Significance of E-lesions in Hodgkin lymphoma and the creation of a new consensus definition: a report from SEARCH.

The International Staging Evaluation and Response Criteria Harmonization for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) seeks to provide an appropriate, universal differentiation between E-lesions and stage IV extranodal disease in Hodgkin lymphoma (HL). A literature search was performed through the PubMed and Google Scholar databases using the terms "Hodgkin disease," and "extranodal," "extralymphatic," "E lesions," "E stage," or "E disease." Publications were reviewed for the number of participants; median age and age range; diagnostic modalities used for staging; and the definition, incidence, and prognostic significance of E-lesions. Thirty-six articles describing 12 640 patients met the inclusion criteria. Most articles reported staging per the Ann Arbor (72%, 26/36) or Cotswolds modification of the Ann Arbor staging criteria (25%, 9/36), and articles rarely defined E-lesions or disambiguated "extranodal disease." The overall incidence of E-lesions for patients with stage I-III HL was 11.5% (1330/11 602 unique patients). Available stage-specific incidence analysis of 3888 patients showed a similar incidence of E-lesions in stage II (21.2%) and stage III (21.9%), with E-lesions rarely seen with stage I disease (1.1%). E-lesions likely remain predictive, but we cannot unequivocally conclude that identifying E-lesions in HL imparts prognostic value in the modern era of the more selective use of targeted radiation therapy. A harmonized E-lesion definition was reached based on the available evidence and the consensus of the SEARCH working group. We recommend that this definition of E-lesion be applied in future clinical trials with explicit reporting to confirm the prognostic value of E-lesions.

Machine Learning Logistic Regression Model for Early Decision Making in Referral of Children with Cervical Lymphadenopathy Suspected of Lymphoma.

While cervical lymphadenopathy is common in children, a decision model for detecting high-grade lymphoma is lacking. Previously reported individual lymphoma-predicting factors and multivariate models were not sufficiently discriminative for clinical application. To develop a diagnostic scoring tool, we collected data from all children with cervical lymphadenopathy referred to our national pediatric oncology center within 30 months (n = 182). Thirty-nine putative lymphoma-predictive factors were investigated. The outcome groups were classical Hodgkin lymphoma (cHL), nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), non-Hodgkin lymphoma (NHL), other malignancies, and a benign group. We integrated the best univariate predicting factors into a multivariate, machine learning model. Logistic regression allocated each variable a weighing factor. The model was tested in a different patient cohort (n = 60). We report a 12-factor diagnostic model with a sensitivity of 95% (95% CI 89-98%) and a specificity of 88% (95% CI 77-94%) for detecting cHL and NHL. Our 12-factor diagnostic scoring model is highly sensitive and specific in detecting high-grade lymphomas in children with cervical lymphadenopathy. It may enable fast referral to a pediatric oncologist in patients with high-grade lymphoma and may reduce the number of referrals and unnecessary invasive procedures in children with benign lymphadenopathy.

Thymus and activation-regulated chemokine (TARC) as treatment response marker for paediatric Hodgkin lymphoma: A pilot study.

Classical Hodgkin lymphoma (cHL) is characterised by malignant Hodgkin Reed-Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active cross-talk between malignant and non-malignant cells. One promising biomarker in adult patients with cHL is thymus and activation-regulated chemokine (TARC). We investigated TARC as marker for interim and end-of-treatment response in paediatric cHL. In this multicentre prospective study, TARC levels were measured among 99 paediatric patients with cHL before each cycle of chemotherapy and were linked with interim and end-of-treatment remission status. TARC levels were measured by enzyme-linked immunosorbent assay. At diagnosis, TARC levels were elevated in 96% of patients. Plasma TARC levels declined significantly after one cycle of chemotherapy (p < 0.01 vs. baseline) but did not differ at interim assessment by positron emission tomography (p = 0.31). In contrast, median plasma TARC at end of treatment was significantly higher in three patients with progressive disease compared to those in complete remission (1.226 vs. 90 pg/ml; p < 0.001). We demonstrate that, in paediatric patients, plasma TARC is a valuable response marker at end-of-treatment, but not at interim analysis after the first two chemotherapy cycles. Further research is necessary to investigate TARC as marker for long-term progression free survival.

