Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Preexisting and treatment-emergent autoimmune cytopenias in patients with CLL treated with targeted drugs.

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs-ibrutinib, idelalisib, and venetoclax-have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

[A population-based database to study malignancies in HIV-infected patients in the Local Health Unit of Brescia (Northern Italy), period 1999-2009]. / Creazione di un database integrato per lo studio dei tumori maligni nei pazienti con infezione da HIV nell'ASL di Brescia nel periodo 1999-2009.

OBJECTIVE: to complete the database of all patients infected by the human immunodeficiency virus (HIV) who lives in the area belonging to the Local Health Unit (ASL) of Brescia, Northern Italy,with all the cancers diagnosed in the period 1999-2009. DESIGN: diagnoses of cancer between 1999 and 2009 registered in the electronic database in use in the Clinic of Infectious and Tropical Diseases (source A) for the clinic follow-up of HIV-infected patients were checked. Then, the cases were integrated with the data recorded in the ASL database (source B) and in the Cancer Registry of Brescia (source C). SETTING AND PARTICIPANTS: all HIV-infected patients belonging to the ASL of Brescia followed-up in the Clinic of Infectious and Tropical Diseases of Brescia. MAIN OUTCOME MEASURES: in the database were included all HIV-positive patients who had a diagnosis of cancer between 1999 and 2009. The diagnosis of cancer had to be present at least in two of the three sources considered; if it was recorded only in one of them, the source had to be an histological document or confirmed directly by the patient him/herself. RESULTS: from the sourceA, 339 diagnoses of cancer were recorded, then other 82 records from the sources B and C were added, achieving a total of 421 cancers, belonging to 391 different patients. Half of the diagnoses was present in all the three sources considered. Among the AIDS-defining cancers (No. 200; 47.5%), Kaposi's sarcoma and non-Hodgkin lymphoma were the most frequent diagnosed tumours (22.8% and 22.33%, respectively). Among the non-AIDS-defining cancers (No. 221; 52.5%), malignancies of the skin other than melanoma (No. 41; 9.74%), tumours of the liver (No. 34; 8.08%) and Hodgkin lymphoma (No. 31; 7.36%) were the most frequent tumours. CONCLUSIONS: the database of all HIVpositive patients, including the diagnoses of cancer between 1999 and 2009, represents an important instrument, not only for the clinical practice: collecting clinical and sociodemographics characteristics of these patients, it would be possible to perform clinical and epidemiological studies.

Impact of Covid-19 pandemic on psychological well-being of firefighters.

Background: Covid-19 pandemic represented a unique stressful event that affected the physical health and the psychological well-being (PWB) of individuals and communities. Monitoring PWB is essential to clarify the burden on mental health effects but also to define targeted psychological-supporting measures. This cross-sectional study evaluated the PWB of Italian firefighters during the pandemic. Methods: Firefighters recruited during the pandemic period filled out a self-administered questionnaire the Psychological General Well-Being Index during the health surveillance medical examination. This tool is usually used to assess the global PWB and explores six subdomains: anxiety, depressed mood, positive well-being, self-control, general health, and vitality. The influencing role of age, gender, working activities, Covid-19 and pandemic restrictive measures was also explored. Results: A total of 742 firefighters completed the survey. The aggregate median PWB global score was in the "no distress" range (94.3±10.3) resulting higher than that observed in studies conducted using the same tool in the Italian general population during the same pandemic period. Similar findings were observed in the specific subdomains thus suggesting that investigated population was in good PWB condition. Interestingly, significantly better outcomes were detected in the younger firefighters. Conclusion: Our data showed a satisfactory PWB situation in firefighters that could be related to different professional factors such as work organization, mental and physical training. In particular, our results would suggest the hypothesis that in firefighters, the maintaining of a minimum/moderate level of physical activity (consisting of even just going to work) might had a profoundly positive impact on psychological health and well-being.

Long-term follow-up of cladribine treatment in hairy cell leukemia: 30-year experience in a multicentric Italian study.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24-88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04-28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p < 0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.

