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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]

Purpose Contemporary data on mortality of hematological patients admitted to the intensive care unit (ICU) are missing. In a Danish nationwide set-up, we assessed 30-day and 1-year mortality in this population including impact of age and comorbidity, with non-hematological patients as reference. Methods This population-based cohort study included all non-surgical patients > 15 years of age admitted to an ICU in Denmark between 2010 and 2015. Data on hematological malignancies were obtained from the Danish Hematological Database, and information on the Charlson Comorbidity Index was obtained from the Danish National Patient Registry. Thirty-day and 1-year mortality was estimated using the Kaplan-Meier method. We used Cox proportional hazards regression to estimate hazard ratios. Results We included 2122 ICU patients with a hematological malignancy and 88,951 non-hematological ICU patients. The 30-day mortality was 44% (95% confidence interval: 42-47%) among hematological patients and 27% (27-27%) among non-hematological patients. Similarly, 1-year mortality was 66% (64-68%) and 37% (37-37%), respectively. The corresponding hazard ratio with adjustment for age, sex, and comorbidity was 1.62 (1.54-1.71). Excess mortality was observed in all subgroups of age or of comorbidity. For example, the 1-year mortality for patients with Charlson Comorbidity Index Score > 3: 70% (66-74%) among hematological patients and 62% (61-63%) among non-hematological patients. Conclusion ICU patients with hematological malignancy had higher mortality than other ICU patients. However, one third of critically ill patients with a hematological malignancy is alive 1 year after ICU admission, Author(s): Peter H. Asdahl [sup.1], Steffen Christensen [sup.2], Anders Kjærsgaard [sup.3], Christian F. Christiansen [sup.3], Peter Kamper [sup.1] Author Affiliations: (1) grid.154185.c, 0000 0004 0512 597X, Department of Hematology, Aarhus [...]

PURPOSE: Patients diagnosed with advanced-stage Hodgkin lymphoma (aHL) have historically been risk-stratified using the International Prognostic Score (IPS). This study investigated if a machine learning (ML) approach could outperform existing models when it comes to predicting overall survival (OS) and progression-free survival (PFS). PATIENTS AND METHODS: This study used patient data from the Danish National Lymphoma Register for model development (development cohort). The ML model was developed using stacking, which combines several predictive survival models (Cox proportional hazard, flexible parametric model, IPS, principal component, penalized regression) into a single model, and was compared with two versions of IPS (IPS-3 and IPS-7) and the newly developed aHL international prognostic index (A-HIPI). Internal model validation was performed using nested cross-validation, and external validation was performed using patient data from the Swedish Lymphoma Register and Cancer Registry of Norway (validation cohort). RESULTS: In total, 707 and 760 patients with aHL were included in the development and validation cohorts, respectively. Examining model performance for OS in the development cohort, the concordance index (C-index) for the ML model, IPS-7, IPS-3, and A-HIPI was found to be 0.789, 0.608, 0.650, and 0.768, respectively. The corresponding estimates in the validation cohort were 0.749, 0.700, 0.663, and 0.741. For PFS, the ML model achieved the highest C-index in both cohorts (0.665 in the development cohort and 0.691 in the validation cohort). The time-varying AUCs for both the ML model and the A-HIPI were consistently higher in both cohorts compared with the IPS models within the first 5 years after diagnosis. CONCLUSION: The new prognostic model for aHL on the basis of ML techniques demonstrated a substantial improvement compared with the IPS models, but yielded a limited improvement in predictive performance compared with the A-HIPI. Machine-Learning based advanced-stage Hodgkin lymphoma (aHL) prognosis surpasses International Prognostic Score, competes with aHL international prognostic index in overall survival and progression-free survival prediction. [ABSTRACT FROM AUTHOR]

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine. [ABSTRACT FROM AUTHOR]

Identifying risk factors for intensive care unit (ICU) admission in acute leukemia (AL) patients may guide decision-making and improve prognosis. We included all adult AL patients receiving high-intensive chemotherapy in Denmark from 2005 to 2016. We examined risk factors [crude and adjusted (a) relative risks (RRs) with 95% confidence intervals (CI)] and calculated RRs of death after 1-, 3-, and 5-years in ICU-admitted patients compared with matched cohorts. In 1417 AML and 306 ALL patients, the 1-year risk of ICU admission was 28.1% for AML and 26.4% for ALL patients, with the majority related to the first course of chemotherapy. Performance status >1 was associated with increased risk. The 1-year mortality was higher in ICU-admitted patients (AML: 69.7 vs. 35.0% [aRR 2.74;CI = 2.17–3.47]; ALL 65.0 vs. 20.0% [aRR 3.04;CI = 1.54–6.02]). The excess mortality decreased with time. In this study, performance status was associated with increased risk of ICU admission and identifies high-risk patients. ICU admission was associated with high mortality, especially within the first year. [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]

