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Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists. Here we present a complex case with HLH and EBV-driven classic Hodgkin lymphoma (cHL) as the presenting manifestation of underlying immune defect. However, the patient's underlying immunodeficiency was not identified until his second recurrence of Hodgkin disease, recurrent episodes of Herpes Zoster, and after he had undergone autologous hematopoietic stem cell transplant (HSCT) for refractory Hodgkin lymphoma. This rare presentation of HLH and recurrent lymphomas without some of the classical immune deficiency manifestations of MAGT1 deficiency led us to review the literature for similar presentations and to report the evolving spectrum of disease in published literature. Our systematic review showcased that MAGT1 predisposes to multiple viruses (including EBV) and adds risk of viral-driven neoplasia. The roles of MAGT1 in the immune system and glycosylation were highlighted through the multiple organ dysfunction showcased by the previously validated Immune Deficiency and Dysregulation Activity (IDDA2.1) score and CDG-specific Nijmegen Pediatric CDG Rating Scale (NPCRS) score for the patient cohort in the systematic review., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients., Methods: Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m 2 IV, and oxaliplatin 100 mg/m 2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT., Results: Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity., Conclusions: Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission., Trial Registration: ClinicalTrials.gov NCT04239170. Registered on January 1, 2020., (© 2024. The Author(s).)

Background: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk., Procedure: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs)., Results: Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26)., Conclusions: Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those <15 years of age, we did not observe strong associations between being born with a birth defect and HL risk., (© 2023 Wiley Periodicals LLC.)

Mediastinal radiotherapy for childhood cancers, particularly Hodgkin disease, has numerous potential adverse effects, including coronary artery disease, pericarditis, cardiomyopathy, valvular disease, and conduction abnormalities. The prevalence of valvular stenosis is relatively low, and regurgitation is more common. Mediastinal radiotherapy-induced valvular disease develops more than 10 years after radiotherapy. Here, we present a case of a 6-year-old boy with moderate to significant mitral stenosis + moderate mitral regurgitation and mild aortic regurgitation that appeared 1.5 months after radiotherapy and showed a progressive course., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study aimed to systematically review and critically appraise cost-effectiveness studies on Brentuximab vedotin (BV) in patients with Hodgkin lymphoma (HL)., Methods: The PubMed, Scopus, Web of Science core collection, and Embase databases were searched until July 3, 2022. We included published full economic evaluation studies on BV for treating patients with HL. The methodological quality of the studies was assessed using the Quality of Health Economic Studies (QHES) checklist. Meanwhile, we used qualitative synthesis to analyze the findings. We converted the incremental cost-effectiveness ratios (ICERs) to the value of the US dollar in 2022., Results: Eight economic evaluations met the study's inclusion criteria. The results of three studies that compared BV plus doxorubicin, vinblastine, and dacarbazine (BV + AVD) front-line therapy with doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) showed that BV is unlikely to be cost-effective as a front-line treatment in patients advanced stage (III or IV) HL. Four studies investigated the cost-effectiveness of BV in patients with relapsed or refractory (R/R) HL after autologous stem cell transplantation (ASCT). BV was not cost-effective in the reviewed studies at accepted thresholds. In addition, the adjusted ICERs ranged from $65,382 to $374,896 per quality-adjusted life-year (QALY). The key drivers of cost-effectiveness were medication costs, hazard ratio for BV, and utilities., Conclusion: Available economic evaluations show that using BV as front-line treatment or consolidation therapy is not cost-effective based on specific ICER thresholds for patients with HL or R/R HL. To decide on this orphan drug, we should consider other factors such as existence of alternative treatment options, clinical benefits, and disease burden., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although classic Hodgkin lymphoma (cHL) is highly curable with current treatment paradigms, therapy fails in 10-25% of patients. This prospective multicenter phase II study attempted to investigate the efficacy and safety of the combination of tislelizumab with gemcitabine and oxaliplatin (T-GemOx) in relapsed or refractory cHL. Participants received six to eight courses of gemcitabine (1 g/m2 on day 1) and oxaliplatin (100 mg/m2 on day 1) combined with tislelizumab (200 mg on day 2) at 21-day intervals, followed by tislelizumab maintenance (every 2 months for 2 years). The main outcome measure was the best complete remission rate. As of August 2022, a total of 30 patients had been consecutively enrolled and given induction therapy. The best overall response rate and complete remission rate were 100% (95% confidence interval [CI]: 88.4-100%) and 96.7% (95% CI: 82.8-99.9%), respectively. The median duration of follow-up after initiation of T-GemOx was 15.8 months. The 12-month progression-free survival rate without autologous stem cell transplant was 96% (95% CI: 74.8-99.4%). There were 122 adverse events recorded, of which 93.4% were grade 1 or 2. Thrombocytopenia (10%) and anemia (6.7%) were the most common grade 3 or 4 adverse events. Overall, T-GemOx demonstrated promising antitumor activity with manageable toxicities as a salvage treatment for relapsed or refractory cHL. A longer follow-up duration is required to determine whether maintenance therapy with tislelizumab rather than transplantation can be curative following such a highly active regimen. This trial was registered with the Chinese Clinical Trials Registry (http://www.chictr.org.cn) on June 1, 2020, identifier ChiCTR2000033441.

