Laura R. de Baaij

Prospective Human Leukocyte Antigen, Endomysium Immunoglobulin A Antibodies, and Transglutaminase Antibodies Testing for Celiac Disease in Children with Down Syndrome

OBJECTIVE To assess the effect of a prospective screening strategy for the early diagnosis of celiac disease (CD) in children with Down syndrome (DS). STUDY DESIGN Blood samples were taken from 155 children with DS. Buccal swabs were also taken from 9 of these children for determination of human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 positivity. Independently, immunoglobulin A anti-endomysium-(EMA) and anti-tissue transglutaminase antibodies (TGA) were tested. An intestinal biopsy was performed to confirm the diagnosis of CD. RESULTS Sixty-three children (40.6%) had test results that were positive for HLA-DQ2 or HLA-DQ8. Results of HLA DQ-typing of DNA isolated from blood and buccal swabs were identical. Eight of the children in whom test results were positive for HLA-DQ2/8 also had positive test results for EMA and TGA. CD was confirmed in 7 of these children with an intestinal biopsy, and in 1 child, CD was suggested with improvement on a gluten-free diet. CONCLUSIONS We found a prevalence of CD in children with DS of 5.2% (10 times higher than the general Dutch population). We recommend HLA-DQ2/8 typing from buccal swabs in the first year of life and initiating serologic screening of children with DS in whom test results are positive for HLA-DQ2 or DQ8 at age 3 years. Early knowledge of negative HLA-DQ2/8 status can reassure most parents that their children do not have a CD risk.

Treatment response in enteropathy associated T‐cell lymphoma; survival in a large multicenter cohort

Enteropathy‐associated T‐cell lymphoma (EATL) is a T‐cell Non‐Hodgkin Lymphoma which is highly associated with celiac disease. The prognosis of EATL has been considered poor and there are no standardized treatment protocols. Here, we evaluate treatment response and survival of EATL patients in a large multicenter cohort. A total of 61 patients diagnosed with EATL were analyzed. Various treatment regimens were applied in EATL during the past fifteen years including either monotherapy consisting of chemotherapy or resection, or combination therapy with both aforementioned regimens whether or not combined with stem‐cell transplantation (SCT). Overall, 50/61 patients (82%) died after a median of 7.4 months. One‐ and five‐year overall survival was 40 and 11%, respectively. Median follow‐up in the survivors was 26 months. Patients treated with the most aggressive treatment, that is, resection, chemotherapy and autologous SCT, showed the most favourable outcome with complete remission in all patients, the lowest relapse rate and one‐ and five‐year overall survival of 100 and 33%, respectively, although overall survival in this group was not significantly better as compared to patients treated with surgery and chemotherapy. This study indicates that combination treatment is superior compared to monotherapy. Whether or not consolidation therapy with autologous SCT may improve survival needs to be substantiated in a larger randomized international trial. Am. J. Hematol. 90:493–498, 2015.

A new and validated clinical prognostic model (EPI) for Enteropathy Associated T-cell Lymphoma

Purpose: Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal non–Hodgkin lymphoma with a poor, though variable prognosis. The International Prognostic Index (IPI) and the prognostic index for peripheral T-cell lymphoma (PIT) have limited predictive value for outcome of EATL. The purpose of this study was to develop and validate a prognostic model for EATL, which can identify high-risk patients who need more aggressive therapy. Experimental Design: This retrospective multicenter study was based on 92 patients and included 45 patients diagnosed with EATL between 1999 and 2009 from the Netherlands and 47 patients from England and Scotland, diagnosed with EATL between 1994 and 1998. A new EATL prognostic index (EPI) was constructed using the RPART (recursive partitioning and regression trees) procedure. Validation was performed applying the bootstrap method. Results: Three risk groups were distinguished (P < 0.0001): a high-risk group, characterized by the presence of B-symptoms [median overall survival (OS) of 2 months]; an intermediate-risk group, comprising patients without B-symptoms and an IPI score ≥ 2 (7 months); and a low-risk group, representing patients without B-symptoms and an IPI score of 0 to 1 (34 months). Internal validation showed stability of statistical significance and prognostic discrimination. In contrast with the IPI and PIT, the EPI better classified patients in risk groups according to their clinical outcome. Conclusions: Our new, validated, prognostic model EPI accurately predicts survival outcome in EATL and may be used for patient selection for new therapeutic strategies and evaluation of clinical trials. Clin Cancer Res; 21(13); 3013–9. ©2015 AACR.

