treatment infections were recorded in 73.6% of patients (mostly respiratory); neutropenia was not associated with infection at any time point, whereas end-of-treatment hypogammaglobulinemia was associated with respiratory infection (p = 0.040). The independent predictors of 6-month neutropenia were a greater number of dose-escalated cycles, lower baseline leukocyte count and the absence of on-treatment infection, whereas 6-month hypogammaglobulinemia was predicted by autologous transplantation and the absence of B symptoms. In exploratory body composition analyses, lower baseline psoas muscle mass was associated with end-of-treatment neutropenia (p = 0.042) and greater muscle loss with other site (skin and gastrointestinal) infection (p = 0.004). Conclusions: After DA-R-EPOCH, LON is a delayed and largely transient event separate from end-of-treatment neutropenia, whereas hypogammaglobulinemia is more persistent and clinically relevant for respiratory infections. Full article

Background/Objectives: Hematological malignancies (HMs) are an important component of the cancer burden in adolescents and young adults (AYA, 15–39 years), requiring long-term specialized care. In Poland, recent healthcare reforms under the National Oncology Network (KSO) have not formally included haemato-oncology or AYA-specific needs. Methods: A population-based study was conducted using data from the Polish National Cancer Registry. AYAs diagnosed with HM between 2000 and 2022 were included. Descriptive analyses and projections were based on cases diagnosed between 2000 and 2022, whereas age-specific incidence trend analyses were restricted to the 2015–2022 period. Tumours were classified according to the HAEMCARE framework. Age-standardized incidence rates (ASIRs), annual percentage changes (APCs), and short-term projections through 2028 were estimated using generalized linear models. Additionally, data from the National Health Fund (NFZ) were analyzed to assess the geographical distribution of reimbursed drug programmes dedicated to selected HMs. Results: A total of approximately 23,000 AYA patients diagnosed with HMs were identified. Hodgkin lymphomas (HL) were the predominant tumour type across all age groups, while lymphoblastic leukemia/lymphoma was most common among younger AYAs and diffuse large B-cell lymphoma (DLBCL) increased in relative importance with age. Between 2015 and 2022, ASIRs remained stable only in two age groups (20–24 and 25–29), whereas statistically significant increases were observed among individuals aged 15–19, 30–34 and 35–39 years. Despite largely stable incidence patterns, projections indicated a growing absolute number of cases for DLBCL and follicular lymphomas. Analysis of NFZ data revealed substantial regional variation in the availability of reimbursed drug programmes, with up to six-fold differences in facility density between voivodships. Conclusions: HM epidemiology among AYAs in Poland is characterized by increasing incidence in selected lymphoma subtypes alongside declining mortality. Incorporating haemato-oncology and AYA-specific needs into national cancer planning frameworks should therefore be considered essential for future healthcare system preparedness. Full article

Radiation-free treatment for early-stage classic Hodgkin lymphoma (eHL) has been shown to be less effective than standard combined-modality treatment (CMT; chemotherapy plus involved-node radiotherapy (INRT)), which achieves long-term disease control of 94–95%. Approximately 70% of patients can be cured with chemotherapy alone, whereas about 5% fail CMT. Identifying patients who can safely receive chemotherapy alone and those requiring intensified CMT could enable a risk-adapted treatment strategy. The RAFTING trial (NCT04866654; EudraCT 2020-002382-33) is an international, prospective, phase 2, non-inferiority study enrolling patients 18–70 years, stage I–IIA eHL without bulky disease, B symptoms, or extranodal involvement. Low-risk (LR) patients are defined by total metabolic tumor volume (TMTV) <84 mL and negative PET-2. Those with at least one modified EORTC (mEORTC) risk factor, in which bulky disease is replaced by a large nodal mass (5–10 cm), receive four ABVD cycles, while those without risk factors receive two ABVD cycles alone. High-risk (HR) patients, defined by TMTV ≥84 mL and/or positive PET-2, receive “triple therapy”: 4 ABVD cycles, INRT (20/30 Gy), and nivolumab (240 mg q2w, ≤doses). LR patients are monitored using cfDNA. Limited relapse is treated with INRT (36 Gy) and nivolumab. The RAFTING trial is the first prospective eHL study to personalize treatment using TMTV and PET-2. It aims to omit radiotherapy in LR patients, intensify treatment in HR patients, and spare relapsed LR patients high-dose chemotherapy and autologous transplantation. CfDNA is being evaluated as a relapse marker. Despite the protocol’s complexity, this study exemplifies personalized medicine and could transform treatment practices. Full article

Background: Perinatal and early-life factors may influence non-Hodgkin lymphoma (NHL) risk, but study results have been mixed and exposure data for childhood ages are limited. Herein, we investigated associations of these exposures with risk of NHL and common subtypes. Methods: This case–control study included 2280 NHL cases and 2253 controls, enrolled from 2002 to 2014 at the Mayo Clinic Rochester. Self-reported perinatal and early-life exposures included maternal age at birth, birth order, birthweight, time breastfed, height and weight at ages 7, 12, and 18 years relative to peers, and age and weight when growth ceased. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for design variables and potential confounders. Linear trend tests were performed for ordinal variables, and heterogeneity tests were performed to evaluate whether associations varied across four NHL subtypes. Results: After multivariable adjustment, greater birth weight (OR = 1.15 for quartile 4 vs. 1; p-trend = 0.04), weight at age 7 relative to peers (compared to average, OR = 1.05 for heavy and OR = 0.87 for thin; p-trend = 0.002), and weight when growth ceased (OR = 1.30 for quartile 4 vs. 1; p-trend < 0.001) were associated with increased NHL risk. An inverse association was observed for breastfeeding duration with NHL risk (OR = 0.77 for >6 months vs. never; 95% CI 0.61–0.97). Associations did not significantly vary by major NHL subtype (p-heterogeneity > 0.05). Other perinatal and early-life exposures were not associated with NHL risk. Conclusions: Greater body weight at birth and through childhood may be associated with increased NHL risk, potentially extending the life-course perspective on adiposity and lymphomagenesis, with implications for prevention. Full article

Background and Objectives: The prognostic effect of the number of neoplastic cells in classic Hodgkin lymphoma (CHL) regardless of the histological subgroup has not been studied to date. We aimed to evaluate the prognostic impact of the number, ratio, and/or grouping of Hodgkin/Reed–Sternberg (HRS) cells in patients with CHL. Materials and Methods: 135 consecutive adult patients with CHL were included. The number, ratio, and grouping of HRS cells were evaluated on hematoxylin–eosin (HE) and CD30-stained slides. The ratio and group formation were scored. Results: Female:male ratio was 0.82. The median age was 36 ± 15.8 (range: 18–82 years). The number of HRS cells was significantly higher in nodular sclerosis CHL than in mixed-cellularity CHL and lymphocyte-rich CHL. Also, the number of HRS cells was significantly higher in syncytial variant nodular sclerosis CHL (SV-NSCHL). HRS cell ratio was in the range of 6–25% in more than 50% of the cases on both HE- and CD30-stained slides. The number of cases with a group score of 0 (no HRS groups) was significantly higher among men compared to women. HRS cells mostly did not form groups in EBER-positive patients. Confluent/large groups were more common in SV-NSCHL. Response to first-line therapy, gender, and EBER positivity were found to be independent prognostic factors. The number, ratio, and grouping of HRS cells were not associated with OS, stage, recurrence, and/or response to first-line treatment. Conclusions: The number, ratio, and/or grouping of HRS cells do not have any significant prognostic impact on CHL patients, however future studies are required to explore their pathogenetic implications. Full article