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Supplementary Table 1 from T Cell Receptor Genotyping and HOXA/TLX1 Expression Define Three T Lymphoblastic Lymphoma Subsets which Might Affect Clinical Outcome

Supplementary Figure 2 from T Cell Receptor Genotyping and HOXA/TLX1 Expression Define Three T Lymphoblastic Lymphoma Subsets which Might Affect Clinical Outcome

Supplementary methods, figures, and tables Figure S1: Variant filters applied to Lymphopanel NGS data. Figure S2: Validation of variants according to SIFT and CADD scores. Figure S3: PMBL samples harbor more mutations than other DLBCL subtypes. Figure S4: Role of AID-induced SHM in DLBCL. Figure S5: Mutation frequency by subtype. Figure S6: Clustering of gene mutations according to subtype. Figure S7: Protein representations of observed mutations. Figure S8: Correlations between age and specific gene mutations. Figure S9: Prognosis according to IPI and subtype. Figure S10: Prognostic impact of gene mutations among the Lymphopanel. Table S1: Clinical characteristics of patients in our cohort. Table S2: Overview of the Lymphopanel used for NGS analysis. Table S3: Overview of pathway selection Table S4: Validation of variant filtering by an independent study of seven non-tumoral samples from DLBCL patients Table S5: Validated variants. Table S6: Lymphopanel NGS detection of genes with high AID target frequencies. Table S7: Prognostic impact of mutations in Lymphopanel genes

Supplemental Figures 1-8. Suppl. Fig 1. Consort flow diagram. Shown are patient numbers throughout the study. The BCCA TMA was built as duplicate 1.5mm cores whereas the PRIMA TMA was built as triplicate 1.0mm cores. Strict QC criteria were applied to each sample to increase accuracy of point estimates for macrophage infiltration. We required each sample to be represented by more than 1 core, to be unequivocally attributable to a patient and the relative standard error to be less than 33.33%. Suppl. Fig 2. Correlation between Aperio and manual scoring in the BCCA cohort for CD68 (left) and CD163 (right). Suppl. Fig 3. Representative microscopy images in low power magnification. (A) Immunohistochemistry using anti-human CD68 (clone KP1) and anti-human CD163 (clone 10D6) for case FL124 (average number of macrophages). (B) Similar images for case FL136 (elevated number of macrophages). Suppl. Fig 4. (A) Distribution of CD68 and CD163 scores in the BCCA and PRIMA cohorts. (B) Double immunofluorescence on formalin-fixed and paraffin-embedded tissue using antibodies against CD68 and CD163. Shown is case FL148 (22.64% CD68 positive pixels and 4.39% CD163 positive pixels by Aperio). Suppl. Fig 5. Distribution of CD68 and CD163 in the BCCA and PRIMA cohorts. Suppl. Fig 6. Correlation between CD68 and CD163 in the BCCA (left) and PRIMA cohorts (right). Suppl. Fig 7. Outcome correlation for CD68 in the BCCA cohort. The most significant cut-off of 2.94% was defined for progression-free survival (PFS) in the training cohort and carried forward into the overall survival (OS) analysis and validation cohorts. PFS and OS are calculated from date of initiation of R-CVP. Suppl. Fig 8. Outcome correlation for CD68 in the PRIMA cohort. The optimal cut-off of 1.41 was defined for progression-free survival (PFS) in the training cohort and carried forward into the overall survival (OS) analysis and validation cohorts. PFS and OS are calculated from date of registration in the trial.

Purpose: T lymphoblastic lymphomas (T-LBL) are rare disorders of immature T cells which predominantly involve the mediastinum. Their oncogenic pathways and prognostic variables are not clear.Experimental Design: We undertook a retrospective study of 41 cytoplasmic CD3+ T-LBL (nine cases aged Results: Application of a TCR-based immunogenetic classification allowed the identification of three subcategories: 11 immature IM0/D-LBL showed no TCR or only incomplete TCRD DJ rearrangement and corresponded to cytoplasmic CD3+ precursors of uncertain lineage. Sixteen mature TCRDdel-LBL showed biallelic TCRD deletion and both TCRG and TCRB rearrangement, consistent with TCRαβ lineage restriction. Fourteen intermediate LBL (Int-LBL) showed complete TCRD VDJ and TCRG VJ rearrangement, with TCRB VDJ rearrangement in the majority. All Int-LBL expressed HOX11/TLX1 or HOXA9 transcripts and a proportion of the latter were associated with CALM-AF10 or NUP214-ABL fusion transcripts. IM0/D-LBL were restricted to adults with extrathymic disease and bone marrow involvement, whereas Int-LBL and TCRDdel-LBL were found in children and adults with predominantly thymic disease. In adults, the Int-LBL subgroup was associated with a significantly superior clinical outcome. This subgroup can be identified either by TCR immunogenotyping or HOXA9/TLX1 transcript quantification.Conclusion: Application of this molecular classification will allow the prospective evaluation of prognostic effects within pediatric and adult protocols.