Polychlorinated biphenyls and non-Hodgkin's lymphoma: a case-control study in Northern Italy.

BACKGROUND: Polychlorinated biphenyls (PCBs) have been hypothesized to increase the risk of non-Hodgkin lymphoma (NHL), although conclusive evidence is still lacking. High levels of PCBs were found in soil in some areas close to a PCB-producing factory in Brescia, North Italy. We conducted a population-based case-control study among residents of the town to investigate the possible association between PCB pollution and NHL in this area. METHODS: We included both incident and deceased NHL cases, and a random sample of the town residents as controls, frequency matched to cases as regards age and gender. Exposure to PCBs was estimated on the basis of the lifetime residential history of cases and controls in four different areas of the town-A, B and C (polluted areas) and D (control area). RESULTS: A total of 495 cases (287 incident cases) and 1467 controls were enrolled. Positive associations were found between NHL and having resided for at least 10 years in the area A, the most polluted area (odds ratio, OR=1.8; p=0.02) and for having resided in any of the polluted areas considered together (A+B+C) (OR=1.4; p=0.08). However, no associations were evident for having resided 20 years or longer in the polluted areas or when analyzing the association with each subject's main residence in his/her lifetime. CONCLUSION: This study provides some evidence for an association between PCB exposure and NHL, though results should be considered with caution in the absence of individual biological measures of exposure.

Polycythemia Vera (PV): Update on Emerging Treatment Options.

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by exuberant red cell production leading to a broad range of symptoms that compromise quality of life and productivity of patients. PV reduces survival expectation, primarily due to thrombotic events, transformation to blast phase and post-PV myelofibrosis or to development of second cancers, which are associates with poor prognosis. Current therapeutic first line recommendations based on risk adapted classification divided patients into two groups, according to age (< or >60 years) and presence of prior thrombotic events. Low-risk patients (age <60 years and no prior history of thrombosis) should be treated with aspirin (81-100 mg/d) and phlebotomy, to maintain hematocrit <45%. High-risk patients (age >60 years and/or prior history of thrombosis), in addition to aspirin and phlebotomies, should receive cytoreductive therapy in order to reduce thrombotic risk. Nowadays hydroxyurea still remains the cytoreductive agent of first choice, reserving Interferon to young patients or childbearing women. During the last years, ruxolitinib emerged as a new treatment in PV patients, as second line therapy: it appeared especially effective in patients with severe pruritus, symptomatic splenomegaly, or post-PV myelofibrosis symptoms. Currently, in PV treatment, several molecules have been tested or are under investigation. At present, the drug that has shown the most encouraging results is givinostat.

Efficacy of low-dose radiotherapy (2 Gy × 2) in the treatment of marginal zone and mucosa-associated lymphoid tissue lymphomas.

OBJECTIVES: To investigate the efficacy of a schedule of low-dose radiotherapy (LDRT) with 4 Gy (2 Gy x 2) in a cohort of unselected MALT or MZL patients. METHODS: We retrospectively collected all patients receiving LDRT, either for cure or palliation, for a stage I-IV histologically proven MALT or MZL between 2016 and 2020. Response to LDRT was evaluated with the Lugano criteria. Local control (LC), distant relapse-free survival (DRFS), progression-free survival (PFS) and overall survival (OS) were stratified for treatment intent (curative vs palliative) and estimated by the Kaplan-Meier product-limit. RESULTS: Among 45 consecutively enrolled patients with a median age of 68 years (range 22-86), 26 (58%) were female. Thirty-one patients (69%) with a stage I-II disease received LDRT as first line therapy and with a curative intent. Overall response rate was 93%, with no significant difference among curative and palliative intent. With a median follow-up of 18 months, LC, DRFS, PFS and OS at 2 years were 93, 92, 76 and 91%, respectively, in the overall population. Patients receiving curative LDRT had a better PFS at 2 years (85% vs 54%, p < 0.01) compared to patients receiving palliative treatment. LDRT was well tolerated in all patients, without any significant acute or chronic side-effect. CONCLUSIONS: LDRT is effective and well tolerated in patients affected with MALT or nodal MZL, achieving high response rates and durable remission at 2 years. ADVANCES IN KNOWLEDGE: This study shows the efficacy of LDRT in the treatment of MALT and MZL.