Treatment of early relapses of T lymphoblastic leukemia/lymphoma is often unsuccessful. We tested an experimental regimen containing daratumumab and nelarabine in two young patients with early relapses of T lymphoblastic lymphoma and T-ALL, respectively. Both patients achieved a deep complete remission. Combining daratumumab with chemotherapy may have a role in relapsing T lymphoblastic leukemia/lymphoma. [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]

In Hodgkin lymphoma (HL) bleomycin can induce pulmonary toxicity (BPT). BPT consists of respiratory tract symptoms during bleomycin-exposure and radiologic pulmonary lesions without concomitant infection. Older age, bleomycin dose, smoking history and the use of granulocyte-colony stimulating factor (G-CSF) have been suggested as possible risk factors for BPT. It is still debated whether BPT affects overall (OS) and progression-free survival (PFS). We investigated the incidence of BPT along with possible risk factors in 412 HL patients treated in 1990-2014. BPT occurred in 34 patients (8%) and was significantly associated with disseminated disease and B-symptoms. It was more frequent in elderly patients (p =.05) but not significantly correlated with a history of smoking. BPT occurred more often in patients receiving G-CSF (p =.03), particularly the poly-ethylenglycol-bound molecule. All significant risk correlations were limited to the age group >45 years. In the present cohort, BPT did not influence OS or PFS regardless of age. [ABSTRACT FROM AUTHOR]

Background: Hodgkin lymphoma (HL) treatment protocols for children, adolescents and young adults traditionally differ, but the biological and clinical justification for this remains uncertain. Material and methods: We compared age-dependent clinical presentation and treatment and outcome for 1072 classical HL patients 0-24 years diagnosed in Denmark (1990-2010) and Sweden (1992-2009) in pediatric (n=315, Denmark <15 years, Sweden <18 years) or adult departments (n=757). Distribution of clinical characteristics was assessed with Pearson's chi2-test and Mantel-Haenszel trend test. The Kaplan-Meier method was used for survival analyses. Hazard ratios (HR) were used to compare the different treatment groups and calculated using Cox regression. Results: Children (0-9 years) less often presented with advanced disease than adolescents (10-17 years) and young adults (18-24 years) (stage IIB-IV: children 32% vs. adolescents 50%, and adults 55%; p<.005). No variation in overall survival (OS) was seen between pediatric and adult departments or by country. Danish pediatric patients received radiotherapy (36%) less frequently than Swedish pediatric patients (71%) (p<.0001). Ten-year event-free survival (EFS) was lower among Danish pediatric patients (0-14 years) (0.79; 95% confidence interval (CI) 0.70-0.86) than among Swedish pediatric patients (0-17 years) (0.88; 95% CI 0.83-0.92), HR (1.93; 95% CI 1.08-3.46). A similar pattern was seen between adult patients in the two countries: Denmark 10-year EFS 0.85 (95% CI 0.81-0.88), Sweden 0.88 (95% CI 0.84-0.91), adjusted HR 1.51 (95% CI 1.03-2.22). Conclusion: Adolescents and young adults shared similar clinical presentation suggesting a rationale of harmonized treatment for these groups. Both adult and pediatric protocols provided high OS with no significant difference between the departments. The less frequent use of radiotherapy in Danish pediatric patients corresponded to a lower EFS, but comparable OS in all groups confirmed effective rescue strategies for the relapsing patients. [ABSTRACT FROM AUTHOR]

We report a case presenting with recurrent episodes of severe hypothermia preceding the diagnosis of Hodgkin lymphoma. The episodes of hypothermia were accompanied by other symptoms of autonomic dysfunction, mainly hypotension, which could be caused by autonomic neuropathy as part of a paraneoplastic syndrome. In comparison with previous reports describing an association between the presence of hypothermia and an adverse outcome, the present patient has responded well to lymphoma-specific treatment and is currently in an ongoing complete remission. Due to the peculiar cyclic pattern of the hypothermic episodes presented in this case, we hypothesize whether intermittent release of disease-related chemo- and cytokines could be a plausible pathogenetic explanation. [ABSTRACT FROM AUTHOR]