Supplementary Figure 1 from T Cell Receptor Genotyping and HOXA/TLX1 Expression Define Three T Lymphoblastic Lymphoma Subsets which Might Affect Clinical Outcome

Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials.Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20+de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays.Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell–like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-κB, epigenetic, and JAK–STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses.Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. Clin Cancer Res; 22(12); 2919–28. ©2016 AACR.See related commentary by Lim and Elenitoba-Johnson, p. 2829

Mastocytosis is a heterogeneous disease characterized by an abnormal accumulation of mast cells (MCs) in 1 or several organs. Although a somatic KIT D816V mutation is detected in ∼85% of patients, attempts to demonstrate its oncogenic effect alone have repeatedly failed, suggesting that additional pathways are involved in MC transformation. From 3 children presenting with both Greig cephalopolysyndactyly syndrome (GCPS, Mendelian Inheritance in Man [175700]) and congenital mastocytosis, we demonstrated the involvement of the hedgehog (Hh) pathway in mastocytosis. GCPS is an extremely rare syndrome resulting from haploinsufficiency of GLI3, the major repressor of Hh family members. From these familial cases of mastocytosis, we demonstrate that the Hh pathway is barely active in normal primary MCs and is overactive in neoplastic MCs. GLI3 and KIT mutations had a synergistic, tumorigenic effect on the onset of mastocytosis in a GCPS mouse model. Finally, Hh inhibitors suppressed neoplastic MC proliferation in vitro and extend the survival time of mice with aggressive systemic mastocytosis (ASM). This work revealed, for the first time, the involvement of Hh signaling in the pathophysiology of mastocytosis and demonstrated the cooperative effects of the KIT and Hh oncogenic pathways in mice with ASM, leading to the identification of new promising therapeutic targets.

International audience; Although follicular lymphoma (FL) is usually graded as FL1-2, FL3A, and FL3B, some borderline cases can be observed and led us to investigate the clinicopathologic diversity of grade 3 FL (FL3). Among 2449 FL patients enrolled in Lymphoma Study Association (LYSA) trials, 1921 cases with sufficient material underwent a central pathologic review. The resulting diagnoses comprised 89.6% FL1-2 (n=1723), 7.2% FL3A (n=138), and 0.5% purely follicular FL3B (n=9). The remaining 51 unclassifiable cases (2.7%) exhibited high-grade features but did not meet WHO criteria for either FL3A or FL3B; and were considered as “unconventional” high-grade FL (FL3U). FL3U morphological pattern consisted of nodular proliferation of large cleaved cells or small-sized to medium-sized blast cells. Compared with FL3A, FL3U exhibited higher MUM1 and Ki67 expression, less BCL2 breaks and more BCL6 rearrangements, together with a higher number of cases without any BCL2, BCL6 or MYC rearrangement. FL3U harbored less frequent mutations in BCL2, KMT2D, KMT2B, and CREBBP than FL3A. MYC and BCL2 were less frequently mutated in FL3U than FL3B. Rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone treated FL3U patients had a worse survival than FL1-2 patients with similar follicular lymphoma international prognostic index and treatment. These results suggest that high-grade FLs encompass a heterogeneous spectrum of tumors with variable morphology and genomic alterations, including FL3U cases that do not strictly fit WHO criteria for either FL3A or FL3B, and display a worse outcome than FL1-2. The distinction of FL3U may be useful to allow a better comprehension of high-grade FLs and to design clinical trials.

Long-term outcomes in children undergoing intestinal transplantation remain unclear. Seventy-one children underwent intestinal transplantation in our center from 1989 to 2007. We report on 10-year posttransplant outcomes with (group 1, n = 26) and without (group 2, n = 9) a functional graft. Ten-year patient and graft survival rates were 53% and 36%, respectively. Most patients were studying or working, one third having psychiatric disorders. All patients in group 1 were weaned off parenteral nutrition with mostly normal physical growth and subnormal energy absorption. Graft histology from 15 late biopsies showed minimal abnormality. However, micronutrient deficiencies and fat malabsorption were frequent; biliary complications occurred in 4 patients among the 17 who underwent liver transplantation; median renal clearance was 87 mL/min/1.73 m2 . Four patients in group 1 experienced late acute rejection. Among the 9 patients in group 2, 4 died after 10 years and 2 developed significant liver fibrosis. Liver transplantation and the use of a 3-drug regimen including sirolimus or mycophenolate mofetil were associated with improved graft survival. Therefore, intestinal transplantation may enable a satisfactory digestive function in the long term. The prognosis of graft removal without retransplantation is better than expected. Regular monitoring of micronutrients, early psychological assessment, and use of sirolimus are recommended.

Resume Dans la plupart des dysglobulinemies, les proteines monoclonales ont une structure semblable aux molecules normales mais en quantite anormale. La maladie des chaines lourdes (MCL) est une pathologie rare definie par la presence d’une immunoglobuline monoclonale (Ig) de structure anormale, constituee uniquement d’un fragment incomplet de la chaine lourde (tronquee) et depourvue de chaines legeres, remarquable par la frequence des maladies immunologiques ou hematologiques associees. Les lymphocytes ou les plasmocytes anormaux secretent les differents types de chaines lourdes (alpha [α], gamma [γ], mu [µ]ou delta [δ]) sans chaines legeres. La majorite des proteines des chaines lourdes tronquees sont des fragments de leurs homologues normaux avec des deletions internes de longueur variable. Ces deletions semblent resulter de mutations structurales. On distingue quatre types de MCL selon l’isotype de chaine lourde d’Ig produite par les cellules clonales : α, ν, µ ou δ. Le tableau clinique est plus proche de celui d’un lymphome que d’un myelome multiple. Le diagnostic des MCL et de maladies associees repose sur l’etude histologique des tissus atteints et sur l’analyse du serum ou des urines. L’histologie, couplee aux immuno-marquages, montre une population monoclonale positive pour une chaine lourde, mais negative pour les deux chaines legeres kappa (κ) et lambda (λ). La frequence de mise en evidence d’une immunoglobuline monoclonale est variable et depend du type de MCL. Le pronostic de ces maladies est tres variable d’un patient a l’autre et le traitement n’est pas standardise mais sera dirige contre la proliferation sous-jacente.