A failed graft-versus-tumor (GVT) effect is a common mechanism of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Although targeting the PD-1/PD-L1 axis may restore GVT effects, PD-1 blockade exacerbates graft-versus-host disease (GVHD) in murine models, and severe GVHD can occur in patients treated with anti-PD-1 therapy after alloHCT. Therefore, we developed a prospective study to assess the safety and efficacy of pembrolizumab in patients relapsing after alloHCT. Eligible patients received pembrolizumab (200 mg every 3 weeks) for up to 2 years. Twelve patients were enrolled (8 patients with acute myeloid leukemia, 1 patient with myelodysplastic syndrome, 1 patient with classical Hodgkin lymphoma, and 2 patients with diffuse large B-cell lymphoma [DLBCL]). All participants received reduced-intensity preparative regimens with in vivo T-cell depletion. The median time from alloHCT to enrollment was 587 days (range, 101-4211). Three participants (25%) experienced grade 3 to 4 immune-related adverse events (irAE) (pneumonitis, 2 patients; hyperthyroidism, 1 patient), all occurring after 1 to 2 cycles, and resolving after pembrolizumab discontinuation and corticosteroid treatment. irAEs of any grade occurred in 5 patients (42%). No treatment-emergent GVHD was observed. Overall and complete response (CR) rates were 22% (2/9). Both patients achieving CRs had PD-L1 gene-amplified lymphomas and diffuse PD-L1 expression on pretreatment biopsies. An acquired EZH2 mutation was identified at relapse in a patient with DLBCL who achieved an initial CR to pembrolizumab, which was associated with downregulated HLA expression on malignant B cells, implicating EZH2 mutations as a potential immune escape mechanism after PD-1-blockade therapy. In conclusion, after alloHCT, treatment with pembrolizumab is feasible and associated with objective responses in relapsed lymphoid malignancies but can induce severe irAEs, requiring vigilant monitoring. This trial was registered at www.clinicaltrials.gov as #NCT02981914., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Primary mediastinal B-cell lymphoma (PMBCL) is a rare but aggressive mature B-cell lymphoma that arises from thymic B cells and most commonly affects adolescents and young adults. PMBCL is now recognized by the WHO as a distinct entity from diffuse large B-cell lymphoma (DLBCL), not otherwise specified, with a unique clinical presentation and distinct morphologic features and molecular alterations. Similar to classic Hodgkin lymphoma, PMBCL tumors are characterized by alterations in the nuclear factor-κB and JAK/STAT pathways. These tumors also exhibit an immune evasion phenotype marked by upregulation of PD-L1 and loss of B2M. Historic data indicates that outcomes for pediatric patients with PMBCL are inferior compared with pediatric patients with DLBCL treated on the same protocols, and there is no current standard approach to initial treatment. Common regimens used for children with PMBCL include multiagent chemotherapy regimens designed for Burkitt lymphoma, such as Lymphomes Malins B (LMB)-based or Berlin-Frankfurt-Münster (BFM)-based chemotherapy ± rituximab. Based on initial data in adults showing excellent outcomes with the use of DA-EPOCH-R regimens, these regimens have also been adopted in pediatrics, although with mixed results. Novel agents are currently being studied in PMBCL with the goal of improving outcomes and reducing reliance on radiation and/or high-dose chemotherapy. Immune checkpoint blockade with PD-1 inhibition is of particular interest given the upregulation of PD-L1 in PMBCL and the known efficacy of these agents in the relapsed setting. Future efforts in PMBCL will also seek to determine the role of FDG-PET in evaluating response to therapy and the role of biomarkers in risk stratification.

Chemotherapy for classic Hodgkin lymphoma (cHL) patients on hemodialysis (HD) is an extremely challenging situation because pharmacokinetic and pharmacodynamic studies of most chemotherapeutics are lacking for the HD patient, and the small amount of evidence available comes mostly from case reports and small case series. In this review, we provide recommendations based on treatment experience of cHL patients on HD in the literature. HD patients undergoing chemotherapy are at risk of overdose and toxicities because many drugs are significantly eliminated by the kidneys, and at the same time, are at risk of undertreatment because many drugs are removed by HD. Therefore, dose modifications and timing of drug administration in relation to HD sessions must be carefully planned according to the distinct traits of each chemotherapeutic. We carried out an exhaustive literature review of reports of actual administrations of chemotherapeutics to cHL on HD, and also extrapolated data from reports of the same chemotherapeutics that were administered to HD patients with malignancies other than cHL. We summarized the information found in the literature, and provide practical and balanced recommendations concerning dose modifications and optimal timing of drug administration in relation to HD sessions for each chemotherapeutic. Chemotherapy regimens and individual chemotherapeutics studied in this review include ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine), BEACOPP (bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisolone), MOPP (mechlorethamine + vincristine + procarbazine + prednisolone), gemcitabine, vinorelbine, brentuximab vedotin, and PD-1 inhibitors (nivolumab and pembrolizumab)., (Copyright © 2022. Published by Elsevier Inc.)

Hodgkin lymphoma can be classified as classical Hodgkin lymphoma (cHL) based on the presence of hallmark Hodgkin and Reed-Sternberg cells. Through radiotherapy and modern chemotherapy, cHL has an impressive cure rate. We discuss normal B-cell maturation and the pathobiology of cHL, correlate significant cHL maturation steps with the sites of action of novel drugs, and highlight these drugs' efficacy in prior trials. In relapsed cHL, the approved agents brentuximab vedotin and immune checkpoint inhibitors have shown efficacy both alone and in combination with chemotherapy for salvage therapy, as maintenance after an autologous stem cell transplant, and after failure of this transplant. Chimeric antigen receptor T-cell therapy is being explored as a potential treatment option in relapsed/refractory cHL, and ongoing clinical trials show promising data without significant toxicity. We illustrate available novel therapeutic options and their efficacy in frontline and relapsed settings and discuss therapeutic benefit in relation to regimen toxicity., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: With the expanding use of immune checkpoint inhibitors (ICIs) in patients with various types of cancers, many more patients are experiencing checkpoint inhibitor-related pneumonitis (CIP). After recovery from CIP, some patients are rechallenged with ICI therapy. The CIP will recur in a considerable proportion of rechallenged patients. When severe or recurrent CIP (rCIP) occurs, ICI therapy is usually terminated, resulting to treatment failure and tumour progression. The feasibility of multiple rechallenges with immunotherapy in patients with rCIP is unknow., Case Presentation: Two patients with refractory classical Hodgkin lymphoma (cHL) were treated with anti-programmed cell death protein 1 (PD-1) immunotherapy. The lymphoma responded well to the ICI therapy, but both patients experienced CIP. The immunotherapy was suspended and steroid was introduced to treated the CIP. When the CIP resolved, however, the lymphoma progressed., Management and Outcome: The patients were rechallenged with anti-PD-1 immunotherapy in the absence of alternative treatment options. The lymphoma responded again, but the CIP recurred. The immunotherapy was suspended again and steroid was reintroduced. These episodes repeated multiple times. At the time of submission of this manuscript, the tumour in both patients has been controlled for more than 4 years, and the immunotherapy is still continuing., Conclusion: Multiple rechallenges with immunotherapy is feasible in selected patients with rCIP.