Real Life Use of Bendamustine in Elderly Patients with Lymphoid Neoplasia.

BACKGROUND: Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients. However, its tolerability in elderly patients is still debated. METHODS: An observational, retrospective study was carried out; patients with chronic lymphocytic leukemia (CLL) or lymphoma, aged ≥ 65 years old, treated with bendamustine-based regimens in first or subsequent lines between 2010 and 2020 were considered eligible. RESULTS: Overall, 179 patients aged ≥ 65 years were enrolled, 53% between 71 and 79 years old. Cumulative Illness Rating Scale (CIRS) comorbidity score was ≥6 in 54% patients. Overall survival (OS) at 12 months was 95% (95% confidence interval [CI]: 90-97%); after a median follow up of 50 months, median OS was 84 months. The overall response rate was 87%, with 56% complete responses; the median time to progression (TTP) was 61 months. The baseline factors affecting OS by multivariable analysis were sex, histological diagnosis, renal function, and planned bendamustine dose, while only type of lymphoma and bendamustine dose impacted on TTP. Main adverse events were neutropenia (grade ≥ 3: 43%) and infections (any grade: 36%), with 17% of patients requiring hospital admission. CONCLUSIONS: The responses to bendamustine, as well as survival, are relevant even in advanced age patients, with a manageable incidence of acute toxicity.

CMV retinitis in a stem cell transplant recipient treated with foscarnet intravitreal injection and CMV specific immunoglobulins.

Cytomegalovirus (CMV) retinitis (CMVR) has been reported rarely in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In addition, little is known about strategies for ophthalmic surveillance and adequate antiviral treatment of CMVR. A case of CMVR in an allogeneic HSCT recipient is described, including clinical signs and therapy. An adult patient received HSCT from a matched unrelated donor for treatment of a Burkitt lymphoma. Donor and recipients were both CMV positive. Starting on day +40, the patient presented multiple CMV reactivation, treated with valganciclovir, foscarnet and a combination of both. On day +160, the patient started complaining of conjunctival hyperaemia and a decrease in visual acuity. Fundoscopy revealed retinal lesions consistent with CMVR, although whole blood CMV DNAemia was negative. Aqueous humor biopsy showed the presence of CMV infection (CMV DNA 230400 UI/ml). CMVR was treated with foscarnet (180 mg i.v. and 1.2 mg intravitreal injection) combined with anti CMV immunoglobulin at 0.5 ml/kg every 2 weeks. After 4 weeks of systemic therapy, 20 weekly doses of intravitreal foscarnet and six cycles of immunoglobulins, a significant improvement of visual acuity was observed. The treatment was well tolerated with no side effect. In conclusion, our case suggests that systemic and local antiviral treatment combined with CMV-specific-IVIG, may reduce CMV load in the eye of patients with CMVR, leading to a consistent improvement of visual acuity. Systematic ophthalmologic examination should be recommended in HSCT recipients with multiple CMV reactivations and high peak CMV DNA levels.

HIV infection among illegal migrants, Italy, 2004-2007.

To determine HIV prevalence and place of exposure for illegal migrants in Italy, we tested 3,003 illegal adult migrants for HIV; 29 (0.97%) were HIV positive. Antibody avidity index results (indicators of time of infection) were available for 27 of those persons and showed that 6 (22.2%) presumably acquired their infection after migration.

Aggressive Non-Hodgkin lymphomas: risk factors and treatment of central nervous system recurrence.