18F-Fluorodeoxyglucose positron emission tomography/ computed tomography (PET/CT) is a highly accurate staging method in classical Hodgkin lymphoma (cHL). We retrospectively compared the staging results obtained in two large cohorts of patients with cHL diagnosed before ( n = 324) and after ( n = 406) the introduction of PET/CT staging in a retrospective study. In PET/CT staged patients, stage I disease was less frequent (16% vs. 27%, p < 0.001) while stage IV disease was more frequent (17% vs. 10%, p = 0.02). Imaging-detected skeletal involvement was recognized more often in PET/CT staged patients (17% vs. 2%, p < 0.001), and the presence of focal skeletal PET/CT lesions was associated with higher risk of progression (hazard ratio [HR] 1.96, 95% confidence interval [CI]: 1.14-3.36). The German Hodgkin Study Group (GHSG) risk classification (early, intermediate, advanced disease) predicted outcome in PET/CT staged patients. In conclusion, PET/CT led to higher disease stages, and the more frequently diagnosed skeletal lesions may be an adverse prognostic factor. [ABSTRACT FROM AUTHOR]

Simple Summary: Classic Hodgkin lymphoma (cHL) patients refractory to standard ABVD chemo-therapy are known to have a dismal prognosis. This has led to the hypothesis that ABVD treatment-sensitive and ABVD treatment-refractory tumours are biologically distinct. In this study, cHL patients refractory to standard ABVD treatment show subtle but significant differences in protein expression that enable clustering of the two response groups, thus indicating differences between ABVD sensitive and refractory patients at the molecular level, and thereby strengthening the hypothesis that ABVD sensitive and ABVD refractory tumours may be biologically distinct. In classic Hodgkin lymphoma (cHL), the tumour microenvironment (TME) is of major pathological relevance. The paucity of neoplastic cells makes it important to study the entire TME when searching for prognostic biomarkers. Cure rates in cHL have improved markedly over the last several decades, but patients with primary refractory disease still show inferior survival. We performed a proteomic comparison of pretreatment tumour tissue from ABVD treatment-refractory versus ABVD treatment-sensitive cHL patients, in order to identify biological differences correlating with treatment outcome. Formalin-fixed paraffin-embedded tumour tissues from 36 patients with cHL, 15 with treatment-refractory disease, and 21 with treatment-sensitive disease, were processed for proteomic investigation. Label-free quantification nano liquid chromatography tandem mass spectrometry was performed on the tissues. A total of 3920 proteins were detected and quantified between the refractory and sensitive groups. This comparison revealed several subtle but significant differences in protein expression which could identify subcluster characteristics of the refractory group. Bioinformatic analysis of the biological differences indicated that a number of pathologically activated signal transduction pathways are disturbed in ABVD treatment-refractory cHL. [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]

The article notes the high incidence of treatment-related late morbidity and mortality among patients treated for Hodgkin lymphoma, and discusses efforts to identify patients in which treatment-related toxicity could be reduced by means of lower treatment intensity. Particular attention is given to a study that found a potential link between the intensity of the PET (positron emission tomography) in Hodgkin lymphoma and the expression of glucose transporters.

The 2016 update of the WHO classification update of lymphoid malignancies includes new entities and modifications, which affect current treatment paradigms and provide a framework for new interventional strategies, as summarised in this review. With the increasing understanding of the pathogenetic mechanisms behind lymphoid malignancies involving surface markers, signaling transduction pathways, epigenetic modulations as well as the tumour micro-environment, novel agents and immune therapeutic strategies have been developed. These precision medicine approaches are gradually improving the prognosis of lymphoma patients. Methods reliably assessing the quality of clinical responses also contribute to this general prognostic improvement.

Recent technological advances have led to an increasing understanding of the pathogenetic mechanisms behind lymphoid malignancies. Based on his new knowledge, novel agents and immune therapeutic strategies have been developed. The combination of diagnostic, therapeutic and surveillance-related precision medicine approaches may eventually represent the key for a substantial improvement in both life expectancy and quality of life, also for those patient groups presently characterised by the highest unmet clinical need, as argued in this review.