Summary Background Lenalidomide plus rituximab is approved to treat patients with relapsed or refractory follicular lymphoma. Obinutuzumab has been shown to enhance antibody-dependent cellular cytotoxicity, phagocytosis, and direct B-cell killing better than rituximab. Our aim was to determine the activity and safety of lenalidomide plus obinutuzumab in previously treated patients with relapsed or refractory follicular lymphoma. Methods In this multicentre, single-arm, phase 2 study, patients were enrolled from 24 Lymphoma Academic Research Organisation centres in France. Eligible patients (age ≥18 years) had histologically confirmed CD20-positive relapsed or refractory follicular lymphoma of WHO grade 1, 2, or 3a; an ECOG performance status of 0–2; and received at least one previous rituximab-containing therapy. Patients received oral lenalidomide (20 mg) plus intravenously infused obinutuzumab as induction therapy (1000 mg; six 28-day cycles), 1-year maintenance with lenalidomide (10 mg; 12 28-day cycles; days 2–22) plus obinutuzumab (1000 mg; alternate cycles), and 1-year maintenance with obinutuzumab (1000 mg; six 56-day cycles; day 1). The primary endpoint was the proportion of patients who achieved an overall response at induction end as per investigator assessment using the 1999 international working group criteria. The secondary endpoints were event-free survival, progression-free survival, overall survival, and safety. Analyses were per-protocol; the efficacy population included all patients who received at least one dose of both obinutuzumab and lenalidomide, and the safety population included all patients who received one dose of either investigational drug. The study is registered with ClinicalTrials.gov , number NCT01582776 , and is ongoing but closed to accrual. Findings Between June 11, 2014, and Dec 18, 2015, 89 patients were recruited and 86 patients were evaluable for efficacy and 88 for safety. Median follow-up was 2·6 years (IQR 2·2–2·8). 68 (79%) of 86 evaluable patients (95% CI 69–87) achieved an overall response at induction end, meeting the prespecified primary endpoint. At 2 years, event-free survival was 62% (95% CI 51–72), progression-free survival 65% (95% CI 54–74), duration of response 70% (95% CI 57–79), and overall survival 87% (95% CI 78–93). Complete response was achieved by 33 (38%, 95% CI 28–50) of 86 patients at induction end, and the proportion of patients achieving a best overall response was 70 (81%, 95% CI 72–89) and 72 (84%, 74–91) of 86 patients during induction and treatment, respectively. The most common adverse events were asthenia (n=54, 61%), neutropenia (n=38, 43%), bronchitis (n=36, 41%), diarrhoea (n=35, 40%), and muscle spasms (n=34, 39%). Neutropenia was the most common toxicity of grade 3 or more; four (5%) patients had febrile neutropenia. 57 serious adverse events were reported in 30 (34%) of 88 patients. The most common serious adverse events were basal cell carcinoma (n=5, 6%), febrile neutropenia (n=4, 5%), and infusion-related reaction (n=3, 3%). One patient died due to treatment-related febrile neutropenia. Interpretation Our data shows that lenalidomide plus obinutuzumab is active in previously treated patients with relapsed or refractory follicular lymphoma, including those with early relapse, and has a manageable safety profile. Randomised trials of new immunomodulatory regimens, such as GALEN or using GALEN as a backbone, versus lenalidomide plus rituximab, are warranted. Funding Lymphoma Academic Research Organisation, and Celgene and Roche

Resume La classification OMS 2016 identifie clairement deux variantes du lymphome a cellules du manteau : une variante classique et une variante indolente. L’identification de ces variantes qui presentent des caracteristiques cliniques, histologiques, phenotypiques et moleculaires differentes est importante car elle conditionne la prise en charge therapeutique pouvant aller d’une surveillance a une chimiotherapie lourde. Le pathologiste doit etre familier avec ces deux variantes dont l’ontogenie est supposee differente mais qui parfois restent de diagnostic differentiel difficile. Le pathologiste doit etre egalement conscient de l’extreme variabilite cytologique et phenotypique de ce lymphome qui peut mimer tous les autres types histologiques de lymphome B et pour lequel la detection d’une hyperexpression de la cycline D1, de SOX 11 et la mise en evidence de la translocation t (11 ;14) (q13; q32) sont des elements majeurs du diagnostic.