We compared secondary primary malignancy risk (SPM) in HIV-uninfected and HIV-infected Hodgkin lymphoma (HL) survivors. We used data from the California Cancer Registry on patients diagnosed with HL from 1990 to 2015 (all ages included), and standardized incidence ratios (SIRs) and multivariable competing risk models for analyses. Of 19,667 survivors, 735 were HIV-infected. Compared with the general population, the risk of SPM was increased by 2.66-fold in HIV-infected and 1.92-fold in HIV-uninfected survivors. Among HIV-infected survivors, median time to development of SPM was shorter (5.4 years) than in HIV-uninfected patients (8.1 years). Additionally, the highest risk of SPM was observed <2 years after diagnosis in HIV-infected survivors (SIR = 4.47), whereas risk was highest ≥20 years after diagnosis (SIR = 2.39) in HIV-uninfected survivors. The risk of SPMs persisted for decades and was higher among HIV-infected survivors, suggesting that these patients should benefit from long-term surveillance and cancer prevention practices.

Thyroid abnormalities are well reported following childhood treatment for Hodgkin Lymphoma (HL). Limited information exists for adult patients and after modern treatments. We analyzed risks of thyroid disorders in 237 female participants treated at the Royal Marsden Hospital 1970-2015. Multivariable analyses of risk according to treatment and time-related factors, survival analyses, and Cox regression modeling were undertaken. Overall, 33.8% of patients reported thyroid disorders (hypothyroidism 30.0% and thyroid nodules 6.8%). Cumulative prevalence was 42.9% by 40 years follow-up. Risks were greatest after supradiaphragmatic radiotherapy (RR = 5.0, p  < 0.001), and increasing dose (RR = 1.03/Gy, p  < 0.001). There was no association with a chemotherapy agent. Risks of thyroid disease were as raised following adult as childhood treatment. There was no trend in risk by decade of supradiaphragmatic radiotherapy treatment. Risks of thyroid disease after supradiaphragmatic radiotherapy are as great after adult as childhood treatment and persist after more recent treatment periods.

Richter syndrome (RS) represents the development of high-grade lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and presents a diagnostic and therapeutic challenge with an adverse prognosis. The genetic background and morphology of RS in CLL patients treated with chemoimmunotherapy is extensively characterised; however, our knowledge about RS in patients treated with targeted oral therapies should be extended. To understand the morphologic and molecular changes leading to RS in CLL patients treated with the Bruton's tyrosine kinase inhibitor, ibrutinib, and the BCL2 inhibitor, venetoclax, sequential samples from six CLL/SLL patients undergoing RS were collected in both the CLL and RS phases. A detailed immunophenotypic analysis of formalin-fixed, paraffin-embedded tissue specimens of RS phase was performed, followed by extensive molecular characterisation of CLL and RS samples, including the immunoglobulin heavy chain gene (IGH) rearrangement, TP53 mutations, drug-induced resistance mutations in BTK and BCL2 genes and various copy number changes and point mutations detectable with multiplex ligation-dependent probe amplification (MLPA). Rare, non-diffuse large B-cell lymphoma phenotypes of RS were observed in 3/6 cases, including plasmablastic lymphoma and a transitory entity between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. The majority of cases were clonally related and harboured an unmutated variable region of the immunoglobulin heavy chain gene. Abnormalities affecting the TP53 gene occurred in all patients, and every patient carried at least one genetic abnormality conferring susceptibility to RS. In the background of RS, 2/5 patients treated with ibrutinib showed a BTK C481S resistance mutation. One patient developed a BCL2 G101V mutation leading to venetoclax resistance and RS. In conclusion, our findings contribute to better understanding of RS pathogenesis in the era of targeted oral therapies. Rare phenotypic variants of RS do occur under the treatment of ibrutinib or venetoclax, and genetic factors leading to RS are similar to those identified in patients treated with chemoimmunotherapy. To our best knowledge, we have reported the first BCL2 G101V mutation in an RS patient treated with venetoclax., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Reinduction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second-line standard of care for transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high-dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant-eligible patients aged 18-60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase-I-part) was administered on day 0-13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end-point of computed tomography (CT)-based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT-based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end-point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Hodgkin's lymphoma (HL) survivors treated with abdominal radiotherapy and/or procarbazine have an increased risk of developing colorectal neoplasia., Aims: We evaluated the clinicopathological characteristics and risk factors for developing (advanced) neoplasia (AN) in HL survivors., Methods: In all, 101 HL survivors (median age 51 years, median age of HL diagnosis 25 years) underwent colonoscopy and 350 neoplasia and 44 AN (classified as advanced adenomas/serrated lesions or colorectal cancer), mostly right-sided, were detected, as published previously. An average-risk asymptomatic cohort who underwent screening colonoscopy were controls (median age 60 years). Clinicopathological characteristics of AN were evaluated in both groups. Mismatch repair (MMR) status was assessed using immunohistochemistry (MLH1/MSH2/MSH6/PMS2). Logistic regression analysis was performed to evaluate the risk factors for AN in HL survivors, including age at HL diagnosis and interval between HL and colonoscopy., Results: In 101 colonoscopies in HL survivors, AN was primarily classified based on polyp size ≥10 mm, whereas (high-grade)dysplasia was more often seen in AN in controls. An interval between HL diagnosis and colonoscopy >26 years was associated with more AN compared with an interval of <26 years, with an odds ratio for AN of 3.8 (95% confidence interval 1.4-9.1) (p < 0.01). All 39 AN that were assessed were MMR proficient., Conclusions: Colorectal neoplasia in HL survivors differ from average-risk controls; classification AN was primarily based on polyp size (≥10 mm) in HL survivors. Longer follow-up between HL diagnosis and colonoscopy was associated with a higher prevalence of AN in HL survivors., (© 2021 The Authors. Digestive Endoscopy published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET-2) tended to be more common (P = 0·1078). Five-year progression-free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49-1·47] and overall survival (HR = 0·85; 95% CI = 0·49-1·51) did not differ between the groups after study treatment with PET-2-guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET-2-guided escalated BEACOPP., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: The current study aimed to describe genotypes associated with Hodgkin lymphoma (HL) in a cohort of Saudi and non-Saudi patients and discuss their possible susceptibility to HL., Methods: We studied clinical, histopathological, and laboratory findings of HL patients admitted over 12 years duration, at King Fahd University Hospital, KSA. The genomic DNAs of HL patients (n = 61) and normal control subjects (n = 36) were extracted, and genotyping was performed using the Illumina human exome bead chip. Set of HL patients and set of normal controls were included in this study., Results: A total of 35 DNA variants were found to be highly significant with the P-value <9.90 × 10 -11 among 243 345 exonic biomarkers and obeying the Hardy-Weinberg equilibrium. Nine, MEGF11-rs150945752 (P-value 1.20 × 10 -12 ), CACNA1I- s58055559 (P-value 1.93 × 10 -12 ), DECR2-rs146760080 (P-value 2.19 × 10 -12 ), STAB1-rs143894786 (P-value 2.45 × 10 -12 ), ZNF526-rs144433879 (P-value 2.76 × 10 -12 ), CPLANE1-rs200612080 (P-value 3.77 × 10 -12 ), DLK1-rs1058009 (P-value 5.95 × 10 -12 ), RTN4RL2-rs61745214 (P-value 7.71 × 10 -12 ), and PGRMC1-rs145582672 (P-value 8.56 × 10 -12 ), exonic variants on chromosomes 15, 22, and 16 were highly associated with HL cases. THE HIGHLY SIGNIFICANT HAPLOTYPES AT CHROMOSOME 3: rs143894786G; rs149982219G with P-value = 3.43 × 10 -14 was found to be the risk haplotype for the HL patients. The opposite alleles at chromosome 3: rs143894786A; rs149982219G is protective with P-value = 2.46 × 10 -12 . Maximum number of SNPs at the chromosome 19: rs144433879C; rs181265966G; rs201144421C; rs145591797G; rs200560875G; rs77270337G (risk P-value = 2.24 × 10 -12 ) and its opposite allele rs144433879A; rs181265966A; rs201144421T; rs145591797A; rs200560875A; rs77270337A (protective P-value = 2.60 × 10 -9 ) were found to be associated haplotype with the HL and controls, respectively, in Saudi population., Conclusion: Our study concludes that the HL is genetically heterogeneous with multigene causation., (© 2021 John Wiley & Sons Ltd.)

Posttransplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases with abnormal proliferation of lymphoid tissue and classical Hodgkin lymphoma (CHL) type PTLD is a very rare subtype. We describe a successfully diagnosed and treated CHL-PTLD stage IV pediatric patient, 8 years after liver transplantation. The patient was treated with standard CHL (Children's Cancer Group 5942 group 3) chemotherapy, rituximab and reduction of immunosuppressant. The patient remains in complete remission after 3 years with stable graft function. To our best knowledge, this is the first pediatric case report of a successfully treated stage IV CHL-PTLD after a liver transplant., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: The etiology of Hodgkin lymphoma (HL) is obscure. Research on air pollution and risk of HL provides inconsistent results. We aimed to investigate the association between long-term residential exposure to air pollution and risk of adult Hodgkin lymphoma in Denmark., Methods: We performed a nationwide register-based case-control study, including all (n = 2,681) Hodgkin lymphoma cases registered in the nationwide Danish Cancer Registry between 1989 and 2014. We randomly selected 8,853 age- and sex-matched controls from the entire Danish population using the Civil Registration System, and identified 20-year residential address history for all cases and controls. We modeled outdoor air pollution concentrations at all these addresses using the high-resolution multiscale air pollution model system DEHM/UBM/AirGIS. We used conditional logistic regression to estimate odds ratios adjusted for individual and neighborhood level sociodemographic variables., Results: There was no association between 1, 5, 10, and 20 years' time-weighted average exposure to fine particles (PM 2.5 ), O 3 , SO 2, NO 2, or the PM 2.5 constituents OC, NH 4 , NO 3 , and SO 4 and risk of Hodgkin lymphoma., Conclusion: Residential exposure to ambient air pollution does not seem to increase the risk of developing Hodgkin lymphoma., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Richter transformation (RT) is the development of aggressive lymphoma - most frequently diffuse large B-cell lymphoma (DLBCL) and rarely Hodgkin lymphoma (HL) - arising on the background of chronic lymphocytic leukaemia (CLL). Despite recent advances in CLL treatment, RT also develops in patients on novel agents, usually occurring as an early event. RT incidence is lower in CLL patients treated with novel agents in the front line compared to relapsed/refractory cases, with a higher incidence in patients with TP53 disruption. The genetic heterogeneity and complexity are higher in RT-DLBCL than CLL; the genetics of RT-HL are largely unknown. In addition to TP53, aberrations in CDKN2A, MYC, and NOTCH1 are common in RT-DLBCL; however, no distinct RT-specific genetic aberration is recognised yet. RT-DLBCL on ibrutinib is frequently associated with BTK and PLCG2 mutations. Here, we update on genetic analysis, diagnostics and treatment options in RT in the era of novel agents., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with prostate cancer (PC) are at a high risk of developing secondary hematologic malignancies (SHMs) after radiation therapy (RT), while no study has assessed the relationship of different treatment modalities with the occurrence of SHMs after PC at early stage. This study aimed to investigate the risks of developing SHMs in patients with T1/T2 PC undergoing different treatment modalities., Methods: Patients with T1/T2 PC were identified from the Surveillance, Epidemiology, and End Results database. Competing risk regression (CRR) model was performed to evaluate the hazard ratios (HRs) of developing SHMs. As SHMs scarcely occur, the relative risk (RR) analysis was employed to compare the risks of different treatment modalities associating with the development of SHMs., Results: The CRR analysis showed that undergoing RT was associated with a higher risk of developing SHMs (external beam radiation therapy [EBRT]: HR = 1.21, 95% confidence interval [CI]: 1.10-1.34; radioactive implant [RI]: HR = 1.20, 95% CI: 1.06-1.36). As for different types of SHMs, EBRT, and RI were correlated with decreased risks of developing CLL (RR = 0.67, 0.72; 95% CI: 0.53-0.85, 0.54-0.96, respectively), but with the increased risks of developing NHL (RR = 1.18, 1.23; 95% CI: 1.02-1.35, 1.05-1.44, respectively); EBRT also showed increased risks of developing acute/ chronic myeloid leukemia (AML/CML, RR = 1.54, 1.56; 95% CI: 1.16-2.03,1.05-2.33, respectively); No increased risk of developing SHMs was detected in patients who only underwent prostatectomy., Conclusions: Although RT was found to be associated with the increased risks of developing SHMs in patients with T1/T2 PC, this finding cannot be extended to diverse types of SHMs. RT was correlated with the increased risks of the development of NHL, AML, and CML, but with the decreased risk of developing CLL. Prostatectomy did not increase the risk of developing SHMs., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The study investigated pretreatment Epstein-Barr virus (EBV) DNA status and its prognostic values in 96 patients newly diagnosed Hodgkin lymphoma (HL). With 13.5 % patients in positive EBV DNA status before therapy, the positive group had inferior progression-free survival (PFS) (P = 0.023) as well as overall survival (OS) (P = 0.001). Pretreatment EBV DNA positivity was observed as an independent prognostic factor in OS (P = 0.036) while a trend to predict PFS (P = 0.064). By monitoring changes of EBV DNA copies in 13 patients with positive pretreatment EBV DNA status, 5 of 6 patients with complete response (CR) had their copies undetectable after 3 cycles of first-line treatment and 7 patients with progressive disease (PD) all had elevated EBV DNA copies during their relapsed period. Whole blood EBV DNA may be an adjunctive biomarker to reflect treatment response, risk of disease relapse as well as prognosis in HL patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction : Hodgkin lymphoma (HL) can occur in different host conditions, i.e. in the general population and immunocompromised individuals, either during HIV infection or solid organ/hematopoietic transplantation and immunosuppressive drug treatment. Areas covered : Areas covered include multidimensional characteristics of tumor cells and cellular composition of tumor microenvironment of HL. Current conventional treatments and new treatment strategies for HL in immunosuppressed patients, especially in persons living with HIV (PLWH), are also discussed.PubMed and MEDLINE were used for database searches to identify articles in English published from 1989 to 2020. Expert opinion : For people with post-transplant HL or for those with HIV/AIDS-associated HL, standard treatments mirror those in the general population. In the last decade, the combination of cART with anti-neoplastic treatments, alongside with current anti-rejection therapies, has increased long-term survival of people with HL and acquired immune deficiencies. High-dose chemotherapy and autologous stem cell transplantation have been favorably proven as salvage therapy in PLWH with relapsed and refractory HL. Immune checkpoint inhibitors emerged as an area of clinical investigation for relapsed and refractory HL in the general population. Pembrolizumab, an anti-programmed cell death protein 1 (PD-1) drug, resulted safe in PLWH indicating that PD-1 ligand assessment should be advisable in HIV-associated HL.

Background: The incidence of cancer is higher in transplant patients than in the normal population, mostly due to the assumption of immunosuppressants able to reduce the possibility of rejection. In addition, immunocompromised patients have a greater susceptibility to EBV, HPV and HIV, infectious agents that by themselves may favor the onset of malignancies. Post-transplant lymphoproliferative diseases (PLDs) are among the most frequent neoplasms in transplant patients which like other aggressive neoplasms may be identified by the [18f] fluoro-D-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT)., Methods: We evaluated the clinical use of FDG-PET/CT in detecting PTLDs and other neoplasms performed at the lowest clinical or laboratory suspicion of malignancy in 127 consecutive subjects who underwent heart transplantation., Results: A SUV>4 more confirmed the suspect of malignancy and induced us to further investigations. Of the 127 transplant subjects who underwent FDG-PET/CT, 64 showed a SUV value >4. Of these 64, 8 had PTLDs, 49 other neoplasms (urinary tract tumors, thyroid cancer, HPV cancer related, Kaposi' sarcoma and EBV related head and neck neoplasms) and 7 patients with chronic non-neoplastic inflammatory diseases., Conclusions: In the present study, FDG-PET/CT examination was of great use for an early identification and for an early treatment of PTLDs and other neoplasms.

Purpose: Programmed death-1 (PD-1) blockade monotherapy is effective in relapsed/refractory classical Hodgkin lymphoma (cHL), but a subset of patients is recalcitrant to PD-1 inhibitors and only a minority of patients achieves durable remission. Effective treatment regimens for those with relapsed/progressive cHL after single-agent anti-PD-1 are urgently needed. Anti-PD-1 combination with the DNA-demethylating agent decitabine showed positive preliminary results in our test cohort patients who were resistant to anti-PD-1. Here, we assess the efficacy of decitabine plus anti-PD-1 therapy in an expansion cohort and after longer follow-up., Patients and Methods: We present the response and progression-free survival rates from patients with relapsed/refractory cHL who relapsed/progressed after prior anti-PD-1 monotherapy, and who received decitabine (10 mg/day, days 1-5) plus the anti-PD-1 camrelizumab (200 mg, day 8), every 3 weeks in a phase II trial (ClinicalTrials.gov: NCT02961101 and NCT03250962)., Results: Overall, 51 patients (test cohort: 25, expansion cohort: 26) were treated and 50 evaluated for efficacy. The objective response rate was 52% [nine complete responses (CR); 36%] in the test cohort, and 68% (six CRs; 24%) in the expansion cohort. Median progression-free survival with decitabine plus camrelizumab was 20.0 and 21.6 months, respectively, which was significantly longer than that achieved with prior anti-PD-1 monotherapy. Durable response was observed in an estimated 78% of patients who achieved CR at 24 months. After decitabine plus camrelizumab, the ratio increase of circulating peripheral central memory T cells directly correlated with both clinical response and progression-free survival., Conclusions: Decitabine plus camrelizumab is associated with high response rates and long-term benefits in patients with relapsed/refractory cHL who failed PD-1 inhibitors., (©2021 American Association for Cancer Research.)

Purpose: Several observational studies have shown contradictory results regarding the association between sunlight exposure and the risk of malignant lymphoma. Thus, we aimed to systematically determine the association between sunlight exposure and lymphoid malignancy risk through a meta-analysis., Methods: A thorough search of four electronic databases (PubMed, Embase, Web of Science, and Scopus) was performed to identify eligible studies until 13 August 2020. A random-effects model was used to calculate risk estimates of sunlight exposure. The main outcome measure was the risk of lymphoid malignancy subtypes with odds ratios (ORs) and 95% confidence intervals (CIs) according to various forms of solar ultraviolet radiation., Results: In total, 17 case-control studies and 9 cohort studies including 216,285 non-Hodgkin lymphoma (NHL) and 23,017 Hodgkin's lymphoma (HL) patients were included in the final analysis. Personal sunlight exposure was significantly associated with a decreased risk of HL (OR 0.77; 95% CI 0.68-0.87) and NHL (OR 0.81; 95% CI 0.71-0.92), including all subtypes except T-cell lymphoma. Ambient sunlight exposure at residence was associated with a reduced risk of HL (OR 0.88; 95% CI 0.81-0.95) and all NHL subtypes (OR 0.84; 95% CI 0.73-0.96), except for chronic lymphocytic leukemia/small lymphocytic lymphoma. As the number of sunburns and sunbaths increased, the risk of NHL tended to decrease., Conclusion: While there was an observed protective effect both from case-control and prospective studies, substantial heterogeneity was found in the current study. Thus, more evidence is required to confirm that promoting sunlight exposure can prevent the development of lymphoid neoplasia.

Classical Hodgkin lymphoma (cHL) is unique among lymphoid malignancies in several key biological features. (i) The Hodgkin and Reed-Sternberg (HRS) tumor cells are rare among an extensive and complex microenvironment. (ii) They derive from B cells, but have largely lost the B-cell typical gene expression program. (iii) Their specific origin appears to be pre-apoptotic germinal center (GC) B cells. (iv) They consistently develop bi- or multinucleated Reed-Sternberg cells from mononuclear Hodgkin cells. (v) They show constitutive activation of numerous signaling pathways. Recent studies have begun to uncover the basis of these specific features of cHL: HRS cells actively orchestrate their complex microenvironment and attract many distinct subsets of immune cells into the affected tissues, to support their survival and proliferation, and to create an immunosuppressive environment. Reed-Sternberg cells are generated by incomplete cytokinesis and refusion of Hodgkin cells. Epstein-Barr virus (EBV) plays a major role in the rescue of crippled GC B cells from apoptosis and hence is a main player in early steps of lymphomagenesis of EBV + cHL cases. The analysis of the landscape of genetic lesions in HRS cells so far did not reveal any highly recurrent HRS cell-specific lesions, but major roles of genetic lesions in members of the NF-κB and JAK/STAT pathways and of factors of immune evasion. It is perhaps the combination of the genetic lesions and the peculiar cellular origin of HRS cells that are disease defining. A combination of such genetic lesions and multiple cellular interactions with cells in the microenvironment causes the constitutive activation of many signaling pathways, often interacting in complex fashions. In nodular lymphocyte predominant Hodgkin lymphoma, the GC B cell-derived tumor cells have largely retained their typical GC B-cell expression program and follicular microenvironment. For IgD-positive cases, bacterial antigen triggering has recently been implicated in early stages of its pathogenesis.

Objective: The purpose of this study was to analyse the clinical and pathological characteristics, treatments and outcomes of post-transplant lymphoproliferative disorder (PTLD) in paediatric liver transplant recipients., Method: A retrospective analysis of records from nine paediatric liver transplant recipients with PTLD who were treated at our Liver Transplant Center over the period from June 2013 to August 2018., Result: Of these nine patients, seven received liver transplantation in our centre and the remaining two patients at other hospitals. The overall incidence of PTLD in paediatric liver transplant recipients in our centre was 1.4% (7/485). The median onset of PTLD after liver transplantation was 11 months. Three cases were classified as infectious mononucleosis PTLD, one case was plasmacytic hyperplasia PTLD, one case was polymorphic PTLD and two cases were Burkitt lymphoma. One case showed diffuse large B-cell lymphoma and one was classical Hodgkin lymphoma-like PTLD. These patients presented with different clinical manifestations including fever, anaemia, diarrhoea, hypoproteinaemia, enlargement of lymph nodes, hepatosplenomegaly, jaundice, bowel obstruction and even intestinal perforation. Nine patients were positive for EBV-DNA in serum. After diagnosis, immunosuppressants were reduced or discontinued in all cases. Eight patients received anti-CD20 monoclonal antibody (Rituximab) therapy, four cases were treated with a combination of chemotherapy (R-CHOP, ABVD, COPP/ABV) and one case was combined with radiotherapy. Two cases received surgical treatment due to bowel obstruction. Eight of these patients achieved a complete remission and remained healthy when assessed at the time of final follow-up. One patient died as a result of PTLD progression., Conclusion: PTLD is one of the most serious and fatal complications after liver transplantation. The definitive diagnosis requires histopathology. Treatment varies and basically includes immunosuppression reduction, anti-CD20 antibody, surgery, radiotherapy and chemotherapy., (© 2020 John Wiley & Sons Ltd.)

Introduction: Post-transplant lymphoproliferative disease (PTLD), a lymphoid proliferation observed after the solid organ transplantation or allogeneic stem cell transplant, is an important and mortal complication that can occur during the post-transplant period. Classical Hodgkin lymphoma-like PTLD is the least form of PTLD. We are presenting an adult case of classical Hodgkin lymphoma-like PTLD which was successfully treated with nivolumab., Case Report: A 31-year-old female was diagnosed with primary myelofibrosis and we performed allogeneic stem cell transplantation from her HLA fully matched brother in 2015. Two years after transplant, classical Hodgkin lymphoma-like PTLD was diagnosed. The patient was resistant to six cycles of ABVD chemotherapy and four cycles of brentuximab vedotin., Management and Outcome: After the failure of ABVD and brentuximab vedotin, we started nivolumab therapy at a dose of 3 mg/kg every 2 weeks. After six cycles, we achieved a PET negative complete remission. After 10 cycles of nivolumab, the patient is still followed with a complete remission. Still, there is no evidence of acute or chronic GvHD, and therefore no need for immunosuppressive treatment. No auto-immune complication was observed. It is planned to give nivolumab treatment to the patient until the progression., Discussion: Our case has depicted that the classical Hodgkin lymphoma type PTLD may be resistant to the conventional treatments and anti-CD30 brentuximab vedotine. In such cases, nivolumab may be an effective and worth assessing agent in terms of both activity and safety profile.

Neoplastic programmed cell death ligand 1 (PD-L1) expression, activated by PD-L1 gene alterations, is strongly associated with classic Hodgkin lymphoma (CHL). This association enabled a diagnostic consensus for lymphocyte-depleted CHL (LD-CHL), a previously enigmatic disease. We describe two patients with LD-CHL and primary extranodal disease. One patient was a 92-year-old female (Case #1) with a large mass that involved the uterus combined with swollen lymph nodes in the pelvic cavity. The second patient was a 76-year-old female (Case #2) with human T-cell leukemia virus type 1 (HTLV-1) who initially exhibited massive bone marrow involvement without peripheral lymphadenopathies. Biopsies of these tumors from the cervix uteri and bone marrow, respectively, revealed lesions rich in Hodgkin and Reed-Sternberg (H-RS) cells and diminished populations of other cell populations. Immunohistochemistry demonstrated that these H-RS cells expressed CD30, BOB1, and fascin, but not CD15, CD20, PAX5, or OCT2. They also expressed PD-L1, which led to our preferred diagnosis of LD-CHL in both patients. Epstein-Barr virus was associated with LD-CHL in Case #1, but not in Case #2. Both patients were deemed too frail for treatment. They died of disease at 1 (Case #1) and 15 months (Case #2) after the diagnosis. These findings highlight the abnormal biological behavior of this immune-escape-related lymphoid neoplasm in patients with immunodeficiency due to immune senescence and HTLV1 infection.

