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Classical Hodgkin lymphoma (cHL) is a common lymphoma that affects young patients. Fortunately, the disease is highly curable as it is susceptible to the currently available treatment modalities. Disease monitoring with Positron Emission Tomography and Computed Tomography (PET/ CT) is an integral part of managing these patients. PET guided protocols are currently used to adjust treatment according to the response. The pivotal idea behind the use of response-adapted approaches is to preserve efficacy while decreasing the toxicity. It also helps to intensify therapy in patients in need because of suboptimal response. However, imaging techniques are limited by their sensitivity and specificity. Minimal Residual Disease (MRD) assessment is a newly emerging concept in many hematologic malignancies. It utilizes various molecular techniques such as polymerase chain reaction (PCR), and next-generation sequencing (NGS) as well as flow cytometry, to detect disease traces. This review looks into MRD detection techniques, its current applications, and the evidence in the literature for its use in cHL.

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The ECHELON-1 trial demonstrated the effectiveness of brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine as a frontline treatment regimen in classical Hodgkin lymphoma. However, peripheral neuropathy (PN) is common with this regimen, occurring in up to two-thirds of patients. While standard prescribing information recommends BV dose modification at the onset of grade 2 PN, management strategies for PN are not well-defined. Most commonly, clinicians dose reduce or discontinue BV, vinblastine, or both. We review evidence-based and practical approaches for managing peripheral neuropathy, emphasizing early detection and dose modification.

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The present case report investigated the clinicopathological features and potential mechanisms underlying the transformation to peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), following treatment for classical Hodgkin lymphoma (CHL) in a 73-year-old man. The patient was admitted to hospital in 2012 and underwent a left cervical lymph node biopsy, which confirmed CHL of the nodular sclerosing type, with evident bone marrow involvement. The patient received four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy, after which they achieved complete remission. However, after 3 years, the patient presented with enlarged left inguinal lymph nodes and a biopsy revealed PTCL-NOS. Molecular studies indicated a T-cell receptor-γ gene rearrangement. A literature review, together with the current case, identified 11 patients with CHL that transformed into PTCL-NOS. Among these, nine patients (81.82%) were middle-aged or elderly (>45 years old), and eight (72.73%) experienced transformation within 3 years post-treatment of CHL. Among these eight patients, seven (87.50%) predominantly exhibited the nodular sclerosis subtype, with a median recurrence time of 26 months. Five (45.45%) patients died of the disease. The rare transformation of CHL to PTCL-NOS, primarily among men, underscores its clinical significance. Notably, nodular sclerosing-type CHL appears to be particularly prone to transformation into PTCL-NOS. The poor prognosis in such cases may be attributed to the complex tumor microenvironment of CHL.

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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.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Perfilación de la Expresión Génica , Simulación del Acoplamiento Molecular , Transcriptoma , Antineoplásicos/farmacología , Antineoplásicos/química , Metaloproteinasa 12 de la Matriz/genética , Metaloproteinasa 12 de la Matriz/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Terapia Molecular Dirigida

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We present a series of 9 follicular lymphomas that progressed/transformed into classical Hodgkin lymphoma (CHL). Three cases of CHL showed a syncytial pattern (SCHL) making the differential diagnosis to Gray zone lymphoma (GZL) challenging. None of these three cases presented in the mediastinum. Based in all molecular data analyzed (BCL2/BCL6 FISH studies, IgH PCR and TNGS with a customized gene panel) we did find clonal relationship between the BCL2-positive FL cases and their CHL components in all cases. The three SCHL/GZL cases showed an activated phenotype according to Hans algorithm, presented the t(14; 18)(q32; q21), two out of three showed B cell markers and all expressed CD30 and p53. Interestingly, we identified three BCL2-negative FL cases with a further diagnosis of CHL expanding the spectrum of these association. In one of these three cases a different mutational profile was found in both the FL and the CHL components. All this data together suggests that CHL associated to BCL2-positive FL could be originated in a common progenitor cell (CPC) that give rise to both FL and CHL, acquiring this last component further genetic events in a linear fashion. On the other hand, no clonal relationship between CHL and BCL2-negative FL could be found, suggesting a fortuity association. Nevertheless, ample series of cases studied with more sensitive techniques are needed to confirm our hypothesis.

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Biomarcadores de Tumor , Enfermedad de Hodgkin , Linfoma Folicular , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Linfoma Folicular/patología , Linfoma Folicular/genética , Linfoma Folicular/diagnóstico , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Hibridación Fluorescente in Situ , Diagnóstico Diferencial , Mutación , Anciano de 80 o más Años

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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.

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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.