Introduction We (Bobée et al, 2020) have recently described a new molecular classifier combining gene expression profiling of 137 genes and machine learning able to diagnose B-cell lymphomas. As this tool can be easily performed from formalin fixed paraffin embedded tissue, we proposed to evaluate how it may be useful after the process of central review by expert pathologists in a LYSA diffuse large B-cell lymphoma (DLBCL) clinical trial, the GAINED trial (Le Gouill et al, 2021). Methods The GAINED trial was a multicenter randomized phase 3 trial comparing obinutuzumab to rituximab followed by a PET-driven consolidation in patients with DLBCL. Histological inclusion criteria were : DLBCL, high grade B-cell lymphoma double/triple hit (DH/TH) or high grade NOS. 670 patients were included and 646 underwent a central review of the biopsy by at least two LYSA pathologists. The central review performed immunostaining of full slides by anti-CD20, CD5, CD10, BCL6, MUM1, MYC, BCL2 if sufficient material was available as well as RNA extraction for the molecular classifier, the nanostring Lymph2CX and DNA extraction for targeted NGS. The molecular classifier was able to deliver 8 different signatures: DLBCL GCB, DLBCL ABC, primary mediastinal large B-cell lymphoma (PMBL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma/lymphoplasmacytic lymphoma, CLL/lymphocytic Lymphoma, T-cell rich signature. We compared classification by the histopathology review and by the molecular classifier. Discordant cases were reviewed both by two histopathologists (JB, TJM) and the molecular biologist (PR) and a reconciliation diagnosis was proposed Results The central histopathological review alone identified 580 patients with DLBCL or high grade B-cell lymphoma and 40 patients with a lymphoma subtype not eligible for the trial. Among the 470 patients evaluated by the molecular classifier, the reconciliation diagnosis identified 292 DLBCL NOS with 40 associated with a small B-cell component, 13 High grade DH/TH, 9 high grade NOS, 109 PMBL, 16 T-cell rich large B-cell Lymphoma (TCRBCL), 5 DLBCL EBV+ NOS. 29 cases did not fit with inclusion criteria and were mainly FL (3A or 3B), MCL, Nodular lymphocyte Predominant Hodgkin Lymphoma (NLPHL). Among them, the classifier helped to identify one case of CD5- MCL initially diagnosed as DLBCL with CD5- marginal zone lymphoma as well as one case of CD10+ follicular T-cell lymphoma (T-cell rich signature with Rho A mutation) initally diagnosed as FL 3B. Among 235 patients with GCB/ ABC subtyping, the correlation with Nanostring was 97.4% for the molecular classifier and 86,4% for the Hans algorithm. Although the main aim of the pathology review was not dedicated to differentiate DLBCL NOS from PMBL but to validate histological inclusion criteria, after reconciliation 22 DLBCL NOS were reclassified as PMBL. Overall, among the 109 PMBL , PET-CT at baseline in 108 cases evaluable found in 93 cases (86%) a mediastinal mass unique (37) or with satellite lymph nodes(56), in 12 cases (11%) a mediastinal mass with extramediastinal localization and in only 3 cases (3%) the absence of mediastinal mass. This observation fits well with the known anatomical distribution of PMBL and with the rare non mediastinal lymphomas with a PMBL signature. However, the molecular classifier was able to identify 8 signatures and could not recognize other lymphoma subtypes such as High grade B-cell Lymphomas NOS or DH/TH. In addition, 14 follicular lymphomas in our series comprising 5 grade 3A and 6 grade 3B were diagnosed molecularly mainly as DLBCL GC or rarely ABC . Although the TCRBCL were all included in the T-cell signature lymphoma, this signature included high grade B-cell lymphoma, DLBCL NOS, PMBL, DLBCL EBV+, NLPHL. Conclusion Overall, the molecular classifier in addition to the expert pathologic review increased accuracy of diagnostic by the pathologists particularly for difficult or rare cases, as well as it strongly helped to identify PMBL and GC/ABC DLCBL. However, the pathologist should be aware of the limit of the tool when dealing with DLBCL differential diagnosis, particularly for the identification of FL3A, FL3B or for cases with a T-cell rich microenvironment such as TCRBCL. Disclosures Bobée: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. . Drieux: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties.. Casasnovas: ROCHE: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Ghesquieres: Mundipharma Research Limited: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Takeda: Other: Travel, accommodation, expenses. Morschhauser: abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; epizyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; jannssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Thieblemont: Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Hospira: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: travel compensation, Research Funding; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel compensation. Ribrag: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Haioun: Takeda: Honoraria, Research Funding; Servier: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Miltenyi: Honoraria, Research Funding. Jardin: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. . Ruminy: Genexpath: Patents & Royalties: The author is a potential inventor on a patent application for the LymphoSign, which has been licensed for by Genexpath Patents & Royalties. .

International audience; BACKGROUND: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to

International audience; Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14)(q13;q32) CCND1/IGH translocation. This lymphoma is however extremely heterogeneous in terms of molecular alterations. Moreover, the course of the disease can vary greatly between indolent forms with slow progression and aggressive conditions rapidly pejorative. The identification of early markers allowing to predict individual patients outcome has however been unsuccessful so far. The LyMa trial treated homogeneously a cohort of young MCL patients. This appeared as a good opportunity to search for biomarkers of response to therapy. DNA extracted from diagnostic paraffin-embedded lymph node biopsies from 100 patients with newly diagnosed MCL, homogeneously treated in this prospective clinical trial, were investigated for copy number alterations and copy neutral loss of heterozygosity using the Oncoscan® SNP-array scanning the whole genome. An independent confirmatory cohort was used to strengthen the possibly relevant anomalies observed. Here we describe the recurrent anomalies identified with this technique. Deletions of 17p(TP53) and 9p(CDKN2A) were more frequent in refractory or early relapsing patients (10%), but had no significant impact in univariate analysis on progression-free (PFS) or overall survival (OS). Regardless of the presence of TP53 or CDKN2A deletions, gains in 7p22 (8,5%) were associated with better PFS in univariate but not in multivariate analysis including MCL International Prognostic Index and treatment. Gains of 11q(CCDN1), suggesting gains of the CCND1/IGH fusion, were associated with worse OS and PFS in univariate and multivariate analyses. This worse prognosis impact was confirmed by FISH in an independent confirmatory cohort. This work, using a whole genome approach, confirms the broad genomic landscape of MCL and shows that gains of the CCND1/IGH fusion can be considered as a new prognostic structural variant. Genomic abnormalities of prognostic impact could be useful to strengthen or de-escalate treatment schedules or choosing targeted therapies or CART-cells. This article is protected by copyright. All rights reserved.