Introduction: Secondary central nervous system lymphoma (SCNSL) is a potentially fatal event in the setting of aggressive Non-Hodgkin Lymphomas. Nowadays, despite of the very poor outcome of SCNSL, several studies are going to identify the high-risk patients' subgroup that could early develop this detrimental event and in whom the central nervous system (CNS) prophylaxis could improve survival. Areas covered: Herein, the authors will review the prophylactic and treatment strategy for SCNSL, focusing on the identification of high-risk subgroup. Expert opinion: The validated CNS International Prognostic Index score lacks sensitivity. The role of prophylaxis has been suggested as an important step for selected patients. Intrathecal prophylaxis is always less consolidated, due to its doubtful efficacy, whereas systemic high-dose methotrexate is becoming the favored option to reduce CNS relapse in high-risk aggressive lymphomas. However, there is no a clear guideline to help physicians in clinical practice. The encouraging results on treatment of primary CNS lymphoma prompted new therapeutic strategies for SCNSL, although larger and randomized prospective studies are needed. Future efforts should be addressed to better clarify these open questions.

High-grade B-cell lymphoma: how to diagnose and treat.

Introduction: High Grade B-cell Lymphomas (HGBL) have been defined as a new separate entity in 2016 revised WHO classification of lymphoid neoplasms. The previously well-known Double- and Triple-Hit Lymphomas (DHL/THL) are included in this umbrella category under the name of HGBL with MYC and BCL2 and/or BCL6 rearrangements (HGBL, R). A comprehensive diagnosis of HGBL is laborious, the diagnostic analyses required are expensive and time-consuming; moreover, a uniform consensus on which patients should be investigated has not been reached yet. Furthermore, there is no agreement on a standard therapeutic approach for this entity. Areas covered: In this article, the biological and clinical peculiarities of HGBL will be reviewed and all tools for a comprehensive diagnosis as well as the current therapeutic landscape will be investigated. Expert opinion: HGBL, R remains a challenging disease in terms of diagnosis and further research should be performed in order to define clear guidelines determining which cases have to be investigated thoroughly with FISH and other probes. Unsatisfying results have been shown in patients with HGBL, R treated with intensified chemoimmunotherapy strategies, therefore, larger prospective clinical trials should be conducted. Investigation into novel drugs that could lead to improvement of the current therapeutic approach should also be addressed.

Point-of-care screening, prevalence, and risk factors for hepatitis B infection among 3,728 mainly undocumented migrants from non-EU countries in northern Italy.

BACKGROUND: Screening migrants from areas where hepatitis B virus (HBV) infection is endemic is important to implement preventive measures in Europe. The aim of our study was to assess (1) the feasibility of point-of-care screening in a primary care clinic and (2) hepatitis B surface antigen (HBsAg) prevalence, associated risk factors, and its clinical and epidemiological implications in undocumented migrants in Brescia, northern Italy. METHODS: A longitudinal prospective study was conducted from January 2006 to April 2010 to assess HBsAg reactivity and associated risk factors among consenting undocumented migrants who accessed the Service of International Medicine of Brescia's Local Health Authority. Genotyping assay was also performed in HBV DNA-positive patients. RESULTS: Screening was accepted by 3,728/4,078 (91.4%) subjects consecutively observed during the study period, 224 (6%) of whom were found to be HBsAg-positive. HBsAg reactivity was independently associated with the prevalence of HBsAg carriers in the geographical area of provenance (p < 0.001). On the contrary, current or past sexual risk behaviors (despite being common in our sample) were not associated with HBV infection. Half of the HBsAg patients (111/224) had either hepatitis B e-antigen (HBeAg)-positive or -negative chronic HBV infection with a possible indication for treatment. HBV genotypes were identified in 45 of 167 HBV-infected patients as follows: genotype D, 27 subjects; genotype A, 8; genotype B, 5; and genotype C, 5. The geographical distribution of genotypes reflected the geographic provenance. CONCLUSIONS: Our results suggest that point-of-care screening is feasible in undocumented migrants and should be targeted according to provenance. Case detection of HBV infection among migrants could potentially reduce HBV incidence in migrants' contacts and in the general population by prompting vaccination of susceptible individuals and care of eligible infected patients.

Frequency of infectious diseases in immigrants in a Western European country: a population-based study.

