Summary Background Reports of an increased risk of lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease are controversial. We assessed this risk in a ...prospective observational cohort study. Methods 19 486 patients with inflammatory bowel disease, of whom 11 759 (60·3%) had Crohn's disease and 7727 (39·7%) had ulcerative colitis or unclassified inflammatory bowel disease, were enrolled in a nationwide French cohort by 680 gastroenterologists, who reported details of immunosuppressive therapy during the observation period, cases of cancer, and deaths. The risk of lymphoproliferative disorder was assessed according to thiopurine exposure. Median follow-up was 35 months (IQR 29–40). Findings At baseline, 5867 (30·1%) of patients were receiving, 2809 (14·4%) had discontinued, and 10 810 (55·5%) had never received thiopurines. 23 new cases of lymphoproliferative disorder were diagnosed, consisting of one case of Hodgkin's lymphoma and 22 cases of non-Hodgkin lymphoproliferative disorder. The incidence rates of lymphoproliferative disorder were 0·90 per 1000 (95% CI 0·50–1·49) patient-years in those receiving, 0·20/1000 (0·02–0·72) patient-years in those who had discontinued, and 0·26/1000 (0·10–0·57) patient-years in those who had never received thiopurines (p=0·0054). The multivariate-adjusted hazard ratio of lymphoproliferative disorder between patients receiving thiopurines and those who had never received the drugs was 5·28 (2·01–13·9, p=0·0007). Most cases associated with thiopurine exposure matched the pathological range of post-transplant disease. Interpretation Patients receiving thiopurines for inflammatory bowel disease have an increased risk of developing lymphoproliferative disorders. Funding Programme Hospitalier de Recherche Clinique National ( AOM05157 ), Association François Aupetit, Délégation Inter-régionale de la Recherche clinique Ile de France-Assistance Publique Hôpitaux de Paris (AP-HP), Ligue contre le Cancer, and Fonds de Recherche de la Société Nationale Française de Gastro-entérologie.
Summary Background Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine ...to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome. Methods This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II–IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II–IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov , number NCT00209222. Findings Of 497 patients (median age 55 years IQR 49–60) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6·1 years (95% CI 5·4–6·4), time to treatment failure was significantly longer in the cytarabine group (median 9·1 years 95% CI 6·3–not reached, 5 year rate 65% 95% CI 57–71) than in the control group (3·9 years 3·2–4·4, 40% 33–46; hazard ratio 0·56; p=0·038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 29% of 241m vs 19 8% of 227 controls; platelets 176 73% of 240 vs 21 9% of 225), grade 3 or 4 febrile neutropenia (39 17% of 230 vs 19 8% of 224), and grade 1 or 2 renal toxicity (creatinine 102 43% of 236 vs 22 10% of 224). The number of ASCT-related deaths was similar (eight 3·4%) in both groups. Interpretation Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma. Funding European Commission, Lymphoma Research Foundation, and Roche.
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.
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.
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.
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.
Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma ...International Prognostic Index MIPI). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI.
Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group GLSG 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort.
The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b.
Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.
Treatment of mantle cell lymphoma (MCL) in younger patients remains a challenge. We report results of a phase 2 trial using cytarabine and rituximab as induction regimen before autologous stem cell ...transplantation. Patients younger than 66 years with stage 3 or 4 MCL were included. Treatment consisted of 3 courses of CHOP21 with rituximab at the third one and 3 of R-DHAP. Responding patients were eligible for autologous stem cell transplantation with TAM6 or BEAM. Sixty patients were included. Median age was 57 years. Characteristics of patients were: BM involvement 85%, leukemic disease 48%, gastrointestinal involvement 52%, Performance Status > 16%, lactate dehydrogenase > 1N 38%, Mantle Cell Lymphoma International Prognostic Index (low 55%, intermediate 38%, high 13%). The overall response rate was 93% after (R)-CHOP and 95% after R-DHAP. Although uncommon after (R)-CHOP (12%), 57% of patients were in complete response after R-DHAP. With median follow-up of 67 months, median event-free survival is 83 months, and median overall survival is not reached. Five-year overall survival is 75%. Comparison with a previous study without rituximab shows improvement of outcome (median event-free survival, 51 vs 83 months). No toxic death or unexpected toxicities were observed. This study confirms that induction with rituximab and cytarabine-based regimens is safe and effective in MCL patients. This regimen is currently compared with R-CHOP21 induction in a multicentric European protocol.