Resume La maladie cœliaque (MC), ou intolerance au gluten, est une pathologie multifactorielle developpee sur un terrain genetique predisposant. Aujourd’hui encore sous diagnostiquee, elle toucherait pres de 1 % de la population mondiale. La presentation clinique classique d’enteropathie avec malabsorption n’est pas la plus frequente, elle est souvent asymptomatique, pauci-symptomatique ou de presentation clinique atypique. Son diagnostic est multidisciplinaire, et l’apport de l’histologie bien que discute, est souvent primordial, confirmant le diagnostic suspecte de MC et justifiant ainsi la mise en place d‘un regime sans gluten (RSG) a vie. L’histologie est utile egalement lors du suivi de la MC, afin de mettre en evidence une pathologie associee ou une evolution defavorable vers une MC refractaire au RSG. Enfin, il faut savoir remettre en question le diagnostic de MC si tous les parametres biologiques ne sont pas reunis et notamment un typage HLA compatible. En effet, la premiere cause d’atrophie villositaire est la MC, mais de nombreuses etiologies peuvent etre associees a une atrophie villositaire. Dans cette revue, les points essentiels du diagnostic, de la physiopathologie, de l’histopathologie et des complications de la MC seront developpes.

Introduction Les mastocytoses sont des neoplasies rares heterogenes liees a l’accumulation clonale de mastocytes dans differents organes. Cette accumulation est a l’origine de manifestations cliniques variees. Des mutations somatiques activatrices dans le gene KIT (comme D816 V) sont identifiees chez la majorite des patients. Ces mutations n’expliquent pas a elles seules l’heterogeneite des phenotypes cliniques. Notre objectif etait d’identifier des evenements genetiques a partir de formes rares de mastocytoses qui expliqueraient cette variabilite par une action en synergie avec la mutation de KIT. Resultats Nous avons identifie une mutation heterozygote perte de fonction dans le gene GLI3 chez 3 patients, de 2 familles independantes, qui presentaient l’association : (i) d’un syndrome de cephalopolysyndactylie de Greig–syndrome rare associant une macrocephalie et une polydactylie ;(ii) d’une mastocytose congenitale agressive (Patient#1) ou familiale (Patients #2 et #3). Le gene GLI3, code le principal facteur de transcription represseur de la voie oncogenique Hedgehog (Hh) : GLI3R. La co-existence de ces 2 evenements rares chez ces 3 patients, nous a mene a etudier le role de la voie Hh dans la physiologie du mastocyte et dans la physiopathologie des mastocytoses, notamment des formes sporadiques agressives. Nous avons montre pour la premiere fois que : (i) la voie Hh etait activee dans les mastocytes primaires normaux et constitutivement hyperactivee dans les mastocytes neoplasiques de patients atteints de mastocytoses agressives et dans toutes les lignees de mastocytes mutees pour KIT ; (ii) l’utilisation de sonidegib (inhibiteur de la voie Hh) inhibait la proliferation et induisait l’apoptose des mastocytes neoplasiques primaires des patients, et retardait significativement la mort chez les souris ayant une mastocytose agressive KITD816V+. Pour confirmer la capacite de l’haploinsuffisance de GLI3 a induire les tumeurs, nous avons montre que les mastocytes derives des souris GLI3Xt±, modele murin du syndrome de Greig, transduits avec le vecteur KIT-D816 V, avaient un fort potentiel proliferatif par rapport aux temoins. Ceci, confirme la cooperation oncogenique entre les voies Hh et KIT. De plus, l’expression ectopique de GLI3R induisait la mort des mastocytes, confirmant son role de gene suppresseur de tumeur dans le mastocyte. Discussion Dans un contexte syndromique particulier, un phenotype rare de mastocytose, a revele un nouveau mecanisme implique dans la physiopathologie des mastocytoses agressives en general et a permis d’identifier une nouvelle cible therapeutique.