The Prognostic Value of Eight Immunohistochemical Markers Expressed in the Tumor Microenvironment and on Hodgkin Reed-Sternberg Cells in Pediatric Patients With Classical Hodgkin Lymphoma.

Immunohistochemical markers are associated with treatment outcome in adults with classical Hodgkin Lymphoma (cHL). Studies in children are scarce and inconsistent. We investigated in 67 children with cHL, whether the expression of CD15, CD30, PAX5, PD-1, PD-L1, CD68, CD163 and TARC at diagnosis is associated with disease free survival (DFS) and with interim remission status. Low CD15 and low TARC expression were associated with relapsed disease. Low expression of PD-L1 was associated with complete remission at interim PET-scan. Our data suggest a difference between pediatric and adult cHL. This underlines the importance of future research into specific prognostic factors in pediatric cHL, indispensable for improvement of treatment in this population.

Novel Circulating Hypermethylated RASSF1A ddPCR for Liquid Biopsies in Patients With Pediatric Solid Tumors.

Liquid biopsies can be used to investigate tumor-derived DNA, circulating in the cell-free DNA (cfDNA) pool in blood. We aimed to develop a droplet digital polymerase chain reaction (ddPCR) assay detecting hypermethylation of tumor suppressor gene RASSF1A as a simple standard test to detect various pediatric tumor types in small volume blood samples and to evaluate this test for monitoring treatment response of patients with high-risk neuroblastoma. METHODS: We developed a ddPCR assay to sensitively detect tumor-derived hypermethylated RASSF1A DNA in liquid biopsies. We tested this assay in plasma of 96 patients with neuroblastoma, renal tumors, rhabdomyosarcoma, or Hodgkin lymphoma at diagnosis and in cerebrospinal fluid of four patients with brain tumors. We evaluated the presence of hypermethylated RASSF1A in plasma samples during treatment and follow-up in 47 patients with neuroblastoma treated according to high-risk protocol and correlated results with blood mRNA-based and bone marrow mRNA-based minimal residual disease detection and clinical outcomes. RESULTS: The total cfDNA level was significantly higher in patients with metastatic neuroblastoma and nephroblastoma compared with healthy adult and pediatric controls. Hypermethylated RASSF1A was present in 41 of 42 patients with metastatic neuroblastoma and in all patients with nephroblastoma, with the median percentage of 69% and 21% of total RASSF1A, respectively. Hypermethylated RASSF1A levels decreased during therapy and recurred at relapse. CONCLUSION: Our findings demonstrate the value of ddPCR-based detection of hypermethylated RASSF1A as a circulating molecular tumor marker in neuroblastoma. Our preliminary investigation of RASSF1A hypermethylation detection in circulating cfDNA of other pediatric tumor entities demonstrates potential as a pan-tumor marker, but requires investigation in larger cohorts to evaluate its use and limitations.

Biology and Clinical Applicability of Plasma Thymus and Activation-Regulated Chemokine (TARC) in Classical Hodgkin Lymphoma.

Thymus and activation-regulated chemokine (TARC) is produced by different cell types and is highly expressed in the thymus. It plays an important role in T cell development, trafficking and activation of mature T cells after binding to its receptor C-C chemokine receptor type 4 (CCR4) and consecutive signal transducer and activator of transcription 6 (STAT6) activation. Importantly, TARC is also produced by malignant Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). In cHL, HRS cells survive and proliferate due to the micro-environment consisting primarily of type 2 T helper (Th2) cells. TARC-mediated signaling initiates a positive feedback loop that is crucial for the interaction between HRS and T cells. The clinical applicability of TARC is diverse. It is useful as diagnostic biomarker in both children and adults with cHL and in other Th2-driven diseases. In adult cHL patients, TARC is also a biomarker for treatment response and prognosis. Finally, blocking TARC signaling and thus inhibiting pathological Th2 cell recruitment could be a therapeutic strategy in cHL. In this review, we summarize the biological functions of TARC and focus on its role in cHL pathogenesis and as a biomarker for cHL and other diseases. We conclude by giving an outlook on putative therapeutic applications of antagonists and inhibitors of TARC-mediated signaling.