Our understanding of the tumorigenesis of classical Hodgkin lymphoma (cHL) and the formation of Reed-Sternberg cells (RS-cells) has evolved drastically in the last decades. More recently, a better characterization of the signaling pathways and the cellular interactions at play have paved the way for new targeted therapy in the hopes of improving outcomes. However, important gaps in knowledge remain that may hold the key for significant changes of paradigm in this lymphoma. Here, we discuss the past, present, and future of cHL, and review in detail the more recent discoveries pertaining to genetic instability, anti-apoptotic signaling pathways, the tumoral microenvironment, and host-immune system evasion in cHL.

Background: Thrombosis increase the acute and long-term morbidity and mortality in malignancy patients. We analyzed venous thromboembolism (VTE) in patients with Hodgkin lymphoma, the impact of VTE on survival, predisposing factors for VTE, and predicting value of Khorana and ThroLy score models., Patients and Methods: We included 150 adult patients with Hodgkin lymphoma between January 2010 and 2018 at our university hospital., Results: VTE was observed in 31 patients (20.7%). The types of VTE were 18 upper and 3 lower extremity deep vein thrombosis and 10 pulmonary embolism (1 with lower extremity deep vein thrombosis). Twenty-nine patients developed VTE during the treatment with a median time of episode as 5 months. In logistic regression analysis, a body mass index of >32 kg/m 2 , high fibrinogen levels, initial thrombocytosis and leukocytosis, splenic and extranodal involvement, presence of a central venous line, advanced stage, line of treatment status of thromboprophylaxis, VTE timing, and better Eastern Cooperative Oncology Group performance scores were observed to be related with VTE. Kaplan Meier survival analysis showed a negative impact of VTE on survival. Khorana and ThroLy risk assessment models were found predictive for VTE (P = .000 and P = .003, respectively), although only ThroLy score was associated with the survival., Conclusion: Thromboprophylaxis and precautions for VTE in patients with Hodgkin lymphoma according to validated risk assessment models can improve prognosis and quality of life owing to the impact of VTE on survival in the study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Epstein Barr Viral infection is a common childhood infection in India and is also nearly 100 % etiologically associated with pediatric Hodgkin Lymphoma (HL). The main question in EBV immunobiology has been, why only a small subset of infected individuals develop EBV associated malignancies, while the vast majority carry this virus asymptomatically for life. Natural Killer (NK) cells, with a phenotype of CD56dim CD16+ exhibit potent cytotoxicity towards both virus infected cells and transformed cells and hence have been considered to be crucial in preventing the development of symptomatic EBV infection and lymphoma. In order to get an insight into the various possible molecular aspects of NK cells, in the pathogenesis of both these EBV mediated diseases in children we studied the whole transcriptome of MACS sorted CD56dim CD16 + NK cells from four patients from each of the three groups of children viz. Infectious Mononucleosis (IM), HL and age matched controls by using a massively parallel sequencing approach. NK cells from both IM and HL had down-regulated innate immunity and chemokine signaling genes. While down-regulation of genes responsible for polarization of the secretory apparatus, activated NK cell signaling and MAP kinase signaling were exclusive to NK cells in patients with IM, in NK cells of HL, specifically, genes involved in extracellular matrix (ECM) - receptor interaction, cytokine-cytokine receptor interaction, TNF signaling, Toll-like receptor signaling pathway and cytosolic DNA-sensing pathways were significantly down-regulated. Enrichment analysis showed STAT3 to be the most significant transcription factor (TF) for the down-regulated genes in IM, whereas, GATA1 was found to be the most significant TF for the genes down-regulated in HL. Analysis of protein interaction network identified functionally important protein clusters. Top clusters, comprised of down-regulated genes, involved in signaling and ubiquitin-related processes and pathways. These may perhaps be responsible for the hypo-responsiveness of NK cells in both diseases. These possibly point to different deficiencies in NK cell activation, loss of activating receptor signaling and degranulation in IM, versus loss of cytokine and chemokine signaling in HL, in the two EBV associated pathologies investigated. Various suppressed molecules and pathways were novel, which have not been reported earlier and could therefore be potential targets for immunotherapy of NK cell reactivation in both the diseases in future., Competing Interests: Declaration of Competing Interest AKK was also the founder director of a private limited company, Shodhaka Life Sciences Pvt. Ltd., during the research period, and DS was an employee of that company. Anup Chugani, Vishnu Priya R are employees of a private company Medgenome. Declaration of interest for other authors – none., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Opinion Statement: Older adults with Hodgkin lymphoma (HL), commonly defined as age ≥ 60 years, represent approximately 20% of the total HL population. Historically, they have significantly inferior outcomes compared with younger patients. The cause of this is multifactorial, including biologic differences (e.g., mixed cellularity and EBV-related disease); high incidence of advanced stage disease; and frequency of comorbidities and decreased organ reserve leading to poorer tolerability of therapy with increased toxicity, including treatment-related mortality. Pretreatment evaluation for older HL patients should entail a geriatric assessment (GA), with evaluation of functional status and comorbidities (e.g., geriatric cumulative illness rating scale, CIRS-G) to determine fitness. Furthermore, treatment selection should be based in part on GA, with fit older patients receiving curative chemotherapy-based regimens and unfit or frail patients considering less intensive or non-chemotherapy-based platforms. Additionally, there may be consideration for pre-phase of therapy (e.g., pulse steroids) in order to improve performance status. The inclusion of anthracycline therapy appears important, while bleomycin-containing regimens (e.g., ABVD) may be associated with prohibitive pulmonary toxicity, and intensive therapies such as BEACOPP are too toxic. benefit ratio/benefit ratio, a priori omission of bleomycin may also be considered (i.e., AVD), especially for patients older than 70 years of age. In addition, newer regimens for older HL patients integrating novel therapeutic agents into frontline treatment have emerged as effective and tolerable options. Data incorporating brentuximab vedotin sequentially before and after AVD chemotherapy represent the best-reported outcomes in older HL patients to date. In the relapsed/refractory setting, salvage chemotherapy regimens followed by autologous stem cell transplantation should be considered for fit patients, while less intensive treatment, including the use of novel targeted agents, is an option for unfit or frail patients. In this review, we examine the epidemiology, importance of GA, and current treatment options for older HL patients.

Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft-versus-host disease., (© 2019 Wiley Periodicals, Inc.)

Objectives: A treatment regimen consisting of bendamustine and brentuximab vedotin (BV) has been described as a highly potent salvage therapy and as an effective induction therapy leading to high response rates before autologous stem cell transplantation (ASCT) in patients with classical Hodgkin lymphoma (cHL). In this retrospective analysis, we aimed to assess this therapy's efficacy in unselected patients with cHL and CD30+ peripheral T-cell lymphoma (PTCL)., Patients and Methods: Data of 28 patients with cHL and five patients with PTCL treated with a combination of bendamustine and BV at three Austrian tertiary cancer centers were analyzed., Results: In patients with cHL, the ORR was 100% (78.6% CR, 21.4% PR). After 17 months median follow-up, median survival times were not reached; 1-year PFS was 81.9%, and 1-year OS was 95.7%. Thirteen eligible patients (46.4%) successfully underwent planned ASCT after salvage therapy with bendamustine and BV and subsequent high-dose chemotherapy. Three of the five PTCL patients achieved CR, while two did not respond and died during or shortly after therapy., Conclusion: A combination of bendamustine and BV is an effective salvage and induction therapy before ASCT in patients with relapsed/refractory cHL. Further research is warranted to evaluate the use in patients with PTCL., (© 2019 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Introduction: Chronic infections and infestations represent one of the leading causes of cancer. Eleven agents have been categorized by the International Agency for Research on Cancer (IARC) in Group 1, 3 in Group 2A and 4 in Group 2B. We previously estimated that the incidence of cancers associated with infectious agents accounted for the 8.5% of new cancer cases diagnosed in Italy in 2014., Methods: In the present study we evaluated the incidence of cancer in Italy and in the 20 Italian regions in 2018, based on the data of Cancer Registries, and calculated the fraction attributable to infectious agents., Results: Cancers of infectious origin contributed to the overall burden of cancer in Italy with more than 27,000 yearly cases, the 92% of which was attributable to Helicobacter pylori, human papillomaviruses, and hepatitis B and C viruses. With the exception of papillomavirus-related cancers, the incidence of cancers of infectious origin was higher in males (16,000 cases) than in females (11,000 cases). There were regional and geographical variations of cancers depending on the type of cancer and on the gender. Nevertheless, the overall figures were rather similar, the infection-related cancers accounting for the 7.2, 7.6, and 7.1% of all cancers in Northern, Central, and Southern Italy, respectively., Conclusions: The estimate of the incidence of cancers attributable to infectious agents in Italy in 2018 (7.3% of all cancer cases) is approximately half of the worldwide burden, which has been estimated by IARC to be the 15.4% of all cancer cases in 2012., (©2019 Pacini Editore SRL, Pisa, Italy.)

Background/aim: Hodgkin's lymphoma (HL) accounts for 1% of cancers and is of largely unknown pathogenesis. This study intended to find clues about potential causes (etiology) of HL through observations on patients and their families., Patients and Methods: In 37 years of a medical oncology practice in Basel, Switzerland, 36 out of 2201 patients (1.6%) had HL. Etiological information has been obtained from the patients with the help of a German translation of the NCI Medical History Questionnaire for Cancer Etiology, and through the study of their medical charts., Results: Findings of etiological interest were observed in the medical history of 26 out of the 36 patients with HL; these findings were grouped as follows: benign tumors (25%), carcinogenic exposures (19%), immunologic disorders (19%), secondary malignancies (14%), infections (11%), congenital disorders (8%) and tonsillectomies (6%). Twenty-two out of 36 patients had one or more relatives with cancer., Conclusion: Personal and family history of patients with HL is a readily available useful tool for etiology research. The fact that HL is frequently associated with other cancers in patients and their relatives points to causal genetic factors., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to Hodgkin lymphoma (HL) is a rare and unexpected event in the course of the disease and data on this phenomenon is still limited. To better understand the clinical and histological characteristics and the outcomes of HL variant of RT (HvRS) the Polish Lymphoma Research Group performed a nationwide survey which identified 22 patients with histologically proven HvRS diagnosed between 2002 and 2016. There were 16 (73%) males. The median age at CLL/SLL and HvRS diagnosis was 59 (39-77) and 64 (40-77) years, respectively. The median interval between CLL/SLL and HvRS diagnosis was 38 months (range: 0-187). All patients had an advanced stage HL, and majority, 17 (77%), presented with B symptoms. The predominant subtypes of HL were nodular sclerosis (12; 55%) and mixed cellularity (9; 41%). Eighteen patients received non-palliative treatment, including 13 who received driamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen first line. Objective response was: 50%, with 33% complete remissions (61% and 46% for ABVD, respectively). Median overall survival reached 13.3 months (95% CI, 3.7-NA). The only adverse prognostic factor for survival was a higher number (≤1 versus ≥2) of prior lines of treatment given for CLL/SLL with HR 3.57 (95% CI, 1.16-10.92). We conclude, HvRS harbors a poor prognosis, especially in patients heavily pretreated for CLL/SLL. Response to standard first-line anti-HL chemotherapy is unsatisfactory, and new agents should be tested to improve the outcome., (© 2019 John Wiley & Sons, Ltd.)

The microenvironment in classical Hodgkin lymphoma (cHL) comprises a mixture of different types of cells, which are responsible for lymphoma pathogenesis and progression. Even though microenvironment composition in adult cHL has been largely studied, only few groups studied pediatric cHL, in which both Epstein Barr virus (EBV) infection and age may display a role in their pathogenesis. Furthermore, our group described that EBV is significantly associated with cHL in Argentina in patients under the age of 10 years old. For that reason, our aim was to describe the microenvironment composition in 46 pediatric cHL patients. M1-like polarization status prevailed in the whole series independently of EBV association. On the other hand, in children older than 10 years, a tolerogenic environment illustrated by higher FOXP3 expression was proved, accompanied by a macrophage polarization status towards M2. In contrast, in children younger than 10 years, M1-like was prevalent, along with an increase in cytotoxic GrB+ cells. This study supports the notion that pediatric cHL exhibits a particular tumor microenvironment composition.