The aim of this population-based study was to assess the incidence rates of infectious diseases in native- (Italian) and foreign-born (immigrants) populations in a North Italy area, in 2006-2010. Crude, age-specific incidence rates (IRs) and age-standardised rate ratios (SRRs) between foreign- and native-born subjects and their 95% confidence intervals (95% CI) were estimated. A total of 32,554 cases of infectious diseases were found (9.9% in foreign-born subjects). The highest SRRs between foreign- and nativeborn subjects were found for tuberculosis (SRR = 27.1; 95% CI 21.3-34.3), malaria (SRR = 21.1; 14.6-30.4), scabies (SRR = 8.5; 7.6-9.4), AIDS (SRR = 2.5; 1.8-3.4) and viral hepatitis B (SRR = 3.3; 2.1-5.2). The highest IR was found for AIDS in people from the Americas (IR = 4.57; 95% CI 2.2-8.4), for malaria and tuberculosis in people from Africa (IR = 13.89; 11.6-16.5 and IR = 11.87; 9.8-14.3 respectively). Therefore immigrants are at a higher risk of acquiring some common infectious diseases compared to the native population in Western European countries.

Polychlorinated Biphenyls, Glycaemia and Diabetes in a Population Living in a Highly Polychlorinated Biphenyls-Polluted Area in Northern Italy: a Cross-sectional and Cohort Study.

UNLABELLED: CONFLICTS OF INTERESTS: the authors declare no potential conflict of interests. BACKGROUND: Polychlorinated biphenyls (PCBs) have been found to be associated with diabetes in some, but not all, studies performed so far. The aim of this study was to assess the association between PCB serum levels and glycaemia and diabetes in people living in Brescia, a highly industrialised PCB-polluted town in Northern Italy. DESIGN AND METHODS: 527 subjects were enrolled in a cross-sectional population-based study: they were interviewed face-to-face in 2003 and also provided a blood sample under fasting conditions. The concentration of 24 PCB congeners was determined using gas-chromatography (GC/MS). Subsequently, all subjects were included in a follow-up (cohort) study. According to the Local Health Authority health-care database, subjects were considered to be diabetic if they had diabetes at interview time (prevalent cases) or during a 7-year follow-up (incident cases). RESULTS: A total of 53 subjects (10.0%) were diabetics: 28 had diabetes at enrolment and other 25 developed the disease subsequently. Diabetes frequency increased according to the serum concentrations of total PCBs and single PCB congeners, but no association was found when estimates were adjusted for education, body mass index, age and gender by logistic regression analysis. Accordingly, glycaemia increased with PCB serum levels, but no association was observed when multiple regression analysis, including confounding factors, was performed. CONCLUSIONS: This study does not support the hypothesis that PCB environmental exposure is strictly associated with diabetes or glycaemia.

Five year time course of celiac disease serology during gluten free diet: results of a community based "CD-Watch" program.

BACKGROUND: Little information is available on the effect of a follow-up strategy in celiac disease patients during gluten-free diet. AIMS: To assess 5 year time course of t-transglutaminase antibodies (t-TG) in celiac disease patients enrolled in a community based follow-up program. METHODS: Annual t-TG testing and periodical clinic visit in 2245 patients. RESULTS: Proportion of patients with negative t-TG progressively increased from 83% to 93% during the 5-year follow-up: poor adherence to gluten-free diet (HR 4.764), long duration of gluten-free diet (HR 0.929) and female gender (HR 1.472) were independently associated with serological outcome. In individual patients, 69% tested t-TG "persistently negative", 1% "persistently positive" and 30% "intermittently negative or positive". By applying mathematical modelling to t-TG conversion rates observed in this latter group at beginning and end of the follow-up program, the predicted proportion of t-TG negative population increased from 90% to 95% over 5 years. CONCLUSIONS: Time-course of t-TG serology in the community fluctuates in 1/3 of celiac disease patients suggesting inconstant adherence to gluten-free diet and need of follow-up strategy. Periodical serological and clinical follow-up is a viable and efficacious strategy to promote adherence to gluten-free diet as inferred from time-course of t-TG serology.