Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop)

background and purpose: cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. methods: this retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. the primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. results: a total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. the study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 +/- 0.25 vs. 0.82 +/- 0.80, p < 0.001). furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. the safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. conclusions: this study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. however, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary

Integration of oncology and palliative care : a Lancet Oncology Commission

Full integration of oncology and palliative care relies on the specific knowledge and skills of two modes of care: the tumour-directed approach, the main focus of which is on treating the disease; and the host-directed approach, which focuses on the patient with the disease. This Commission addresses how to combine these two paradigms to achieve the best outcome of patient care. Randomised clinical trials on integration of oncology and palliative care point to health gains: improved survival and symptom control, less anxiety and depression, reduced use of futile chemotherapy at the end of life, improved family satisfaction and quality of life, and improved use of health-care resources. Early delivery of patient-directed care by specialist palliative care teams alongside tumour-directed treatment promotes patient-centred care. Systematic assessment and use of patient-reported outcomes and active patient involvement in the decisions about cancer care result in better symptom control, improved physical and mental health, and better use of health-care resources. The absence of international agreements on the content and standards of the organisation, education, and research of palliative care in oncology are major barriers to successful integration. Other barriers include the common misconception that palliative care is end-of-life care only, stigmatisation of death and dying, and insufficient infrastructure and funding. The absence of established priorities might also hinder integration more widely. This Commission proposes the use of standardised care pathways and multidisciplinary teams to promote integration of oncology and palliative care, and calls for changes at the system level to coordinate the activities of professionals, and for the development and implementation of new and improved education programmes, with the overall goal of improving patient care. Integration raises new research questions, all of which contribute to improved clinical care. When and how should palliative care be delivered? What is the optimal model for integrated care? What is the biological and clinical effect of living with advanced cancer for years after diagnosis? Successful integration must challenge the dualistic perspective of either the tumour or the host, and instead focus on a merged approach that places the patient's perspective at the centre. To succeed, integration must be anchored by management and policy makers at all levels of health care, followed by adequate resource allocation, a willingness to prioritise goals and needs, and sustained enthusiasm to help generate support for better integration. This integrated model must be reflected in international and national cancer plans, and be followed by developments of new care models, education and research programmes, all of which should be adapted to the specific cultural contexts within which they are situated. Patient-centred care should be an integrated part of oncology care independent of patient prognosis and treatment intention. To achieve this goal it must be based on changes in professional cultures and priorities in health care

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Backthrusts and passive roof duplexes in fold-and-thrust belts. The case of Central-Western Sicily based on seismic reflection data

Seismic reflection profiles crossing the area bounded by the M. Kumeta Ridge and the M. Maranfusa-M. Galiello-Rocca Busambra morphostructural feature (central-western Sicily) were used to constrain the deep structural setting of the Sicilian-Maghrebian fold-and-thrust belt (FTB). By integrating seismic, field and well data, we attempted to correlate outcropping and deep-seated contractional structures, shedding light on the internal geometries of the thrust system. Results of the new seismostratigraphic analysis presented in this paper reveal structural variations along the tectonic edifice. This suggests dividing the study area into two sectors: the western sector is characterized by foreland-verging thrusts comparable to the already known structural model of the chain, conversely in the easternmost sector duplexes and hinterland-verging structures, here highlighted for the first time, prevail. In fact, the main carbonate relief of this area (Rocca Busambra Ridge) appears as the outcropping part of a thick tectonic pile bounded on its northern side by a high-angle backthrust, while at depth a blind southern verging (i.e. forelandward) thrust can been recognized; this structural setting suggests that underthrusting of the buried S-verging carbonate body induced the N-verging (i.e. hinterlandward) dislocation of the overlying units.On the whole, this structure can be interpreted as a triangle zone, where the outcropping relief represents a passive-roof duplex bounded, on its northern side, by the high-angle backthrust deeply connected with a low-angle décollement layer. The recognized backthrust appears as the product of a deep-seated tectonic activity, that played a key role for the upper thrust-sheet emplacement

La “Dorsale di Camporeale” (Sicilia NW):significato strutturale nel contesto della tettonica deep-seated.

The “Camporeale Ridge” (NW Sicily): structural significance within deep-seated tectonics. The “Camporeale Ridge” is a morphostructural element cropping out in NW Sicily. Detailed structural and stratigraphic analysis carried out in the study area allows us to reconstruct a main E-W-trending anticline partially exposed along the ridge. Its development is due to the action of high-angle transpressive faults which bound both northwards and southwards site of the ridge. Seismic reflection profile crossing the study area images a tectonic stack made up of carbonates rocks (Trapanese Units, TP) overlain a numidian flysch and Neogene terrigenous units along a low angle thrust plane. The profile images also that high angle faults affected the Trapanese Unit (TP) locally producing a back-verging younger structural high. The tectonic strain associated to high angle faults, within the TP units, is transferred along the oldest thrust plane to the upper structural layers moving northward to the innermost sectors

Effectiveness of 0.1% topical salicylic acid on blepharoconjunctivitis affecting glaucoma patients treated with topical prostaglandin analogues: a prospective randomized trial

AIM: To evaluate the efficacy of 0.1% topical salicylic acid (TSA) to treat iatrogenic chronic blepharoconjunctivitis in patients with primary open angle glaucoma (POAG), treated with topical prostaglandin analogues (TPAs). METHODS: Totally 60 patients were randomly distributed into 3 equal size groups, two of which treated with 0.1% TSA (OMKASA®) and 0.1% topical clobetasone butyrate (TCB; VISUCLOBEN®) respectively, and one consisting of untreated controls. The parameters taken into account at baseline (T0) and after 30d (T1) of therapy were: conjunctival hyperemia, lacrimal function tests [Schirmer I test and break up time (BUT)] and intraocular pressure (IOP). RESULTS: Conjunctival hyperemia showed a substantial improvement in both treated groups (P<0.001) but not among controls. Similarly, lacrimal function tests displayed an improvement of Schirmer I test in both treated groups (P<0.05) and an extension of BUT only in the group treated with 0.1% TSA (P<0.05). The IOP increase was statistically significant only in those patients treated with 0.1% TCB (P<0.001). CONCLUSION: The 0.1% TSA has proved to be an effective anti-inflammatory treatment of blepharoconjunctivitis affecting glaucoma patients on therapy with TPAs, leading to a sizeable decrease of inflammation as well as both quantitative and qualitative improvement of tear film. Furthermore, differently from 0.1% TCB, it does not induce any significant IOP increase