Introduction Les mastocytoses sont liees a l’accumulation clonale de mastocytes dans un ou plusieurs tissus. Les symptomes sont lies a la degranulation mastocytaire et a l’infiltration tissulaire de mastocytes. Chez l’enfant, celles-ci s’expriment surtout dans une forme cutanee pure. Cependant, des formes systemiques agressives sont possibles. La mutation somatique la plus frequente est celle du site catalytique du recepteur KIT :KIT D816V. Cette mutation peut etre trouvee dans des formes tres differentes de la maladie et n’explique pas a elle seule l’heterogeneite des mastocytoses. Materiel et methodes Observations : un garcon, 5 ans, sans antecedent, presentait des la naissance, une hepato-splenomegalie, une macrocephalie isolee (+3DS), une infiltration cutanee diffuse avec signe de Darier positif et des signes d’activation mastocytaire : bulles, prurit, flush et nombreuses reactions alimentaires. La biopsie osteomedullaire montrait une infiltration myelomonocytaire et 15 % de mastocytes CD25+ CD30+. Le diagnostic de mastocytose systemique (MS) avec maladie de la lignee hematologique non mastocytaire clonale associee (SM-AHNMD) a ete retenu. Le sequencage de KIT (peau et moelle) a identifie la mutation D816V. Les autres genes habituellement associes au SM-AHNMD etaient normaux : TET2, SRSF2, ASXL1, RUNX1, JAK2 et RAS. L’analyse d’exome a permis d’identifier une mutation germinale heterozygote dans le gene EZH2 (Enhancer of Zeste Homolog 2), [c.541G>C/p.(G181R)]. A l’image des SM-AHNMD KITD816V+ de l’adulte, un traitement par midostaurine per os a ete debute permettant une nette diminution des signes d’activation mastocytaire, une remission complete de la myelomonocytose et une stabilisation de l’infiltrat medullaire et cutane. Le recul est de 4 ans. Resultats Des mutations heterozygotes dans EZH2 sont associees au syndrome de Weaver, caracterise par un gigantisme, une macrocephalie, une avance de l’âge osseux et une susceptibilite aux cancers (surtout hemopathies). Sa penetrance est incomplete et son expressivite variable. EZH2 code une histone methyltransferase, element epigenetique represseur, impliquee dans la modelisation de la chromatine et la repression transcriptionnelle. Recemment, des mutations somatiques dans EZH2 ont ete identifiees dans des MS de l’adulte ; elles sont associees a un mauvais pronostic. Ainsi, l’association d’une mutation germinale dans EZH2 et de la mutation KIT D816V conduit probablement a une MS congenitale particulierement agressive. Discussion Des cofacteurs d’expression pouvant expliquer les formes rares systemiques des mastocytoses pediatriques restent a identifier. Nous rapportons ici le premier cas de MS agressive congenitale expliquee par l’association des mutations KIT D816V et EZH2.

Summary Background Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18–75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8–24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073. Findings Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2–10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment). Interpretation These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis. Funding AB Science (Paris, France).

Resume L’Organisation Mondiale de la Sante va publier prochainement une edition revisee de la classification des tumeurs du tissu lymphoide et du tissu hematopoietique. Depuis la derniere edition publiee en 2008, les donnees de la recherche fondamentale et translationnelle en hematologie associees a l’avancee des techniques moleculaires et du diagnostic multidisciplinaire, ont permis de mieux caracteriser et individualiser les differents sous-types de lymphomes. Cette revue reprend les principales modifications ainsi que les nouvelles entites provisoires ou definitives. De la lymphocytose B monoclonale au lymphome folliculaire de type pediatrique, des modifications importantes apportees au groupe des lymphomes diffus a grandes cellules B ou a celui des lymphomes T peripheriques, ces nouveautes seront incluses dans la prochaine edition de la classification des tumeurs du tissu lymphoide.

Background Patients with mast cell diseases may suffer from various distressing symptoms, which can be insufficiently controlled with available therapies, severely affecting their quality of life. There is a need for new and safe treatment options for these patients. Objectives We aimed to evaluate safety and efficacy of omalizumab administration in patients with a symptomatic mast cell disorder. Methods We included 55 patients with a mast cell disorder associated with debilitating symptoms who received omalizumab treatment between January 2015 and December 2017, after a multidisciplinary team meeting at the French National Reference Center for Mastocytosis. Results A complete response was achieved for 1 patient (1.8%), a major response for 30 patients (54.5%), and a partial response for 12 patients (21.8%), resulting in an overall best response rate of 78.2% (43 of 55 patients). The response was persistent at least 3 months in 33 of 43 responding patients (76.7%). At the last follow-up, the final overall response rate was 58.2% (32 of 55 patients). Median time to first response was 2 months and median time to best response was 6 months. Omalizumab was dramatically effective on all superficial and general vasomotor symptoms and on most gastrointestinal or urinary symptoms, and partially effective on most neuropsychiatric symptoms. Safety profile was acceptable, except for one severe adverse event (edema of the larynx and dyspnea after the first injection of omalizumab). Side effects were reported in 16 patients (29%), mainly of low to mild intensity, yet causing interruption of treatment in 5 patients (9%). Conclusion Omalizumab seems to be a useful therapeutic option to control mast cell–mediator symptoms and displays a favorable safety profile.

Background: The prevalence of Hepatitis C virus in Egypt reaches 15%, which is considered the highest in the world. Genotype 4 represents 93 % of Egyptian HCV infections. Non-Hodgkin lymphoma (NHL) is the 5th most common cancer in Egypt. The association between HCV infection and occurrence of B-cell NHL is well known while data are scarce in Eastern countries. Objectives: We aimed to evaluate the prevalence of HCV infection among patients with B-cell NHL and the clinical characteristics of HCV associated B-cell NHL in Delta region (Mansoura-Egypt). Methods: Between March 2012 and March 2013, 110 adult patients newly diagnosed with B-cell NHL were enrolled in the current study. This study was carried out at Oncology Center, Mansoura University. Study subjects provided serum for HCV testing and for HCV RNA. Results: The prevalence of HCV infection among these patients was 61% (67/110 patients) which is the highest reported value in literature. Among them, 80% (32/40 tested patients) presented with viremia. Contrasting with the histological distribution previously described in Northern regions, the majority of HCV associated lymphomas were DLBCLs (72 %) followed by SLL/CLL (13 %), follicular lymphomas (7.5%) and 7.5% of marginal zone lymphomas. In conclusion: B-cell lymphomas are highly associated with HCV infection in Egypt. Further developments are needed to give access to antiviral treatment for those patients in Delta region.

