Alessio Signori

Scoring treatment response in patients with relapsing multiple sclerosis

Background: We employed clinical and magnetic resonance imaging (MRI) measures in combination, to assess patient responses to interferon in multiple sclerosis. Objective: To optimize and validate a scoring system able to discriminate responses to interferon treatment in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: Our analysis included two large, independent datasets of RRMS patients who were treated with interferons that included 4-year follow-up data. The first dataset (“training set”) comprised of 373 RRMS patients from a randomized clinical trial of subcutaneous interferon beta-1a. The second (“validation set”) included an observational cohort of 222 RRMS patients treated with different interferons. The new scoring system, a modified version of that previously proposed by Rio et al., was first tested on the training set, then validated using the validation set. The association between disability progression and risk group, as defined by the score, was evaluated by Kaplan Meier survival curves and Cox regression, and quantified by hazard ratios (HRs). Results: The score (0–3) was based on the number of new T2 lesions (>5) and clinical relapses (0,1 or 2) during the first year of therapy. The risk of disability progression increased with higher scores. In the validation set, patients with score of 0 showed a 3-year progression probability of 24%, while those with a score of 1 increased to 33% (HR = 1.56; p = 0.13), and those with score greater than or equal to 2 increased to 65% (HR = 4.60; p < 0.001). Conclusions: We report development of a simple, quantitative and complementary tool for predicting responses in interferon-treated patients that could help clinicians make treatment decisions.

Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis

We have analyzed 1448 patients with acquired aplastic anemia grafted between 2005 and 2009, and compared outcome of identical sibling (n=940) versus unrelated donor (n=508) transplants. When compared to the latter, sibling transplants were less likely to be performed beyond 180 days from diagnosis (39% vs. 85%), to have a cytomegalovirus negative donor/recipient status (15% vs. 23%), to receive antithymocyte globulin in the conditioning (52% vs. 61%), and more frequently received marrow as a stem cell source (60% vs. 52%). Unrelated donor grafts had significantly more acute grade II–IV (25% vs. 13%) and significantly more chronic graft-versus-host disease (26% vs. 14%). In multivariate analysis, the risk of death of unrelated donor grafts was higher, but not significantly higher, compared to a sibling donor (P=0.16). The strongest negative predictor of survival was the use of peripheral blood as a stem cell source (P<0.00001), followed by an interval of diagnosis to transplant of 180 days or more (P=0.0005), patient age 20 years or over (P=0.0005), no antithymocyte globulin in the conditioning (P=0.003), and donor/recipient cytomegalovirus sero-status, other than negative/negative (P=0.04). In conclusion, in multivariate analysis, the outcome of unrelated donor transplants for acquired aplastic anemia, is currently not statistically inferior when compared to sibling transplants, although patients are at greater risk of acute and chronic graft-versus-host disease. The use of peripheral blood grafts remains the strongest negative predictor of survival.

Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome

HBsAg-negative/HBcAb-positive haematopoietic stem cell transplant (HSCT) recipients are at high risk of hepatitis B virus (HBV) reactivation. Allogeneic HSCT recipients from years 2000 to 2010 were evaluated in order to study the impact of being HBsAg-negative/HBcAb-positive in this population. Overall, 137 of 764 patients (18%) were HBsAg-negative/HBcAb-positive before HSCT. Overall survival, non-relapse mortality (NRM), acute and chronic graft-vs.-host disease were similar in HBcAb-positive and HBcAb-negative patients. Reactivation occurred in 14 patients (10%) within a median of 19 months after HSCT (range 9-77). Cause-specific hazard for reactivation was decreased in the case of an HBV-immune/exposed donor (HRadjusted = 0.12; 95% CI, 0.02-0.96; p 0.045) and increased in patients who received rituximab treatment (HRadjusted = 2.91; 95%CI, 0.77-10.97; p 0.11). Competing risk analyses documented a protective role of an HBV-immune/exposed donor (p 0.041) and an increased probability associated with the length of treatment with cyclosporine (p <0.001) and treatment with rituximab (but not with low-dose rituximab prophylaxis, p <0.001 at each landmark point). No differences in overall survival and NRM were found between patients with and without HBV reactivation. The donors immunity was independently and consistently associated with a decreased risk of HBV reactivation, while rituximab and cyclosporine treatments increased the probability.