Purpose Our aim was to capture the biology of classical Hodgkin lymphoma (cHL) at the time of relapse and discover novel and robust biomarkers that predict outcomes after autologous stem-cell transplantation (ASCT). Materials and Methods We performed digital gene expression profiling on a cohort of 245 formalin-fixed, paraffin-embedded tumor specimens from 174 patients with cHL, including 71 with biopsies taken at both primary diagnosis and relapse, to investigate temporal gene expression differences and associations with post-ASCT outcomes. Relapse biopsies from a training cohort of 65 patients were used to build a gene expression-based prognostic model of post-ASCT outcomes (RHL30), and two independent cohorts were used for validation. Results Gene expression profiling revealed that 24% of patients exhibited poorly correlated expression patterns between their biopsies taken at initial diagnosis and relapse, indicating biologic divergence. Comparative analysis of the prognostic power of gene expression measurements in primary versus relapse specimens demonstrated that the biology captured at the time of relapse contained superior properties for post-ASCT outcome prediction. We developed RHL30, using relapse specimens, which identified a subset of high-risk patients with inferior post-ASCT outcomes in two independent external validation cohorts. The prognostic power of RHL30 was independent of reported clinical prognostic markers (both at initial diagnosis and at relapse) and microenvironmental components as assessed by immunohistochemistry. Conclusion We have developed and validated a novel clinically applicable prognostic assay that at the time of first relapse identifies patients with unfavorable post-ASCT outcomes. Moving forward, it will be critical to evaluate the clinical use of RHL30 in the context of positron emission tomography-guided response assessment and the evolving cHL treatment landscape.

Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1 + (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1 + (HR = 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 × 10 9 /L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 × 10 9 /L, sex, and country). A high proportion of PD-L1 + leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1 + and PD-L1 + leukocytes in the tumor microenvironment., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.

(18)F-Fluorodeoxyglucose positron emission tomography/ computed tomography (PET/CT) is a highly accurate staging method in classical Hodgkin lymphoma (cHL). We retrospectively compared the staging results obtained in two large cohorts of patients with cHL diagnosed before (n = 324) and after (n = 406) the introduction of PET/CT staging in a retrospective study. In PET/CT staged patients, stage I disease was less frequent (16% vs. 27%, p < 0.001) while stage IV disease was more frequent (17% vs. 10%, p = 0.02). Imaging-detected skeletal involvement was recognized more often in PET/CT staged patients (17% vs. 2%, p < 0.001), and the presence of focal skeletal PET/CT lesions was associated with higher risk of progression (hazard ratio [HR] 1.96, 95% confidence interval [CI]: 1.14-3.36). The German Hodgkin Study Group (GHSG) risk classification (early, intermediate, advanced disease) predicted outcome in PET/CT staged patients. In conclusion, PET/CT led to higher disease stages, and the more frequently diagnosed skeletal lesions may be an adverse prognostic factor.

Background: Classical Hodgkin's lymphoma is characterized by a minority of neoplastic cells surrounded by a heterogeneous background population of non-neoplastic cells including lymphoma-associated macrophages. High levels of expression of both the monocyte/macrophage lineage-associated antigens CD68 and CD163 have been suggested to have pro-tumor effects. The aim of our study was to correlate expression of CD68 and CD163 with the clinico-pathological features and prognosis of a cohort of patients with previously untreated Hodgkin's lymphoma., Design and Methods: A tissue microarray was constructed from paraffin-embedded tumor tissues from 288 cases of classical Hodgkin's lymphoma. CD68 and CD163 expression was assessed immunohistochemically and the degree of macrophage infiltration within the tumor was scored using point grid counting. Clinical data were obtained from clinical records., Results: The patients' median age was 37 years (range, 6-86 years). The male to female ratio was 1.2. In classical Hodgkin's lymphoma (n = 288) high CD68 and CD163 expression correlated, at the univariate level, with poorer overall survival (P=0.002 and P=0.03, respectively) and event-free survival (P=0.03 and P=0.04, respectively). At the multivariate level, high CD68 expression remained significantly predictive of overall survival (P=0.004). In addition, we demonstrated that both high CD68 and CD163 expression were associated with the presence of Epstein-Barr virus in the neoplastic cells (P=0.001 and P=0.0002, respectively)., Conclusions: In classical Hodgkin's lymphoma, high expression of the macrophage/monocyte-related antigens CD68 and CD163 correlates with adverse outcome and with the presence of Epstein-Barr virus in the tumor cell population.