Bortezomib a Safe Treatment for Patients with Multiple Myeloma and Cystic Fibrosis

Introduction: Bortezomib is a proteasome inhibitor that targets myeloma cell and its bone marrow micro-environment. Intravenous Bortezomib (1.3 mg/m2 administered on days 1,4,8 and 11 of a 21 day cycle), with or without dexamethasone, is effective and well tolerated in patients with relapsed/refractory multiple myeloma (MM). Methods:  We treated a MM patient with Cystic Fibrosis with Bortezomib alone to avoid the use of corticosteroid and consequently the risk of lung infection reactivations, first of all due to the patient Pseudomonas aeruginosa colonization. Bortezomib was administrated at 1.3 mg/m2 on days 1,4,8 and 11 with a 10 day rest period  and four 21-day cycles were administered. We evaluate the treatment response and toxicity. Results: After four cycles of therapy the patient achieved a  very good partial response (VGPR) according to the IMWG response criteria, without clinically significant side effects. Conclusions: Bortezomib can be successfully utilized for the management of this difficult disease situatio

Executive function impairment in early - treated PKU subjects with normal mental development

Executive functions were studied in 14 early and continuously treated PKU subjects (age 10.8 years, range 8-13) in comparison with controls matched for IQ, sex, age and socioeconomic status. Brain MRI examination was normal in all PKU patients. Neuropsychological evaluation included Wisconsin Card Sorting Test, Rey-Osterreith Complex Figure Test, Elithorn's Perceptual Maze Test, Weigl's Sorting Test, Tower of London, Visual Search and Motor Motor Learning Test. Whatever the IQ, PKU subjects performed worse than controls in tests exploring executive functions. Subgrouping the PKU subjects according to the quality of dietary control for the entire follow-up period (using 400 micromol/L as cut-off value for blood phenylalanine (Phe) concentration) showed that patients with worse dietary control performed more poorly than both the PKU group with the best dietary control and the control group. However, a mild impairment of executive functions was still found in PKU patients with a good dietary control (Phe 400 micromol/L) compared to controls. Concerning the PKU group as a whole, no linear correlation was found between neuropsychological performance and historical and concurrent biochemical parameters. We conclude that (a) PKU patients, even when treated early, rigorously and continuously, show an impairment of frontal lobe functions; (b) a protracted exposure to moderately high levels of Phe can affect frontal lobe functions independently of the possible effect of the same exposure on IQ; (c) in order to reduce the risk of frontal lobe dysfunction, the target of dietary therapy should be to maintain blood Phe concentration below 400 micromol/L

Efficacy and safety of once-weekly bortezomib in multiple myeloma patients

AbstractIn a recent phase 3 trial, bortezomib-melphalan-prednisone-thalidomide followed by maintenance treatment with bortezomib-thalidomide demonstrated superior efficacy compared with bortezomib-melphalan-prednisone. To decrease neurologic toxicities, the protocol was amended and patients in both arms received once-weekly instead of the initial twice-weekly bortezomib infusions: 372 patients received once-weekly and 139 twice-weekly bortezomib. In this post-hoc analysis we assessed the impact of the schedule change on clinical outcomes and safety. Long-term outcomes appeared similar: 3-year progression-free survival rate was 50% in the once-weekly and 47% in the twice-weekly group (P > .999), and 3-year overall survival rate was 88% and 89%, respectively (P = .54). The complete response rate was 30% in the once-weekly and 35% in the twice-weekly group (P = .27). Nonhematologic grade 3/4 adverse events were reported in 35% of once-weekly patients and 51% of twice-weekly patients (P = .003). The incidence of grade 3/4 peripheral neuropathy was 8% in the once-weekly and 28% in the twice-weekly group (P < .001); 5% of patients in the once-weekly and 15% in the twice-weekly group discontinued therapy because of peripheral neuropathy (P < .001). This improvement in safety did not appear to affect efficacy. This study is registered at http://www.clinicaltrials.gov as NCT01063179

Empowering Reentrant Projections from V5 to V1 Boosts Sensitivity to Motion

Evidence from macaques [1] and humans [2, 3] has shown that back projections from extrastriate areas to the primary visual area (V1) determine whether visual awareness will arise. For example, reentrant projections from the visual motion area (V5) to V1 are considered to be critical for awareness of motion [2, 3]. If these projections are also instrumental to functional processing of moving stimuli [4–8], then increasing synaptic efficacy in V5-V1 connections should induce functionally relevant short-term plastic changes, resulting in enhanced perception of visual motion. Using transcranial magnetic stimulation (TMS), we applied a novel cortico-cortical paired associative stimulation (ccPAS) protocol to transiently enhance visual motion sensitivity and demonstrate both the functional relevance of V5-V1 reentrant projections to motion perception and their plasticity. Specifically, we found that ccPAS aimed at strengthening reentrant connectivity from V5 to V1 (but not in the opposite direction) enhanced the human ability to perceive coherent visual motion. This perceptual enhancement followed the temporal profile of Hebbian plasticity [9–18] and was observed only when an optimal timing of 20 ms between TMS pulses [2, 3, 5, 6] was used, not when TMS pulses were delivered synchronously. Thus, plastic change is critically dependent on both the direction and timing of connectivity; if either of these requirements was not met, perceptual enhancement did not take place. We therefore provide novel causal evidence that V5-V1 back projections, instrumental to motion perception, are functionally malleable. These findings have implications for theoretical models of visual awareness and for the rehabilitation of visual deficits

Cervical cancer screening in women vaccinated against human papillomavirus infection: Recommendations from a consensus conference

In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age (25&nbsp;years) for cervical cancer (CC) screening from 2017. The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention. The ONS (National Screening Monitoring Centre) Directive and the GISCi (Italian Group for Cervical Screening) identified the consensus conference as the most suitable method for addressing this topic. A summary of consensus recommendations is reported here. The main objective was to define the best screening methods in girls vaccinated against HPV and the knowledge required for defining evidence-based screening strategies. A Jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews of literature and evidence. The Jury considered changing the screening protocols for girls vaccinated in their twelfth year as appropriate. Tailored screening protocols based on vaccination status could be replaced by \u201cone size fits all\u201d protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5&nbsp;years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept

Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination

Objective Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. Methods We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. Results Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). Conclusions In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022Peer reviewe