Leukaemia relapse after allogeneic transplants for acute myeloid leukaemia: predictive role of WT1 expression

We assessed WT1 expression (expressed as messenger copies/104 ABL1) from marrow cells of 122 patients with acute myeloid leukaemia (AML), before and after an unmanipulated allogeneic haemopoietic stem cell transplant (HSCT). The median age was 44 years (15–69), 59% were in first remission, 74% received a myeloablative conditioning regimen and the median follow up was 865 d (34–2833). Relapse was higher in 67 patients with WT1 expression, at any time post‐HSCT, exceeding 100 copies (54%), as compared to 16%, for 55 patients with post‐HSCT WT1 expression <100 copies (P < 0·0001). Similarly, actuarial 5‐year survival (OS) was 40% vs. 63%, respectively (P = 0·03). In multivariate Cox analysis, WT1 expression post‐HSCT was the strongest predictor of relapse (Hazard Ratio [HR] 4·5, P = 0·0001), independent of disease phase (HR 2·3, P = 0·002). Donor lymphocyte infusions (DLI) were given to 17 patients because of increasing WT1 levels: their OS was 44%, vs. 14% for 21 patients with increasing WT1 expression who did not receive DLI (P = 0·004). In conclusion, WT1 expression post‐HSCT is a strong predictor of leukaemia relapse and survival in AML; WT1 may be used as a marker for early interventional therapy.

Miniscrew design and bone characteristics: an experimental study of primary stability.

INTRODUCTION The purpose of this study was to evaluate the correlations between bone characteristics, orthodontic miniscrew designs, and primary stability. METHODS Four different miniscrews were placed in pig ribs. The miniscrews were first scanned with a scanning electron microscope to obtain measurable images of their threads. Subsequently, the maximum insertion torque of the screws and the maximum load value in the pullout force tests were measured; furthermore, bone specimen characteristics were analyzed by using cone-beam computed tomography. For each bone sample, the insertion site cortical thickness as well as both cortical and marrow bone density were evaluated. The nonparametric Kendall rank correlation (tau) was used to evaluate the strength of the associations among the characteristics measured. The nonparametric Kruskall-Wallis test was used to evaluate the differences among the groups, and post-hoc comparisons were assessed by using the Nemenyi-Damico-Wolfe-Dunn test. RESULTS A significant dependence was found between pitch and maximum insertion torque (tau, -0.49). Positive correlations were also found between pullout force and maximum insertion torque (tau, 0.64), cortical thickness (tau, 0.36), and marrow bone density (tau, 0.35). CONCLUSIONS In this in-vitro experimental study, strong correlations were observed among miniscrew geometry, bone characteristics, and primary stability.

Refining response to treatment as defined by the Modified Rio Score

Dear Editor, In a previous number of this journal we published a score (Modified Rio Score) based on magnetic resonance imaging (MRI) lesions and relapses after one year of treatment that was able to predict disability progression over time in relapsing–remitting multiple sclerosis (RRMS) patients treated with interferons.1 While patients in the two extreme risk groups defined by the Modified Rio Score could be classified after one year of treatment as patients at a low and high risk of progression, a number of patients (about 30% in the previous study)1 were in an intermediate situation and classified as having a medium risk of disease progression. In this case, it might be very difficult to decide how they should be considered in terms of treatment response and planning. With the objective of refining the score to better predict treatment response in the intermediate risk group, we re-evaluated the 112 RRMS patients from the previous analysis classified by the Modified Rio Score as at medium-risk of progression,1 among the 365 patients enrolled in the treatment arms of the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study.2 These patients were re-evaluated after an additional six-month clinical and MRI follow-up. They were a priori reclassified as medium-low risk if they had no relapses and <2 new MRI lesions (64 patients), and as medium-high risk if they had ≥1 relapse or ≥2 new MRI lesions (48 patients) in the period between 12–18 months from treatment start. The disability progression probability was estimated, as in the previous paper, in the three years following the oneyear evaluation.1 Progression probabilities at follow-up, as assessed by Kaplan-Meier survival curves, were 28% for medium-low and 54% for medium-high risk, very close to those of patients classified by the Modified Rio Score as low-risk (32%) and high-risk (50%), respectively (Figure 1). This suggests that when a given patient is classified as medium risk by the Modified Rio Score, he/she may undergo an additional clinical visit and MRI scan after six months: then, if new clinical relapses have not occurred in the additional six months and the new MRI scan at this time shows <2 new T2 lesions, the patient can be associated with the low-risk group; otherwise, if the patient has experienced ≥1 relapse in the additional six months or ≥2 new T2 lesions have appeared at the six-months MRI scan, then he/ she can be associated with the high-risk group. This observation is an additional step towards the use of a simple, evidence-based score for assessing therapeutic response to interferons in RRMS patients. 483892 MSJ19910.1177/1352458513483892Multiple Sclerosis JournalSormani et al. 2013