Plasma-cell post-transplantation lymphoproliferative disorder (PC-PTLD) is a rare monomorphic PTLD entity divided into plasma cell myeloma (PCM) and plasmacytoma-like lesion (PLL) PTLD. To date, there are no exhaustive published cytogenetic data on PC-PTLD. We report array-based comparative genomic hybridization (aCGH) of 10 cases of PCM and PLL-PTLD. Patients had received kidney (n = 6), heart (n = 2), lung (n = 1) or bone marrow (n = 1) transplantation. There were six men and median age at time of PTLD was 56.5 years (3–74). We identified two different cytological features, plasmacytic and plasmablastic, among six PLL and three PCM PTLD. Eight cases were associated with EBV. First line treatment was heterogeneous: rituximab alone (n = 5), CHOP-like (n = 3) and multiple myeloma-like (n = 1). One patient died before any treatment. After a median follow-up of 19.5 months (0–150), five patients died (four from PTLD) and five were alive without evidence of disease. By aCGH, 5/10 demonstrated a complex profile. The most frequent abnormalities were +7q (5/10), +16q (5/10), +17q (5/10), +17p (4/10), +5q (4/10), t7 (4/10), t9 (3/10), del1p (3/10). No del17p13 (TP53) were observed. Del1p32.3 (CDKN2C) was observed in 2 cases. On univariate prognostic analysis, a complex aCGH was associated with a shorter OS. Thus, cytogenetic abnormalities seem to be closely related to those reported in multiple myeloma or diffuse large B cell lymphoma. Complex aCGH constitutes an unfavorable prognostic marker and aCGH should be integrated in the evaluation of patients with PLL/PCM-PTLD. © 2016 Wiley Periodicals, Inc.

Resume Les mastocytoses representent un groupe heterogene d’affections rares, sporadiques ou familiales, liees a la proliferation clonale de mastocytes (MC) anormaux qui s‘accumulent dans un ou plusieurs organes. Elles sont caracterisees par la presence multifocale d’agregats compacts de MC anormaux dans les organes infiltres. Leur physiopathologie est dominee par plusieurs mutations activatrices de c- KIT dont la plus frequente est la mutation D816V. Le diagnostic des mastocytoses est base sur l’identification de MC anormaux associee a des criteres genetiques et moleculaires en utilisant la classification de l’Organisation Mondiale de la Sante (OMS) 2008. Nous decrivons ici les principaux aspects cytologiques et histologiques des mastocytoses systemiques (MS) rencontres en hematologie et en particulier, les formes « classiques » et plus atypiques des MS medullaires, les MS associees a des hemopathies non mastocytaires myeloides ou non myeloides, la leucemie mastocytaire, les aspects histologiques de l’envahissement ganglionnaire et splenique des MS et les sarcomes mastocytaires. Enfin, nous concluons sur la place respective du myelogramme et de la biopsie medullaire dans le diagnostic des mastocytoses medullaires.

Through a retrospective study within the national registry of CEREDIH, the French National Reference Center for primary immune deficiency, we identified 13 patients with WAS/XLT who had LPD before allogeneic stem cell transplantation (alloSCT) among the 189 patients with WAS and 46 patients with XLT treated between 1988 and October 2017. Considering that patients with WAS/XLT were at risk before undergoing alloSCT, the crude rate and incidence ratio of LPD in untransplanted patients were 8.4% and 511 per 1 × 105 patient-years (95% CI, 272–873 per 1 × 105 patient-years), respectively, which is greater than in the general population (7.5 per 1 × 105 patient-years [95%CI 7.1–7.8]; P < .001). Crude rates (4.3% [95% CI, 0.5% to 14%] for the XLT cohort and 5.8% [95% CI, 2.9% to 10.2%] for the WAS cohort) and incidence ratios (334 [95% CI, 40–1200] and 531 per 1 × 105 patient-years [95% CI, 265–943], respectively) of LPD were similar in patients with XLT and those with WAS. The cumulative incidence of LPD was 1.9% at age 10 years and 9.9% at age 30 years, as shown by competing risk analysis. After age 40 years, the risk of LPD persists in untransplanted patients with WAS/XLT as 3 cases occurred at age 43.2, 50.3, and 50.6 years (Fig 1, A). The median age at diagnosis of WAS/XLT was similar in the entire cohort and in the subgroup of patients who developed LPD (1 year; interquartile range, 0–3 years).

Mastocytosis is a clonal haematological disease characterized by uncontrolled proliferation and the activation of mast cells. The value of FDG-PET/CT (FDG-PET) in mastocytosis has yet to be determined.We retrospectively identified patients with an established diagnosis of systemic mastocytosis (SM), according to the WHO criteria, who underwent PET using the French Reference Centre for Mastocytosis database. Semi-quantitative and visual analysis of FDG-PET was performed and compared to the clinico-biological data.Our cohort included 19 adult patients, median age 65 years [range 58-74], including three with smouldering SM (SSM), three with aggressive SM (ASM), 10 with an associated clonal haematological non-mast-cell lineage disease (SM-AHNMD), and three with mast cell sarcoma (MCS). FDG-PET was performed at the time of the SM diagnosis (15/19), to evaluate lymph node (LN) activity (3/19) or the efficacy of therapy (1/19). FDG uptake was observed in the bone marrow (BM) (9/19, 47%), LN (6/19, 32%), spleen (12/19, 63%), or liver (1/19, 5%). No significant FDG uptake was observed in the SSM and ASM patients. A pathological FDG uptake was observed in the BM of 6/10 patients with SM-AHNMD, appearing as diffuse and homogeneous, and in the LN of 5/10 patients. All 3 MCS patients showed intense and multifocal BM pathological uptake, mimicking metastasis. No correlation was found between the FDG-PET findings and serum tryptase levels, BM mast cell infiltration percentage, and CD30 and CD2 expression by mast cells.FDG uptake does not appear to be a sensitive marker of mast cell activation or proliferation because no significant FDG uptake was observed in most common forms of mastocytosis (notably purely aggressive SM). However, pathological FDG uptake was observed in the SM-AHNMD and in MCS cases, suggesting a role of FDG-PET in their early identification and as a tool of therapeutic assessment in this subgroup of patients.

Chronic intestinal failure (CIF) requires long term parenteral nutrition (PN) and, in some patients, intestinal transplantation (ITx). Indications and timing for ITx remain poorly defined. In the present study we aimed to analyze causes and outcome of children with CIF.118 consecutive patients referred to our institution were assessed by a multidisciplinary team and four different categories were defined retrospectively based on their clinical course: Group 1: patients with reversible intestinal failure; group 2: patients unsuitable for ITx, group 3: patients listed for ITx; group 4: patients stable under PN. Analysis involved comparison between groups for nutritional status, central venous catheter (CVC) related complications, liver disease, and outcome after transplantation by using non parametric tests, Mann-Whitney tests, Kruskal-Wallis, Wilcoxon signed rank tests and chi square distribution for percentage.118 children (72 boys) with a median age of 15 months at referral (2 months-16 years) were assessed. Etiology of IF was short bowel syndrome [n = 47], intractable diarrhea of infancy [n = 37], total intestinal aganglionosis [n = 18], and chronic intestinal pseudoobstruction [n = 17]. Most patients (89.8%) were totally PN dependent, with 48 children (40.7%) on home-PN prior to admission. Nutritional status was poor with a median body weight at -1.5 z-score (ranges: -5 to +2.5) and median length at -2.0 z-score (ranges: -5.5 to +2.3). The mean number of CVC inserted per patient was 5.2 (range 1-20) and the mean number of CRS per patient was 5.5 (median: 5; range 0-12) Fifty-five patients (46.6%) had thrombosis of ≥2 main venous axis. At admission 34.7% of patients had elevated bilirubin (≥50 μmol/l), and 19.5% had platelets100,000/ml, and 15% had both. Liver biopsy performed in 79 children was normal (n = 4), or showed F1 or F2 fibrosis (n = 29), bridging fibrosis F3 (n = 20), or cirrhosis (n = 26). Group 1 included 10 children finally weaned from PN (7-years survival: 100%). Group 2 included 12 children with severe liver disease and associated disorders unsuitable for transplantation (7-years survival: 16.6%). Group 3 included 66 patients (56%) who were listed for small bowel or liver-small bowel transplantation, 62/66 have been transplanted (7 years survival: 74.6%). Factors influencing outcome after liver-ITx were body weight (p.004), length (p.001), pre-Tx bilirubin plasma level (p.001) and thrombosis (p.01) for isolated ITx, Group 4 included 30 children (25.4%) with irreversible IF considered as potential candidates for isolated ITx. Four children were lost from follow up and 3 died within 2 years (survival 88.5%). Among potential candidates, the following parameters improved significantly during the first 12 months of follow up: Body weight (p.0001), length (p.0001) and bilirubin (p.0001).many patients had a poor nutritional status with severe complications especially liver disease. PN related complications were the most relevant indication for ITx, but also a negative predictor for outcome. Early patient referral for Tx-assessment might help to identify and separate children with irreversible IF from children with transient IF or uncomplicated long-term PN, allowing to adapt a patient-based treatment strategy including or not ITx.

Purpose Biallelic mutations in ATM cause ataxia-telangiectasia (AT), a rare inherited disease with a high incidence of cancer. Precise estimates of the risk, presentation, and outcomes of cancer in patients with AT need to be addressed in large series. Patients and Methods In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT. Centralized review was performed on 60% of the lymphomas. Incidence rates were compared with the French population, and risk factors were analyzed. Results Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P < .001). The majority of NHLs were aggressive B-cell NHL. Epstein-Barr virus was associated with all of the HLs and 50% of the NHLs. Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001). Survival was improved in patients who achieved a major response to treatment (3.46 v 0.87 years for major v minor responses, respectively; P = .011). Immunodeficiency was associated with increased risk of cancer. ATM mutation type was associated with a difference in survival in the entire cohort but not with cancer incidence or cancer survival. Conclusion B-cell NHL, HL, and acute lymphoblastic leukemia occur at a high rate and earlier age than carcinomas in AT. T-PLLs are rarer than initially reported. Prognosis is poor, but patients may benefit from treatment with an improved survival.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.