Surgery in (pre)malignant celiac disease

AIM To report the outcome of surgery in patients with (pre)malignant conditions of celiac disease (CD) and the impact on survival. METHODS A total of 40 patients with (pre)malignant conditions of CD, ulcerative jejunitis (n = 5) and enteropathy associated T-cell lymphoma (EATL) (n = 35), who underwent surgery between 2002 and 2013 were retrospectively evaluated. Data on indications, operative procedure, post-operative morbidity and mortality, adjuvant therapy and overall survival (OS) were collected. Eleven patients with EATL who underwent chemotherapy without resection were included as a control group for survival analysis. Patients were followed-up every three months during the first year and at 6-mo intervals thereafter. RESULTS Mean age at resection was 62 years. The majority of patients (63%) underwent elective laparotomy. Functional stenosis (n = 13) and perforation (n = 12) were the major indications for surgery. In 70% of patients radical resection was performed. Early postoperative complications, mainly due to leakage or sepsis, occurred in 14/40 (35%) of patients. Eight patients required reoperation. More patients who underwent resection in the acute setting (n = 3, 20%) died compared to patients treated in the elective setting. With a median follow-up of 20 mo, seven patients (18%) required reoperation due to long-term complications. Significantly more patients who underwent acute surgery could not be treated with adjuvant chemotherapy. Patients who first underwent surgical resection showed significantly better OS than patients who received chemotherapy without resection. CONCLUSION Although the complication rate is high, the preferred first step of treatment in (pre)malignant CD consists of local resection as early as possible to improve survival.

M2032 HLA-DQ Typing of Extra-Intestinal T-Cell Lymphomas: Evidence for An Association with Undiagnosed Celiac Disease? a Pilot Study On Anaplastic Large Cell Lymphomas

Introduction: The prevalence of celiac disease (CD) is 0.5-1% in the Western population. As CD is widely underdiagnosed, the majority of CD patients is still untreated and therefore at greater risk of developing complicated CD, including Enteropathy Associated T-cell Lymphoma (EATL). Differentiation between various T-cell lymphomas is difficult because of similar morphology and immunophenotype. The final diagnosis is based on clinical presentation and localisation of the lymphoma. Consequently, T-cell lymphomas in CD patients and T-cell lymphomas in the small bowel are always diagnosed as EATLs. However, 25% of EATLs are located extra-intestinal. The most frequent type of T-cell lymphomas is anaplastic large cell lymphoma (ALCL). ALCLs are either anaplastic lymphoma kinase (ALK) negative or positive. EATLs are always ALK negative. As is the case for most EATLs, ALCLs are CD30 positive. CD and EATL are strongly associated with HLA-DQ2 and/or -DQ8. HLADQ2 and/or -DQ8 expression is found in 98% of CD and EATL patients, compared to 40% in the Western population. Aims and Methods: We investigated whether the frequency of HLA-DQ2 and/or -DQ8 is increased in extra-intestinal ALCLs compared to the general population, in order to determine if extra-intestinal ALCLs might in fact be undiagnosed EATLs. For this purpose, extra-intestinal ALCL samples, ALK-positive and ALK-negative, were collected and DNA was isolated. DQA1 and DQB1 alleles were amplified using PCR. HLA-DQ typing was subsequently performed using a single strand conformation polymorphism / heteroduplex based method (SSCP/HD). Results: So far, 21 anaplastic large-cell lymphomas have been HLA-DQ typed. HLA-DQ2 was present in 10 lymphomas, of which 3 were homozygous. HLA-DQ8 was present in 4 lymphomas, all heterozygous. In total, twelve lymphomas (57%) were HLA-DQ2 and/or -DQ8 positive, indicating only a slightly higher prevalence than in the general population. However, within the subgroup of ALKnegative ALCLs, representing potentially undiagnosed EATLs, 71% was HLA-DQ2 and/or DQ8 positive (p=0.05). Conclusion: The increased prevalence of HLA-DQ2 and/or -DQ8 in ALK-negative ALCLs suggests underdiagnosis of EATL within this group of extra-intestinal T-cell lymphomas.