Autologous hematopoietic stem cell transplantation in multiple sclerosis A meta-analysis

Objective: To summarize the evidence on immunoablative therapy followed by autologous hematopoietic stem cell transplantation (aHSCT) to manage severe and treatment-refractory multiple sclerosis (MS). Methods: We collected all the published studies of aHSCT in any form of MS from 1995 to 2016, carefully excluding reports that were updated in subsequent studies. Endpoints were transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. A weighted metaregression based on a Poisson model was run, assessing whether there were study-specific characteristics with an effect on TRM and progression. Results: Fifteen studies including 764 transplanted patients were pooled in the meta-analysis. The pooled estimate of TRM was 2.1% (95% confidence interval [CI] 1.3%–3.4%). TRM was higher in older studies (p = 0.014) and in studies with a lower proportion of patients with relapsing-remitting MS (RRMS) (p = 0.028). A higher baseline Expanded Disability Status Scale (p = 0.013) was also significantly associated with a higher TRM. Pooled rate of progression was 17.1% at 2 years (95% CI 9.7%–24.5%) and 23.3% (95% CI 16.3%–31.8%) at 5 years. Lower 2-year progression rate was significantly associated with higher proportions of patients with RRMS (p = 0.004). The pooled proportion of NEDA patients at 2 years was 83% (range 70%–92%) and at 5 years was 67% (range 59%–70%). Conclusions: The emerging evidence on this therapeutic approach in MS indicates that the largest benefit/risk profile form this therapeutic approach can be obtained in patients with aggressive MS with a relapsing-remitting course and who have not yet accumulated a high level of disability.

Diagnostic performance of contrast-enhanced spectral mammography: Systematic review and meta-analysis

PURPOSE To estimate sensitivity and specificity of CESM for breast cancer diagnosis. METHODS Systematic review and meta-analysis of the accuracy of CESM in finding breast cancer in highly selected women. We estimated summary receiver operating characteristic curves, sensitivity and specificity according to quality criteria with QUADAS-2. RESULTS Six hundred four studies were retrieved, 8 of these reporting on 920 patients with 994 lesions, were eligible for inclusion. Estimated sensitivity from all studies was: 0.98 (95% CI: 0.96-1.00). Specificity was estimated from six studies reporting raw data: 0.58 (95% CI: 0.38-0.77). The majority of studies were scored as at high risk of bias due to the very selected populations. CONCLUSION CESM has a high sensitivity but very low specificity. The source studies were based on highly selected case series and prone to selection bias. High-quality studies are required to assess the accuracy of CESM in unselected cases.

Adenoidal hypertrophy and allergic rhinitis: is there an inverse relationship?

Background Nasal obstruction is a very common symptom in children. The main causes are allergic rhinitis (AR) and adenoidal hypertrophy (AH); the possible correlation between AR and AH has been investigated by few studies, mainly conducted using radiographic craniometry. This study aimed at investigating this topic by nasal endoscopy. Methods There were 205 children (134 boys; mean age, 6.7 years age range, 4–12 years) studied. Clinical visit, nasal endoscopy, and skin-prick test were performed in all patients. Anterior nasal obstruction was graded using the Friedmanns classification. Adenoid size was graded using the Parikhs classification. Perception of symptoms by children was also assessed using the visual analog scale. Results Ninety-two children (44.9%) had complete nasal obstruction and 28 children (13.7%) had choanae invasion. There was a negative significant correlation (r = –0.41; p < 0.001) between nose obstruction severity and volume of adenoids. Decreased probability of greater adenoid volume was associated with increased severity of nose obstruction (odds ratio [OR] = 0.13) and in patients with allergy compared with nonallergic patients (OR = 0.31). Conclusion This real-life study shows that large adenoids may be associated with absence of allergy, whereas large turbinates may be associated with small adenoids.

Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials

Objective: To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints. Methods: Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting model of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters. Results: Assuming a 50% reduction in new T2 lesions over 6 months, 90 patients/arm are required, whereas 165 patients/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (ϑ), sample sizes range from 70 patients/arm (using ARR) to 105 patients/arm (TTFR) for a 50% reduction in relapses, and 230 patients/arm (ARR) to 365 patients/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative ϑ, 2-year trials using ARR require 45 patients/arm (60 patients/arm for TTFR) for a 50% reduction in relapses and 145 patients/arm (200 patients/arm for TTFR) for a 30% reduction. Conclusion: Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration.