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Summary: Late toxicities can impact survivorship in patients with classical Hodgkin lymphoma (cHL) with pulmonary toxicity after bleomycin‐containing chemotherapy being a concern. The incidence of pulmonary diseases was examined in this Danish population‐based study. A total of 1474 adult patients with cHL treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, vincristine, etoposide, doxorubicin, cyclophosphamide, procarbazine and prednisone) between 2000 and 2018 were included along with 7370 age‐ and sex‐matched comparators from the background population. Median follow‐up was 8.6 years for the patients. Patients with cHL had increased risk of incident pulmonary diseases (HR 2.91 [95% CI 2.30–3.68]), with a 10‐year cumulative risk of 7.4% versus 2.9% for comparators. Excess risks were observed for interstitial lung diseases (HR 15.84 [95% CI 9.35–26.84]) and chronic obstructive pulmonary disease (HR 1.99 [95% CI 1.43–2.76]), with a 10‐year cumulative risk of 4.1% and 3.5% respectively for patients. No excess risk was observed for asthma (HR 0.82 [95% CI 0.43–1.56]). Risk factors for interstitial lung diseases were age ≥60 years, the presence of B‐symptoms and low albumin. These findings document a significant burden of pulmonary diseases among patients with cHL and emphasize the importance of diagnostic work‐up of pulmonary symptoms. [ABSTRACT FROM AUTHOR]

Summary: We analysed a large cohort of Hodgkin lymphoma (HL) patients in order to characterize: (1) the pattern of late recurrence of lymphoid malignancies (LR) after initial treatment for HL over a 35‐year period; (2) the clinicopathological parameters influencing the risk of LR; and (3) the outcome of patients experiencing LR. We reviewed data of 3350 HL patients diagnosed in Denmark between 1982 and 2018 and registered in the Danish National Lymphoma Registry (LYFO). LR was defined as a recurrence of lymphoid malignancy at least five years after initial diagnosis. LR occurred in 58 patients, with a cumulative incidence at 10, 15 and 20 years of 2.7%, 4.0% and 5.4% respectively. LR was more frequently observed in patients with nodular lymphocyte‐predominant HL (NLPHL) [hazard ratio (HR) 4.5; 95% confidence interval (CI): 2.4–8.4, p < 0.001]. In classical HL (cHL) patients, older age and lymphocytopenia were risk factors for LR with HRs of 1.04 per additional year (95% CI: 1.02–1.06) and 5.6 (95% CI: 2.7–11.5) respectively. Mixed cellularity histological subtype was a risk factor for LR, but only in females, with a HR of 5.4 (95% CI: 1.4–20.4, p = 0.014). In contrast to what was observed in NLPHL, LR in cHL was associated with an almost threefold increased risk of death compared with patients in continuous complete remission. Approximately one fifth (22.4%) of patients with LR experienced a second relapse. [ABSTRACT FROM AUTHOR]

Background: The programmed cell death protein 1 (PD‐1) and its ligand 1 and 2 (PD‐L1/PD‐L2) regulate the immune system, and the checkpoint pathway can be exploited by malignant cells to evade anti‐tumor immune response. Soluble forms (sPD‐1/sPD‐L1/sPD‐L2) exist in the peripheral blood, but their biological and clinical significance is unclear. Method: Time‐resolved immunofluorometric assay (TRIFMA) and enzyme‐linked immunosorbent assay (ELISA) were used to measure sPD‐1, sPD‐L1, and sPD‐L2 levels in serum from 131 lymphoma patients and 22 healthy individuals. Results: Patients had higher sPD‐1 and sPD‐L2 levels than healthy individuals. In diffuse large B‐cell lymphoma, patients with high International Prognostic Index score had higher sPD‐1 levels and sPD‐L2 levels correlated with subtype according to cell of origin. Compared to other lymphoma types, follicular lymphoma displayed higher sPD‐1 and lower sPD‐L1 levels along with lower ligand/receptor ratios. Conclusion: This is the first study to simultaneously characterize pretherapeutic sPD‐1, sPD‐L1, and sPD‐L2 in a variety of lymphoma subtypes. The relation between higher sPD‐1 levels and adverse prognostic factors suggests a possible biological role and potential clinical usefulness of sPD‐1. Moreover, the reverse expression pattern in follicular lymphoma and T‐cell lymphoma/leukemia may reflect biological information relevant for immunotherapy targeting the PD‐1 pathway. [ABSTRACT FROM AUTHOR]

