Multiplex spatial analysis reveals increased CD137 expression and m-MDSC neighboring tumor cells in refractory classical Hodgkin Lymphoma.

The Hodgkin and Reed - Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL) actively modify the immune tumor microenvironment (TME) attracting immunosuppressive cells and expressing inhibitory molecules. A high frequency of myeloid cells in the TME is correlated with an unfavorable prognosis, but more specific and rare cell populations lack precise markers. Myeloid-derived suppressor cells (MDSCs) have been identified in the peripheral blood of cHL patients, where they appear to be correlated with disease aggressiveness. TNFRSF9 (CD137) is a T cell co-stimulator expressed by monocytic and dendritic cells. Its expression has also been described in HRS cells, where it is thought to play a role in reducing antitumor responses. Here, we perform qualitative and quantitative analyses of lymphocytic and MDSC subtypes and determine the CD137 cell distribution in cHL primary tumors using multiplex immunofluorescence and automated multispectral imaging. The results were correlated with patients' clinical features. Cells were stained with specific panels of immune checkpoint markers (PD-1, PD-L1, CD137), tumor-infiltrating T lymphocytes (CD3, PD-1), and monocytic cells/MDSCs (CD68, CD14, CD33, Arg-1, CD11b). This approach allowed us to identify distinct phenotypes and to analyze spatial interactions between immune subpopulations and tumor cells. The results confirm CD137 expression by T, monocytic and HRS cells. In addition, the expression of CD137, T exhausted cells, and monocytic MDSCs (m-MDSCs) in the vicinity of malignant HRS cells were associated with a worse prognosis. Our findings reveal new elements of the TME that mediate immune escape, and confirm CD137 as a candidate target for immunotherapy in cHL.

CD137-expressing immune cells and HRS cells are more abundant and in closer proximity in refractory patients than in responders.Monocytic myeloid-derived suppressor cells (m-MDSCs) are associated with unfavorable outcomes and relapse in cHL, unlike granulocytic MDSCs (g-MDSCs), which are located far from HRS cells in non-responders.The cHL tumor microenvironment promotes immune escape in refractory patients by holistically driving polarization and/or recruitment of several cell types with increased expression of CD137 and PD-L1 checkpoints.

Insights into the Gene Expression Profile of Classical Hodgkin Lymphoma: A Study towards Discovery of Novel Therapeutic Targets.

Classical Hodgkin lymphoma (cHL) is a common B-cell cancer and a significant health concern, especially in Western and Asian countries. Despite the effectiveness of chemotherapy, many relapse cases are being reported, highlighting the need for improved treatments. This study aimed to address this issue by discovering biomarkers through the analysis of gene expression data specific to cHL. Additionally, potential anticancer inhibitors were explored to target the discovered biomarkers. This study proceeded by retrieving microarray gene expression data from cHL patients, which was then analyzed to identify significant differentially expressed genes (DEGs). Functional and network annotation of the upregulated genes revealed the active involvement of matrix metallopeptidase 12 (MMP12) and C-C motif metallopeptidase ligand 22 (CCL22) genes in the progression of cHL. Additionally, the mentioned genes were found to be actively involved in cancer-related pathways, i.e., oxidative phosphorylation, complement pathway, myc_targets_v1 pathway, TNFA signaling via NFKB, etc., and showed strong associations with other genes known to promote cancer progression. MMP12, topping the list with a logFC value of +6.6378, was selected for inhibition using docking and simulation strategies. The known anticancer compounds were docked into the active site of the MMP12 molecular structure, revealing significant binding scores of -7.7 kcal/mol and -7.6 kcal/mol for BDC_24037121 and BDC_27854277, respectively. Simulation studies of the docked complexes further supported the effective binding of the ligands, yielding MMGBSA and MMPBSA scores of -78.08 kcal/mol and -82.05 kcal/mol for MMP12-BDC_24037121 and -48.79 kcal/mol and -49.67 kcal/mol for MMP12-BDC_27854277, respectively. Our findings highlight the active role of MMP12 in the progression of cHL, with known compounds effectively inhibiting its function and potentially halting the advancement of cHL. Further exploration of downregulated genes is warranted, as associated genes may play a role in cHL. Additionally, CCL22 should be considered for further investigation due to its significant role in the progression of cHL.