•Treatment of young patients with mantle cell lymphoma requires induction chemotherapy followed by autologous stem cell transplantation.•Higher efficacy without excess toxicity is obtained with high-dose cytarabine and rituximab before stem cell transplantation.
Background Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk ...factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. Objective We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. Methods We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP , including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Results Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)–mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. Conclusion IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.
Monogenic interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe inflammatory bowel disease. Here, we report that 5 patients with an IL-10R1 (n = 1) or IL-10R2 ...(n = 4) deficiency developed B-cell non-Hodgkin lymphoma between the ages of 5 and 6 years (which was recurrent in 1 patient). These lymphomas had some of the characteristics of diffuse large B-cell lymphomas and contained monoclonal, Epstein-Barr virus–negative germinal center B cells. The tumors displayed a remarkably homogeneous signature, with original activation of the nuclear factor κB pathway and a decrease in intratumor T-cell infiltration. Hence, IL-10R deficiency is associated with a high risk of developing B-cell lymphoma. Our results revealed an unexpected role of the IL-10R pathway in lymphomagenesis.
•Human inherited IL-10 receptor deficiency is associated with a very high risk of non-EBV–related diffuse large B-cell lymphoma.•IL-10 signaling may be involved in the immune control of germinal center B-cell lymphoma.
Background Inflammatory bowel disease (IBD) is one of the most common chronic gastrointestinal diseases, but the underlying molecular mechanisms remain largely unknown. Studies of monogenic diseases ...can provide insight into the pathogenesis of IBD. Objective We thought to determine the underlying molecular causes of IBD occurring in 2 unrelated families in association with an immune deficiency. Methods We performed genetic linkage analysis and candidate gene sequencing on 13 patients from a large consanguineous family affected by early-onset IBD, progressive immune deficiency, and, in some cases, autoimmunity and alopecia, a condition we named enteropathy-lymphocytopenia-alopecia. The candidate gene was also sequenced in an unrelated patient with a similar phenotype. We performed histologic analysis of patients' intestinal biopsy specimens and carried out functional assays on PBMCs. Gut organoids derived from a patient's biopsy specimen were analyzed. Results We identified biallelic missense mutations in tetratricopeptide repeat domain 7A (TTC7A) in all patients from both families. The resulting TTC7A depletion modified the proliferation, adhesion, and migratory capacities of lymphocytes through inappropriate activation of the RhoA signaling pathway. Normal function was restored by wild-type TTC7A expression or addition of a RhoA kinase inhibitor. The growth and polarity of gut epithelial organoids were also found to be dependent on the RhoA signaling pathway. Conclusions We show that TTC7A regulates the actin cytoskeleton dynamics in lymphocytes through the RhoA signaling pathway and is required in both lymphocytes and epithelial cells for maintaining equilibrium between cell proliferation, migration, polarization, and cell death. Our study highlights variability in the phenotypic expression resulting from TTC7A deficiency and outlines that impairment of both epithelial cells and lymphocytes cooperatively causes IBD.
Anti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut ...immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).
Medical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes.
Among seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-α therapy was needed in two.
This case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple intestinal atresia (MIA) is a rare cause of bowel obstruction that is sometimes associated with a combined immunodeficiency (CID), leading to increased susceptibility to infections. The ...factors underlying this rare disease are poorly understood. We characterized the immunological and intestinal features of 6 unrelated MIA-CID patients. All patients displayed a profound, generalized lymphocytopenia, with few lymphocytes present in the lymph nodes. The thymus was hypoplastic and exhibited an abnormal distribution of epithelial cells. Patients also had profound disruption of the epithelial barrier along the entire gastrointestinal tract. Using linkage analysis and whole-exome sequencing, we identified 10 mutations in tetratricopeptide repeat domain–7A (TTC7A), all of which potentially abrogate TTC7A expression. Intestinal organoid cultures from patient biopsies displayed an inversion of apicobasal polarity of the epithelial cells that was normalized by pharmacological inhibition of Rho kinase. Our data indicate that TTC7A deficiency results in increased Rho kinase activity, which disrupts polarity, growth, and differentiation of intestinal epithelial cells, and which impairs immune cell homeostasis, thereby promoting MIA-CID development.
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