The burden of late effects among Hodgkin lymphoma (HL) survivors treated according to contemporary protocols remains poorly characterized. We used nation‐wide registers to assess number of inpatient bed‐days and specialist outpatient visits among 1048 HL‐patients (<25 years, diagnosed 1990‐2010) and 5175 country‐, sex‐, and age‐matched comparators. We followed them for up to 24 years, with time‐dependent assessment of relapse status. International Classification of Diseases (ICD‐10) chapter‐specific hazard ratios (HRs) were assessed in Cox regression analyses, and nonparametric statistics described patterns of health‐care‐use. Relative to comparators, relapse‐free survivors were at increased risk of infections, diseases of the blood, endocrine, circulatory and respiratory systems, and unspecific symptoms, HRs ranging from 1.86 to 3.05. Relative to comparators, relapsed survivors had at statistically significantly increased risk of diseases reflecting practically all investigated disease‐chapters, HRs ranging from 1.60 to 18.7. Among relapse‐free survivors, 10% of the patients accounted for 80% of all hospital bed days, and 55% were never hospitalized during follow‐up. Among relapsed‐survivors, 10% of the patients accounted for 50% of the bed days, and only 24% were never hospitalized during follow‐up. In contrast, 10% of the comparators accounted for 90% of hospital bed days and 75% were never hospitalized. These findings challenge the impression of a uniformly distributed long‐term morbidity among all HL survivors and emphasize the need for early identification and attention to patients particularly susceptible to late effects, such as relapsed survivors. [ABSTRACT FROM AUTHOR]

Summary: 18F‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography (FDG‐PET/CT) is used for staging classical Hodgkin lymphoma (cHL) with high sensitivity for skeletal involvement. However, it is unclear whether a single bone lesion carries the same adverse prognosis as multifocal lesions and if this is affected by type of chemotherapy [ABVD (adriamycin, bleomycin, vincristine, dacarbazine) versus BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone)]. We reviewed the clinico‐pathological and outcome data from 209 patients with newly diagnosed cHL staged by FDG‐PET/CT. Patterns of skeletal/bone marrow uptake (BMU) were divided into 'low' and 'high' diffuse BMU (i.e. without focal lesions), and unifocal or multifocal lesions. Additional separate survival analysis was performed, taking type of chemotherapy into account. Forty patients (19·2%) had skeletal lesions (20 unifocal, 20 multifocal). The 3‐year progression‐free‐survival (PFS) was 80% for patients with 'low BMU', 87% for 'high BMU', 69% for 'unifocal' and 51% for 'multifocal' lesions; median follow‐up was 38 months. The presence of bone lesions, both uni‐ and multifocal, was associated with significantly inferior PFS (log rank P = 0·0001), independent of chemotherapy type. Thus, increased diffuse BMU should not be considered as a risk factor in cHL, whereas unifocal or multifocal bone lesions should be regarded as important predictors of adverse outcome, irrespective of the chemotherapy regimen used. [ABSTRACT FROM AUTHOR]

The tumour microenvironment in classical Hodgkin's lymphoma ( cHL) is characterised by a minor population of neoplastic Hodgkin and Reed-Sternberg cells within a heterogeneous background of non-neoplastic bystanders cells, including mast cells. The number of infiltrating mast cells in cHL has been reported to correlate with poor prognosis. We used immunohistochemistry to assess the degree of tumour-infiltrating mast cells in cHL tissue microarrays and correlated this with clinico-pathological features and prognosis in a cohort of homogeneously treated patients with Hodgkin's disease. A high degree of tumour mast cells was associated with nodular sclerosis ( NS) subtype histology ( P = 0.0002). Moreover, the number of mast cells was inversely correlated with the numbers of CD68+ and CD163+ macrophages ( P = 0.0001 and P = 0.003, respectively) and with the number of granzyme+ cytotoxic cells ( P = 0.004). The degree of mast cell infiltration was not a prognostic factor in cHL of nodular sclerosis subtype. In contrast, in mixed cellularity cHL a high number of intratumoral mast cells correlated with significantly poorer outcome both in terms of overall ( P = 0.03) and event-free survival ( P = 0.01). Further studies are warranted into the biological mechanisms underlying this adverse outcome and their possible therapeutic implications. [ABSTRACT FROM AUTHOR]

In Western countries, the age distribution of Hodgkin lymphoma ( HL) follows a characteristic bimodal curve showing an early and a late peak at approximately 35 and 70 yr, respectively. Furthermore, the presence of latent Epstein- Barr virus ( EBV) genome in the Hodgkin Reed- Sternberg cells, the tumour cell population of classical HL (c HL), has been found to have adverse prognostic impact in elderly, but not in younger c HL patients. We have characterised the protein expression in tumour tissue samples from younger (≤55 yr) and elderly (>55 yr) c HL patients and correlated the findings with EBV status. Differentially expressed proteins according to patients' age as well as tumoural EBV status belonged to different biological functional domains, such as apoptosis, cytoskeletal organisation, response to oxygen levels and regulation of catabolic/metabolic processes. The differential expression of selected proteins, cytosolic aminopeptidase, heterogeneous nuclear ribonucleoprotein K, serotransferrin and alpha-1-antitrypsin was further validated by Western blot analysis. Discovery-based proteomics characterising biological features distinctive for subsets of c HL patients may be useful for the identification of novel biomarkers with potential therapeutic relevance. An evaluation of the prognostic impact of protein expression pattern in general and individually expressed proteins in particular is warranted. [ABSTRACT FROM AUTHOR]

The article offers information on the identification of homozygous deletion in aggrecan (ACAN gene) and other candidate variants in classical Hodgkin lymphoma by exome sequencing. Topics discussed include aetiology of classical Hodgkin lymphoma (CHL), role in CHL tumourigenesis, and association of Epsteinâ€Barr virus (EBV) infection with CHL.

We report familial Hodgkin lymphoma (FHL) in a family with five children, of which three were human leucocyte antigen (HLA) class I identical. These three siblings were diagnosed with Epstein-Barr virus (EBV)-positive Hodgkin lymphoma within a 6-year period. All three were treated with chemo- and/or radiotherapy and are presently in complete remission. None of the children had evidence of overt immunodeficiency or autoimmune disease. This case contributes to the existing material on FHL and implies a role for both HLA class I antigens and EBV infection of the tumour cell population in the pathogenesis of some cases of FHL. [ABSTRACT FROM AUTHOR]

Summary The documented treatment‐induced excess mortality in Hodgkin lymphoma (HL) has spurred important treatment changes over recent decades. This study aimed to examine mortality among young HL patients treated with contemporary strategies, including historical data comparison. This nationwide study included 1348 HL patients, diagnosed in 1995–2015 and aged 15–40 at diagnosis. Among the patients, 66.5% had Ann Arbor stage I–II and 33.5% had stage III–IV disease. With a median follow‐up of 14.76 years, 139 deaths occurred, yielding a 5‐year overall survival of 94.6%. Older age, advanced disease, earlier treatment periods and extensive regimens were associated with higher overall mortality risk. The cumulative risk of HL‐related death showed an initial sharp rise, with a plateau at 5.3% 10‐year post‐diagnosis. Deaths due to cardiovascular or pulmonary diseases and second cancers initially had minimal risk, gradually reaching 1.2% and 2.0% at the 20‐year mark respectively. HL cases had a 7.5‐fold higher mortality hazard than the background population. This study suggests that contemporary HL treatment still poses excess mortality risk, but recent changes have notably reduced overall and cause‐specific mortality compared to earlier eras. Balancing treatment efficacy and toxicity remains crucial, but our findings highlight improved outcomes with modern treatment approaches. [ABSTRACT FROM AUTHOR]