Efficacy of escalating therapy with brentuximab vedotin-AVD in advanced stage Hodgkin lymphoma patients with positive interim positron emission tomography after ABVD.

Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.

Posterior reversible encephalopathy syndrome (PRES) in classic Hodgkin's lymphoma, complicated by anthracycline-induced cardiomyopathy.

A woman in her 20s with no medical history was diagnosed with bulky stage II classic Hodgkin's lymphoma after an 8-week history of shortness of breath, cough and lethargy. A regimen of doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) was commenced with six cycles planned. During the first cycle, the patient was profoundly hypertensive. She then suffered two self-terminating tonic-clonic seizures.Examination and investigations diagnosed posterior reversible encephalopathy syndrome (PRES), which resolved completely in 11 days with strict blood pressure control and withholding chemotherapy. Treatment was further complicated by anthracycline-induced cardiomyopathy, requiring a switch in regimen to gemcitabine BVD.The patient made a full recovery from neurology and cardiology perspectives and completed six cycles of chemotherapy, achieving a complete metabolic response by the tumour. We illustrate the case, describe differential diagnoses and management of PRES, its association with chemotherapy and the successful chemotherapy rechallenge.

[Hodgkin lymphoma - pain at alcohol consumption as the only symptom]. / Diagnostik och behandling av klassiskt Hodgkins lymfom.

The authors Lanke and Relander describe a patient with classical Hodgkin lymphoma (cHL) stage IIA, who had pain at alcohol consumption as the only symptom at diagnosis. The patient was treated with 4 cycles of ABVD chemotherapy and proton therapy 29.75 Gy (RBE). Apart from FDG-PET/CT the course of the disease was followed with serum-TARC. The case illustrates the value of knowing also rare symptoms at the general practice, the usefulness of TARC as a tumour marker in cHL, and the use of proton therapy in order to further reduce late radiotherapy side effects.

Distressed personality is associated with late adverse effects in long-term survivors of Hodgkin lymphoma.

BACKGROUND AND PURPOSE: There are few studies of personality traits in long-term Hodgkin lymphoma survivors (HLSs) treated according to contemporary stage-and risk-adapted approaches. The Distressed Personality (DP) Scale covers negative affectivity and social inhibition. We examined differences in self-reported late adverse effects (LAEs) between HLSs with and without DP and other explanatory variables. MATERIAL AND METHODS: This cross-sectional questionnaire-based study included a population-based cohort of HLSs treated from 1997 to 2006, aged 8-49 years at diagnosis, and alive in 2016. Among 518 eligible HLSs, 303 responded (58%), and 294 completed the DP scale. DP was defined by scores above cut-off on both the negative affectivity and social inhibition subscales. LAEs studied were major depression, posttraumatic stress disorder, sleep problems, obesity, neuropathy, fatigue, memory problems, and general health. DP and 10 other explanatory variables were tested against LAEs as dependent variables in multivariable regression analyses. RESULTS: The mean age at survey was 45.9 years (standard deviation [SD] 4.6), mean follow-up time 16.7 years (SD 3.0), and 48% were females. Eighty-two HLSs had DP (28%, 95% confidence interval 23% - 33%). All LAEs except obesity were significantly more common/had higher mean score in HLSs with DP. In multivariable analyses, presence of DP was significantly associated with all LAEs except obesity. INTERPRETATION: The presence of DP is common among HLSs. The presence of DP was associated with most self-report LAEs examined. Including assessment of personality traits in the survivorship care plans of HLSs should be considered. Prospective studies assessing the influence of pretreatment DP on LAEs are warranted.

Cytotoxic T-lymphocyte-associated 4 protein expression is associated with a high international prognostic score in advanced-stage classical Hodgkin lymphoma.

OBJECTIVE: Twenty percent of all classical Hodgkin lymphoma (CHL) cases relapse and recur, especially in advanced stages with a high International Prognostic Score (IPS). Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a regulatory molecule that can inhibit the immune response and is related to tumor aggressiveness. This study aimed to determine the relationship between CTLA-4 expression in advanced-stage CHL and IPS, identifying it as a potential therapy target. RESULTS: In advanced-stage CHL, the group with a high IPS exhibited significantly higher mean CTLA-4 expression compared to the group with a low IPS (p = 0.003).The group with Hb level < 10.5 g/dl, leukocyte count > 15,000/µL, lymphocyte count < 8%, albumin level < 4 g/dl, and stage 4 exhibited higher CTLA-4 expression than the other group, although only leukocyte count and stage showed statistical significance (p = 0.004 and p = 0.020). Mean CTLA-4 expression was 239.84 ± 76.36 for nodular sclerosis, 293.95 ± 147.94 for mixed cellularity, 271.4 ± 23.56 for lymphocyte depleted, and 225.2 for lymphocyte-rich subtypes. The results suggest that CTLA-4 expression is associated with adverse prognostic factors in the IPS for advanced-stage CHL, supporting the notion that immune checkpoints play a role in cancer progression.

Survival Outcomes for US and Canadian Patients Diagnosed with Hodgkin Lymphoma before and after Brentuximab Vedotin Approval for Relapsed/Refractory Disease: A Retrospective Cohort Study.

Cost-effectiveness analyses are required for therapies within Canada's universal healthcare system, leading to delays relative to U.S. healthcare. Patients with Hodgkin lymphoma (HL) generally have an excellent prognosis, but those who relapse after or are ineligible for transplant benefit from novel therapies, including brentuximab vedotin (BV). BV was FDA-approved in 2011 but not Canadian-funded until 2014. To assess the impact of access delays, we compared changes in survival for U.S. (by insurer) and Canadian patients in periods pre/post-U.S. approval. Patients were 16-64 years, diagnosed with HL in 2007-2010 (Period 1) and 2011-2014 (Period 2) from the U.S. SEER and Canadian Cancer Registries. Approval date (surrogate) was utilized as therapy was unavailable in registries. Kaplan-Meier survival curves and adjusted Cox regression models compared survival between periods by insurance category. Among 12,003 U.S. and 4210 Canadian patients, survival was better in U.S. patients (adjusted hazard ratio (aHR) 0.87 (95%CI 0.77-0.98)) between periods; improvement in Canadian patients (aHR 0.84 (95%CI 0.69-1.03) was similar but non-significant. Comparisons between insurers showed survival was significantly worse for U.S. uninsured and Medicaid vs. U.S. privately insured and Canadian patients. Given the increasingly complex nature of oncologic funding, this merits further investigation to ensure equity in access to therapy developments.

[Analysis of 10 cases of brentuximab vedotin combined with chemotherapy in the treatment of children with refractory and or relapsed classic Hodgkin lymphoma].

Objective: To evaluate the efficacy and safety of CD30 antibody-drug conjugates (ADC) brentuximab vedotin (BV) combined with chemotherapy in children with refractory or relapsed classic Hodgkin's lymphoma (R/R cHL). Methods: Clinical data (including age, gender, B symptoms, clinical stage, previous treatment, etc.) of the 10 R/R cHL children diagnosed and treated at Beijing Children's Hospital Affiliated to Capital Medical University from October 2021 to August 2023 were analyzed retrospectively. According to the different intensity of chemotherapy drugs, the dose of BV applied in the same course of treatment was 1.8 mg/kg for BV applied once every 3 weeks, and 1.2 mg/kg for BV applied once every 2 weeks. All 10 patients received at least 2 cycles of BV combined with chemotherapy and were evaluated every 2 cycles. The patients were followed up until May 31, 2024. The infusion reactions and adverse reactions after treatment were recorded. Results: In all 10 patients, there were 7 males and 3 females, the age ranged from 5.3-16.9 years, and there were 6 cases of refractory and 4 cases of relapsed. There were 6 cases of nodular sclerosis type, 2 cases of mixed cell type, 1 case of lymphocyte-rich type, and 1 case of lymphodepletion type. There were 5 cases of stage Ⅳ and 5 cases of stage Ⅲ. Previous treatment was mainly chemotherapy, 4 cases received radiotherapy and 1 case received programmed cell death protein 1 (PD-1) antibody therapy. The follow-up time ranged from 9 to 27 months. A total of 43 courses with 49 doses of BV alone or combined with chemotherapy were recorded, and the number of courses was 2 to 10 times. All 10 children responded to the treatment, and 9 achieved complete remission. BV infusion was successfully completed in all cases. A total of 28 cases of grade 3 or above adverse events were recorded, mainly myelosuppression, all of which were related to chemotherapy and did not affect sequential treatment. Conclusion: Brentuximab vedotin has demonstrated efficacy and a tolerable safety profile in the treatment of refractory and relapsed CD30-positive Hodgkin's lymphoma in children.

Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial.

BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.

Hodgkin lymphoma and liquid biopsy: a story to be told.

Hodgkin lymphoma (HL) represents a neoplasm primarily affecting adolescents and young adults, necessitating the development of precise diagnostic and monitoring tools. Specifically, classical Hodgkin lymphoma (cHL), comprising 90% of cases, necessitating tailored treatments to minimize late toxicities. Although positron emission tomography/computed tomography (PET/CT) has enhanced response assessment, its limitations underscore the urgency for more reliable progression predictive tools. Genomic characterisation of rare Hodgkin Reed-Sternberg (HRS) cells is challenging but essential. Recent studies employ single-cell molecular analyses, mass cytometry, and Next-Generation Sequencing (NGS) to unveil mutational landscapes. The integration of liquid biopsies, particularly circulating tumor DNA (ctDNA), extracellular vesicles (EVs), miRNAs and cytokines, emerge as groundbreaking approaches. Recent studies demonstrate ctDNA's potential in assessing therapy responses and predicting relapses in HL. Despite cHL-specific ctDNA applications being relatively unexplored, studies emphasize its value in monitoring treatment outcomes. Overall, this review underscores the imperative role of liquid biopsies in advancing HL diagnosis and monitoring.

A comparison of clinical profile and treatment outcome of Hodgkin's Lymphoma in Tanzania according to HIV status during the HAART era.

BACKGROUND: The incidence of Hodgkin's lymphoma (HL) in people living with HIV (PLWHA) and on HAART is approximately 20-30 times higher than in HIV-negative individuals. Most patients with HIV-HL present at an advanced stage (III-IV) have 'B' symptoms and extranodal involvement. The natural history and risk stratification of HIV-HL has undergone a significant change as a result of HAART's rollout. This study investigated the differences in clinicopathological and survival patterns of HL among individuals with and without HIV disease in Tanzania during the HAART era. METHODOLOGY: This hospital-based retrospective cohort study was conducted at the ORCI, Dar-Es-Salaam, Tanzania. Chi-square and Fisher's exact tests were used to compare proportions. The student t-test was used to compare means. To determine factors that predict survival, we used the log-rank test to analyze the variables in univariate analysis. A Cox regression model was used to analyze the significant factors from univariate analysis in multivariate analysis. RESULTS: Eighty-three patients with HL were recruited, and the prevalence of HIV-positive status was 27.7%. Most of the patients with HIV-HL had an age of > 30 years (73.9%), while most of the non-HIV-HL patients had an age of ≤ 30 years (63.3%) (P = 0.02). The 2-year OS rate for HIV-HL was 34%, while that for non-HIV-HL was 67%. Among the HIV-HL patients, predictors of a poorer outcome were a CD4 count ≤ 200 cells/mm3 (P = 0.05), lack of HAART use (P = 0.00), and the use of HAART for ≤ 10 months (P = 0.00). CONCLUSION: The prevalence of HIV-HL was 27.7% among HL patients. HIV positivity is still a poor prognostic factor in our setting, especially for patients not on HAART, on HAART for ≤ 10 months, or with a low CD4 count below 200 cells/mm3. Patients with HIV-HL were older and had higher LDH levels, whereas patients with non-HIV-HL were younger and had low LDH levels.

Unmasking an unusual presentation of Hodgkin's lymphoma masquerading as ocular inflammation: a case report.

BACKGROUND: Hodgkin's lymphoma (HL) is an extremely rare cause of ocular inflammation that is usually not considered in the typical workup of uveitis and other eye diseases. A few cases of ocular inflammation were reported previously showcasing HL with absence of typical symptoms of HL at presentation. Acknowledging the potential ocular inflammation associated with HL can prompt ophthalmologists to broaden their diagnostic approach and collaborate with internal medicine departments to investigate this rare yet significant etiology. CASE PRESENTATION: A 17-year-old Caucasian woman presenting unilateral panuveitis was later diagnosed with HL. The ocular findings were non-necrotizing scleritis, anterior uveitis, vitritis, white/yellowish chorioretinal lesions, papillitis and vasculitis. A left supra-clavicular lymph node biopsy confirmed the diagnosis of nodular sclerosing Hodgkin's lymphoma stage IIB. Other causes of uveitis were excluded. Chemotherapy led to remission of the disease and the ocular lesions became quiescent with persistent pigmented chorioretinal scars. CONCLUSIONS: Hodgkin's lymphoma should be considered in the differential diagnosis of diseases that can occasionally be revealed by unilateral ocular inflammation. A comprehensive, multidisciplinary approach is key to properly assessing such cases.

A proteome-wide analysis unveils a core Epstein-Barr virus antibody signature of classic Hodgkin lymphoma across ethnically diverse populations.

Epstein-Barr virus (EBV) is an oncogenic virus associated with various malignancies, including classical Hodgkin lymphoma (cHL). Despite its known association, the specific role of humoral immune response to EBV remains poorly characterized in cHL. To address this, we conducted a study using a custom protein microarray to measure the antibody responses in cHL patients and matched healthy controls recruited from an East-Asian hospital-based case-control study. We identified 16 IgG antibodies significantly elevated in EBV-positive cHL compared with controls, defining an "East-Asian antibody signature of EBV-positive cHL." We evaluated responses against these 16 antibodies in a distinct European population, leveraging data from our previous European cHL case-control study from the UK, Denmark, and Sweden. A subset of antibodies (14/16, 87.5%) from the "East-Asian antibody signature of EBV-positive cHL" exhibited significant associations with cHL in the European population. Conversely, we assessed the "European antibody signature of EBV-positive cHL" identified in our prior study which consisted of 18 EBV antibodies (2 IgA, 16 IgG), in the East-Asian population. A subset of these antibodies (15/18, 83.3%) maintained significant associations with cHL in the East-Asian population. This cross-comparison of antibody signatures underscores the robust generalizability of EBV antibodies across populations. Five anti-EBV IgG antibodies (LMP-1, TK, BALF2, BDLF3, and BBLF1), found in both population-specific antibody signatures, represent a "core signature of EBV-positive cHL." Our findings suggest that the antibody responses targeting these core EBV proteins reflect a specific EBV gene expression pattern, serving as potential biomarkers for EBV-positive cHL independent of population-specific factors.

Paraneoplastic Glomerular Diseases.

Paraneoplastic glomerular disease (PGD) develops from tumor cell products, leading to renal dysfunction. Unlike direct tumor effects, PGD illustrates the complex association between cancer and diverse clinical presentations and outcomes. Initially detected in a Hodgkin's disease patient, current research has defined diagnostic criteria based on PGD symptoms and cancer progression. PGDs, although rare (found in <1% of adult cancer patients with overt renal manifestations), are crucial, as they can signal cancer onset and frequently resist standard glomerulonephritis treatments. The emerging field of onconephrology studies this relationship between kidney disorders and cancers. The exact cause of many PGD cases remains unknown. This review examines PGDs, their clinicopathological features, related cancers, and mechanisms, emphasizing the need for early diagnosis and tailored treatment for kidney disease and linked cancer.