Improved survival for adolescents and young adults with Hodgkin lymphoma and continued high survival for children in the Netherlands: a population-based study during 1990-2015.

Population-based studies that assess long-term patterns of incidence, major aspects of treatment and survival are virtually lacking for Hodgkin lymphoma (HL) at a younger age. This study assessed the progress made for young patients with HL (<25 years at diagnosis) in the Netherlands during 1990-2015. Patient and tumour characteristics were extracted from the population-based Netherlands Cancer Registry. Time trends in incidence and mortality rates were evaluated with average annual percentage change (AAPC) analyses. Stage at diagnosis, initial treatments and site of treatment were studied in relation to observed overall survival (OS). A total of 2619 patients with HL were diagnosed between 1990 and 2015. Incidence rates increased for 18-24-year-old patients (AAPC + 1%, P = 0·01) only. Treatment regimens changed into less radiotherapy and more 'chemotherapy only', different for age group and stage. Patients aged 15-17 years were increasingly treated at a paediatric oncology centre. The 5-year OS for children was already high in the early 1990s (93%). For patients aged 15-17 and 18-24 years the 5-year OS improved from 84% and 90% in 1990-1994 to 96% and 97% in 2010-2015, respectively. Survival for patients aged 15-17 years was not affected by site of treatment. Our present data demonstrate that significant progress in HL treatment has been made in the Netherlands since 1990.

Plasma thymus and activation-regulated chemokine (TARC) as diagnostic marker in pediatric Hodgkin lymphoma.

Pediatric classical Hodgkin's lymphoma (cHL) is characterized by Hodgkin Reed-Sternberg cells located in an inflammatory microenvironment. Blood biomarkers result from active crosstalk between these cells. One promising biomarker in adult cHL patients is "thymus-and-activation-regulated chemokine" (TARC). The objectives of this study were to define normal TARC values in non-cHL children and to investigate and correlate pretherapy TARC as diagnostic marker in pediatric cHL. In this multicenter prospective study, plasma and serum samples were collected of newly diagnosed cHL patients before start of treatment (n = 49), and from randomly selected non-cHL patients (n = 81). TARC levels were measured by enzyme-linked immunosorbent assay. The non-cHL patients had a median plasma TARC value of 71 pg/mL (range: 18-762), compared to 14 619 pg/mL (range: 380-73 174) in cHL patients (P < .001). TARC values had a high discriminatory power (AUC = .999; 95% confidence interval, .998-1). A TARC cutoff level of 942 pg/mL maximized the sum of sensitivity (97.9%) and specificity (100%). TARC plasma levels were associated with age, treatment level, bulky disease, B-symptoms, and erythrocyte sedimentation rate. TARC was found to be a highly specific and sensitive diagnostic marker for pediatric cHL. This noninvasive marker could be of great value as screening test in the work-up for pediatric patients with lymphadenopathy.

[Bronchiolitis obliterans after Stevens-Johnson syndrome]. / Bronchiolitis obliterans na stevens-johnsonsyndroom.

BACKGROUND: Bronchiolitis obliterans is a non-reversible lung disease in which the inflammatory process ultimately leads to obstruction of the bronchioles. This condition often occurs after a lung or bone marrow transplantation, and sometimes respiratory tract infection. Clinical presentation is that of persistent and increasing airway obstruction. The gold standard for diagnosis is open lung biopsy. Treatment is symptomatic and aimed at preventing further lung damage. CASE DESCRIPTION: An 8-year-old girl was treated for a suspected pneumonia. Two weeks later she developed Stevens-Johnson syndrome followed by severe dyspnoea. A CT scan of the chest revealed findings consistent with bronchiolitis obliterans. Methylprednisone pulse therapy was ineffective. Due to respiratory insufficiency she underwent a lung transplantation, which to date has been successful. CONCLUSION: Bronchiolitis obliterans after Stevens-Johnson syndrome should be considered in patients with recurrent and progressive respiratory symptoms with typical findings on a CT scan. Lung transplantation is often the only therapeutic option.