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Enfermedad de Hodgkin , Células Supresoras de Origen Mieloide , Células de Reed-Sternberg , Microambiente Tumoral , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral , Humanos , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Microambiente Tumoral/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/patología , Femenino , Masculino , Adulto , Persona de Mediana Edad , Células de Reed-Sternberg/patología , Células de Reed-Sternberg/metabolismo , Anciano , Análisis Espacial , Adulto Joven , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Adolescente , Pronóstico , Biomarcadores de Tumor/metabolismo

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BACKGROUND: Classical Hodgkin lymphoma (CHL) is characterized by a proliferation of malignant cells of the lymphoreticular system and often involves lymph nodes, spleen, liver, and bone marrow; it is rare in the head and neck region. CASE DESCRIPTION: A 58-year-old man had an enlargement with ulceration in the left palatine tonsil that was causing dysphagia. Microscopic examination revealed an infiltrate of large, atypical lymphoid cells positive for cluster of differentiation 30, cluster of differentiation 15, PAX5, and Epstein-Barr virus. Complementary tests initially ruled out other sites of the disease. The results led to diagnosis of a rare development of CHL in the palatine tonsil, which was staged as IIEB. Before therapy was initiated, nodal lesions developed in the neck and the CHL was restaged as IIB. The patient was treated successfully with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine. After a review of the literature, the authors found only 3 cases with the clinical, imaging, and microscopic features of primary CHL of the palatine tonsil. PRACTICAL IMPLICATIONS: Despite being a rare event, CHL may first develop in extranodal sites, such as the palatine tonsil. In this context, the role of the dentist is pivotal for early diagnosis of the disease. Investigations into the development of primary tonsillar CHL in the oropharynx are needed because the disease has a different clinical course than nodal lesions.

Asunto(s)

Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/diagnóstico , Masculino , Persona de Mediana Edad , Neoplasias Tonsilares/patología , Neoplasias Tonsilares/diagnóstico , Tonsila Palatina/patología , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/diagnóstico

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Patients with cancer are at risk for thrombotic complications due to a hypercoagulable state. However, the benefit of prophylactic anticoagulation is unclear in many subsets of these patients. For the first episode of acute thromboembolic disease (VTE) in patients with active cancer, anticoagulant therapy is administered for at least three to six months. Herein, we present a 31-year-old female with active, recurrent stage IIIa classical Hodgkin lymphoma (CHL) (nodular sclerosis), previously treated for proximal upper extremity deep vein thrombosis (DVT), presenting for evaluation of shortness of breath and eventually diagnosed with bilateral pulmonary embolism (PE) secondary to a right atrial thrombus. The patient was successfully treated with surgical resection of the thrombus. With this case report, we hope to encourage physicians to use prophylactic indefinite anticoagulation in patients with active cancer and previous DVT, including patients with upper extremity DVT.

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Objective Non-Hodgkin lymphoma (NHL) arising as a secondary malignancy in patients treated for classical Hodgkin lymphoma (cHL) is an infrequent and challenging clinical scenario. NHL can be presented synchronously with cHL or may develop later, sequentially, up to years after treatment for cHL. The relationship between the two lymphomas is unclear, and there are no clear guidelines for the management of these patients. We would like to find a better clinical understanding of this issue so this study investigates the occurrence and clinical characteristics of secondary NHL. Materials and methods In this retrospective cohort examination, we collected cHL cases when NHL occurred during or after the course of treating cHL. We performed the histopathologic revisions of the samples, and in every case where the quality of the sample was lower, we performed molecular examinations to find the association between cHL and NHL. We performed next-generation genome sequencing (NGS) and immunoglobulin heavy-chain variable region gene (IgHV) clonality testing. Results In a cohort of 164 cHL patients diagnosed between 2011 and 2020, six patients were identified with NHL during rebiopsy prompted by lymphoma relapse or progression. Among these, five patients were diagnosed with post-germinal center-originated diffuse large B-cell lymphoma (post-GC DLBCL), and one patient presented high-grade B-cell lymphoma (HG-BCL). The NHL manifestation differed in its timing: three cases emerged after successful cHL treatment, with at least 18 months of complete remission, while the other three patients faced primary refractory cHL. Notably, the primary refractory cases did not exhibit a confirmed clonal relationship between cHL and NHL, but NGS data raised the possibility of synchronous NHL in one case. In contrast, among the patients with sequentially occurring NHL, polymerase chain reaction (PCR) testing of the IgHV gene affirmed a clonal connection between cHL and secondary DLBCL in one case, while the high morphological similarity suggested a potential clonality between the two lymphomas in another case. Conclusion This study reveals that secondary NHL may manifest both synchronously and sequentially following cHL. Our results suggest that synchronous NHL has a worse prognosis compared to sequential cases when the different lymphomas are not recognized at the time of diagnosis. As our data showed, in some cases, mutations that accompany the tumor cells throughout their clonal evolution can be identified, with additional mutations later on. In the future, next-generation sequencing (NGS)-based processing of liquid biopsy samples can overcome the limitations resulting from the spatial heterogeneity of lymphoid malignancies. Over the long term, this identification could lead to early patient selection and alternative treatment strategies, ultimately leading to improved prospects for cure.

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Classical Hodgkin Lymphoma (CHL) is a rare malignant neoplasm of the lymphatic system. While CHL typically responds well to conventional treatments, some cases may experience relapse to other subtypes, with the development of secondary peripheral T-cell lymphoma (PTCL) being relatively uncommon. Herein, we report a rare case of nodal T follicular helper cell lymphomas,nos (nTFHL-NOS) secondary to CHL, accompanied by aberrant CD20 expression and clonal rearrangements of T-cell receptor (TCR) and immunoglobulin (IG). A 74-year-old male, was diagnosed with CHL, leaning toward the mixed cell type, 6 years ago. He received six cycles of the Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) regimen, achieving complete clinical remission. The patient was admitted to our hospital due to the appearance of multiple skin nodules 66 months later. Histopathological analysis revealed nTFHL-NOS, with aberrant CD20 expression and clonal rearrangements of TCR and IG. The patient underwent two cycles of chemotherapy with brentuximab vedotin and the Gemcitabine-Oxaliplatin (G-mox) regimen, resulting in a reduction of the skin lesions to 2 cm × 1 cm. We discuss this rare case and review related literature.

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Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.

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OBJECTIVE: The primary objective is to describe the real-life effectiveness and safety of nivolumab treatment in patients with relapsed or refractory classical Hodgkin's lymphoma. The secondary objective is to describe the therapeutic management after nivolumab monotherapy. METHOD: Observational, retrospective, multidisciplinary study including all patients with relapsed or refractory classical Hodgkin's lymphoma treated with nivolumab monotherapy from November 2015 to March 2023. Patient and treatment-related variables were collected. Effectiveness was measured as overall response rate, progression-free survival and overall survival. Safety was measured as percentage of patients with adverse effects and severity. RESULTS: Thirteen patients were included, median age 37.5 years (RIQ: 25.3-54.7), 84.6% male. The median number of previous lines of therapy was 3 (RIQ: 2.0-4.5), including autologous hematopoietic stem cell transplantation (84.6%) and brentuximab vedotin (100%). All received nivolumab 3 mg/kg/14 days, with a median of 11 cycles (RIQ: 6.5-20.5) per patient. Median time on treatment was 4.9 months (RIQ: 3.0-9.6) and median follow-up time was 9.2 months (RIQ: 5.6-32.3). Complete response was achieved by 3 patients (23.1%), partial response by 3 (23.1%), stable disease by 3 (23.1%) and progression by 4 (30.8%). The objective response rate was 46.2%. Median progression-free survival was 23.9 months (95%CI: 0-49.1), median overall survival was not reached. At the study cutoff date, five patients had died (38.5%), four were in complete remission without active treatment (30.8%) and four were continuing treatment (30.8%). Adverse events occurred in 76.9% of patients, 44% of severity ≥3, the most frequent being hypothyroidism and hepatotoxicity. One patient discontinued treatment due to pneumonitis, two suffered treatment delays (thrombocytopenia and hypertransaminemia) and one changed the regimen to monthly (pulmonary toxicity). CONCLUSIONS: Nivolumab in the treatment of relapsed or refractory classical Hodgkin's lymphoma has confirmed in the study sample favorable effectiveness data, expressed as objective response rate of 46.2% and clinical benefit of 69.2%. Safety was acceptable, manageable, and consistent with that described in the literature.

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Introduction: In classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly conserved serine/threonine kinase, consisting of two catalytic (α) and two regulatory (ß) subunits, which is involved in several cellular processes and both subunits were found overexpressed in solid tumors and hematologic malignancies. Methods and results: Biochemical analyses and in vitro assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2ß compared to normal B lymphocytes. Mechanistically, CK2ß was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin. Conclusions: Our data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2ß has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL.

Asunto(s)

Antígeno B7-H1 , Quinasa de la Caseína II , Enfermedad de Hodgkin , Transducción de Señal , Humanos , Enfermedad de Hodgkin/metabolismo , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Quinasa de la Caseína II/metabolismo , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Línea Celular Tumoral , Fenazinas , Naftiridinas/farmacología , Apoptosis , Regulación Neoplásica de la Expresión Génica , Fosforilación

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This systematic literature review evaluated frontline treatment burden in pediatric and adolescent/young adult (AYA) patients with high-risk classical Hodgkin lymphoma (cHL) among studies originating from the United States. Data were extracted from 32 publications (screened: total, n = 3115; full-text, n = 98) representing 12 studies (randomized controlled trials [RCTs], n = 2; non-comparative, non-randomized, n = 7; observational, n = 3). High-risk disease definitions varied across studies. Five-year event-free survival (EFS)/progression-free survival (PFS) was 86%-100% and 79%-94%, and complete response rates were 35%-100% and 5%-64% for brentuximab vedotin (BV)-containing and chemotherapy-alone regimens, respectively. In identified RCTs, BV-containing compared with chemotherapy-alone regimens demonstrated significantly longer 3-year EFS/5-year PFS. Hematological and peripheral neuropathy were the most commonly reported adverse events of interest, although safety data were inconsistently reported. Few studies evaluated humanistic and no studies evaluated economic burden. Results from studies with the highest quality of evidence indicate an EFS/PFS benefit for frontline BV-containing versus chemotherapy-alone regimens for pediatric/AYA patients with high-risk cHL.

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Enfermedad de Hodgkin , Adolescente , Niño , Humanos , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/terapia , Pronóstico , Tasa de Supervivencia

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Classical Hodgkin lymphoma (cHL) is a hematological malignancy of B-cell origin. The tumor cells in cHL are referred to as Hodgkin and Reed-Sternberg (HRS) cells. This review provides an overview of the currently known miRNA-target gene interactions. In addition, we pinpointed other potential regulatory roles of microRNAs (miRNAs) by focusing on genes related to processes relevant for cHL pathogenesis, i.e., loss of B-cell phenotypes, immune evasion, and growth support. A cHL-specific miRNA signature was generated based on the available profiling studies. The interactions relevant for cHL were extracted by comprehensively reviewing the existing studies on validated miRNA-target gene interactions. The miRNAs with potential critical roles included miR-155-5p, miR-148a-3p, miR-181a-5p, miR-200, miR-23a-3p, miR-125a/b, miR-130a-3p, miR-138, and miR-143-3p, which target, amongst others, PU.1, ETS1, HLA-I, PD-L1, and NF-κB component genes. Overall, we provide a comprehensive perspective on the relevant miRNA-target gene interactions which can also serve as a foundation for future functional studies into the specific roles of the selected miRNAs in cHL pathogenesis.

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Objective To analyze the clinical characteristics of thyroid dysfunction induced by camrelizumab in the treatment of classical Hodgkin lymphoma(cHL)and explore the influencing factors.Methods The medical records of cHL patients treated with camrelizumab from January 1st,2017 to December 31st,2020,were collected.The clinical characteristics of thyroid dysfunction induced by camrelizumab were analyzed,and the influencing factors of adverse drug reactions(ADRs)were discussed.Results A total of 47 patients were included,12 patients(25.53%)experiencing thyroid dysfunction after receiv-ing camrelizumab.Among them,3 patients had hypothyroidism,7 had subclinical hypothyroidism,and 2 had subclinical hyperthy-roidism.The severity of ADRs was between grade 1 and 2(mild to moderate).None of the patients with thyroid dysfunction dis-continued camrelizumab.Thyroid dysfunction occurred between 1 and 22 months after camrelizumab treatment,with a median time of 6 months.2 patients with hypothyroidism treated with levothyroxine,the thyroid function returned to normal in 1 patient and was improved in the other.1 patient with subclinical hypothyroidism was treated with levothyroxine with the thyroid function continued to be abnormal.The rest of the 9 patients with thyroid dysfunction received no intervention,and 4 of them returned to normal,and others remained with no obvious change or loss in follow-up.Thyroid dysfunction was associated with baseline thyroid stimulating hormone level(P=0.03).The level of thyroglobulin antibodies and thyroid peroxidase antibodies was increased in 2 patients a-mong 3 patients with moderate thyroid dysfunction.Conclusion The incidence of thyroid dysfunction induced by camrelizum-ab in cHL was high.Camrelizumab-induced thyroid dysfunction was related to TSH baseline level(P=0.03).The severity was between grade 1 and 2,which was related to the level of TgAb and TPOAb.The subtype of thyroid dysfunction was mainly sub-clinical hypothyroidism with a long period.Patients could continue camrelizumab treatment,and the thyroid function of patients with grade 2 hypothyroidism was improved after the treatment with levothyroxine.

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Here we present the case of a 28-year-old man with X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection and neoplasia (XMEN) disease. He presented with immune thrombocytopenia within 1 year after successful autologous hematopoietic stem cell transplantation for recurrent EBV-associated classical Hodgkin lymphoma (CHL). The combination of EBV- associated malignancy, autoimmunity, recurrent airway infections at young age and bronchiectasis, prompted immunological investigation for an inborn error of immunity (IEI). Genetic testing revealed XMEN disease. XMEN disease is characterized by a glycosylation defect due to mutations in the MAGT1 gene. Germline mutations in the MAGT1 gene disrupt glycosylation of the NKG2D receptor in immune cells, including natural killer and CD8-positive T cells, vital for immune surveillance, especially against EBV. Consequently, individuals with XMEN disease, are prone to EBV-associated lymphoproliferative disorders in addition to auto-immunity. Early recognition of adult onset IEI-related B-lymphoproliferative disorders, including CHL is of vital importance for treatment decisions, including (allogeneic) haematopoietic stem cell transplantation and family screening.

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Classical Hodgkin lymphoma (cHL) accounts for 0.4% of all new cancer cases globally. Despite high cure rates with standard treatment, approximately 15% of patients still experience relapsed or refractory (RR) disease, and many of these eventually die from lymphoma-related causes. Exciting new targeted agents such as anti-PD-1 agents and brentuximab vedotin have changed the therapeutic paradigm beyond chemotherapy and radiotherapy alone. Advances in understanding of the molecular biology are providing insights in the context of novel therapies. The signature histology of cHL requires the presence of scant malignant Hodgkin Reed-Sternberg cells (HRSCs) surrounded by a complex immune-rich tumour microenvironment (TME). The TME cellular composition strongly influences outcomes, yet knowledge of the precise characteristics of TME cells and their interactions with HRSCs is evolving. Novel high-throughput technologies and single-cell sequencing allow deeper analyses of the TME and mechanisms elicited by HRSCs to propagate growth and avoid immune response. In this review, we explore the evolution of knowledge on the prognostic role of immune cells within the TME and provide an up-to-date overview of emerging prognostic data on cHL from new technologies that are starting to unwind the complexity of the cHL TME and provide translational insights into how to improve therapy in the clinic.

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Patients with relapsed/refractory classical Hodgkin lymphoma (cHL) achieve complete response (CR) after decitabine-plus-camrelizumab therapy, while long-term outcome especially after treatment discontinuation remains unclear. We present a retrospective analysis of 87 relapsed/refractory cHL patients who acquired CR after decitabine-plus-camrelizumab. Patients were divided into two groups and received consolidation treatment every 3-4 or 6-12 weeks, and 1-year of continuous CR was guaranteed for treatment cessation. At a median follow-up of 5.3 years, the median relapse-free survival (RFS) after achieving CR with decitabine-plus-camrelizumab therapy was 4.5 years, and patients underwent consolidation per 3-4 weeks might have longer RFS. The baseline percentage of peripheral central memory T cells was not associated with RFS, while patients with higher pretreatment serum levels of interleukin-6 (IL-6) and lactate dehydrogenase (LDH) had significantly shorter RFS and increased risk for disease recurrence. Fifty-seven patients completed and discontinued decitabine-plus-camrelizumab, and their median RFS had not been reached. The 2-year RFS rate after treatment cessation was 78% (95% CI, 67-90%). Patients in the high-risk subgroup with higher pretreatment IL-6 and LDH levels showed poor treatment-free remission. Moreover, decitabine-plus-camrelizumab therapy was safe and cost-effective. In conclusion, patients who obtained CR with decitabine-plus-camrelizumab and received consolidation per 3-4 weeks can achieve long-term remission after treatment discontinuation.

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Optimal management of patients who present with Hodgkin lymphoma continues to evolve. Most patients are cured with current treatment strategies, some but both short and long-term morbidity and mortality from treatment have particular relevance given the youth of the patient population. Combininations of targeted agents together with conventional chemotherapy have recently been investigated in phase 3 cliniial trials for advanced-stage Hodkgkin lymphoma, and have demonstrated improved efficacy compared with chemotherapy alone. These include both antibody-drug conjugates and PD-1 blockade. Treatment approaches have historically differed between pediatric and adult groups, but recent collaborations between adullt and pediatric groups via the NCTN mechanism have resulted in the successful completion of enrollment in an advanced-stage Hodgkin lymphoma and the opening of an early-stage trial that will enroll patients accross a broad age spectrum. Novel approachs incorporating targeted and immunomodulatory agents in the relapse setting are being actively investagated in the relapse setting as well.