Abstract: A new national survey has been carried out by the Italian Centers for Cognitive Disorders and Dementias (CCDDs). The aim of this new national survey is to provide a comprehensive description of the characteristics, organizational aspects of the CCDDs, and experiences during the COVID-19 pandemic. Methods A list of all national CCDDs was requested from the delegates of each Italian region. The online questionnaire is divided in two main sections: a profile section, containing information on location and accessibility, and a data collection form covering organization, services, treatments, activities, and any service interruptions caused by the COVID-19 outbreak. Results In total, 511 out of 534 (96%) facilities completed the profile section, while 450 out of 534 (84%) CCDDs also completed the data collection form. Almost half of the CCDDs (55.1%) operated for 3 or fewer days a week. About one-third of the facilities had at least two professional figures among neurologists, geriatricians and psychiatrists. In 2020, only a third of facilities were open all the time, but in 2021, two-thirds of the facilities were open. Conclusion This paper provides an update on the current status of CCDDs in Italy, which still shows considerable heterogeneity. The survey revealed a modest improvement in the functioning of CCDDs, although substantial efforts are still required to ensure the diagnosis and care of patients with dementia.

Abstract: Remission in systemic lupus erythematosus (SLE) is defined through a combination of ‘clinical SLE Disease Activity Index (cSLEDAI)=0’, ‘physician's global assessment (PGA) 〈 0.5’ and ‘prednisone (PDN) ≤5 mg/day’. We investigated the performance of these items, alone or in combination, in defining remission and in predicting SLICC/ACR Damage Index. Methods We tested seven potential definitions of remission in SLE patients followed-up for ≥5 years: PDN ≤5 mg/day; PGA 〈 0.5; cSLEDAI=0; PGA 〈 0.5 plus PDN ≤5 mg/day; cSLEDAI=0 plus PGA 〈 0.5; cSLEDAI=0 plus PDN ≤5 mg/day; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA 〈 0.5. The effect of these definitions on damage was evaluated by Poisson regression analysis; the best performance was identified as the lowest Akaike and Bayesian information criterion (AIC and BIC). Positive and negative predictive values in identifying no damage increase were calculated. Results We included 646 patients (mean±SD disease duration 9.2±6.9 years). At multivariate analysis, ≥2 consecutive year remission according to all definitions protected against damage (OR, 95% CI: PGA 〈 0.5 0.631, 0.444 to 0.896; cSLEDAI=0 0.531, 0.371 to 0.759; PGA 〈 0.5 plus PDN ≤5 mg/day 0.554, 0.381 to 0.805; cSLEDAI=0 plus PGA 〈 0.5 0.574, 0.400 to 0.826; cSLEDAI=0 plus PDN ≤5 mg/day 0.543, 0.376 to 0.785; cSLEDAI=0 plus PDN ≤5 mg/day plus PGA 〈 0.5 0.532, 0.363 to 0.781, p 〈 0.01 for all), except PDN ≤5 mg/day, which required four consecutive years (OR 0.534, 95% CI 0.325 to 0.877, p=0.013). Positive and negative predictive values were similar; however, cSLEDAI=0 showed the best performance (AIC 1082.90, BIC 1109.72, p 〈 0.0001). Adding PGA 〈 0.5 and/or PDN ≤5 mg/day to cSLEDAI=0 decreased remission duration (−1.8 and −1.5 year/patient, respectively) without increasing cSLEDAI=0 performance in predicting damage accrual. Conclusions cSLEDAI=0 is the most attainable definition of remission, while displaying the best performance in predicting damage progression in the short-to-mid-term follow-up.

Abstract: Solar thermal collector system is a widely used solution involving renewable energy source to cover the energy demand for domestic hot water production. At Italian level, the UNI TS 11300 provides a calculation methodology based on two approaches: the asset rating, which is easy to be applied but provides approximated results, and the tailored rating, which is more reliable but requires several detailed information. In this context, the present work proposes a new methodological approach to develop a simplified calculation method in order to obtain accurate energy performance results with no-additional cost for assessors and final users. Different case studies were analysed carrying out parametric simulations. The obtained results have led to the definition of the new simplified calculation methodology to predict the thermal energy supplied by solar thermal collectors; it allows also calculating the domestic hot water volume to be covered by other technical building systems, becoming a useful tool for their pre-dimensioning. Besides, the results open to new scenarios of interest, such as the application of the same approach to other energy services in order to integrate the outcomes of the asset rating provided by the UNI TS 11300.

Abstract: INTRODUCTION. Bortezomib- and/or lenalidomide-based combinations are standard initial approaches in transplant (ASCT) ineligible NDMM. Different studies confirmed the advantages of continuous treatment. Despite the benefits of bortezomib maintenance, the parenteral administration and the risk of peripheral neuropathy (PN) limit its long-term use. The oral proteasome inhibitor (PI) Ixazomib plus Lenalidomide-dexamethasone was effective and well tolerated at diagnosis or relapse. The need for a convenient and well tolerated PI-based frontline therapy for an extended duration with minimal cumulative toxicity remains an unmet need for the elderly. In this prospective, multicenter, phase II randomized study, we assessed Ixazomib in combination with dexamethasone, Cyclophosphamide, Thalidomide or Bendamustine, followed by Ixazomib maintenance in ASCT-ineligible NDMM. METHODS. NDMM patients (pts) ≥65 years old or younger ASCT-ineligible could be enrolled. Treatment consisted of nine 28-day induction cycles of Ixazomib 4 mg on days 1,8,15 and dexamethasone 40 mg on days 1,8,15,22 (Id) or combined with Cyclophosphamide 300 mg/m2 orally on days 1,8,15 (ICd) or plus Thalidomide 100 mg/day (ITd) or plus Bendamustine 75 mg/m2 iv on days 1,8 (IBd); followed by maintenance with Ixazomib 4 mg on days 1,8,15 until progression. Because the study included the novel drug Ixazomib, dual stopping rules combining efficacy (at least very good partial response [VGPR] rate), and safety (predefined toxicity possibly related to Ixazomib) were planned and analyzed in a cohort of 5 patients in each arm during the first 4 cycles. Here we report the results of the cohort analysis during the first 4 cycles and the efficacy and safety analysis during induction treatment. RESULTS. In February 2017, the protocol was amended due to a low enrolment and the IBd arm, the only one including an iv drug, was closed. After closing this arm, all the other all oral arms continued the enrolment. Overall, 175 pts were enrolled (Id 42, ICd 61, ITd 61, and IBd 11 pts) and 171 pts started treatment. Median age was 74 years, 20% of pts had high risk cytogenetics, 44% were fit, 30% intermediate and 26% frail, according to the IMWG frailty score. Median follow-up was 13.2 months (IQR 8.9-20.7). During the first 4 cycles, at least VGPR rate was 24% with Id, 33% with ICd, 31% with ITd and 18% with IBd. In March 2018, after the analysis of the 4th cohort, the Id arm was closed due to high risk of inefficacy. Overall response rate (ORR) during induction was 73%, VGPR was 39%. ≥VGPR rates were 24% in Id, 48% in ICd, 43% in ITd and 27% in IBd. Median time to first response was 2.4 and to the best response 4 months. Responses were comparable according to cytogenetics: in high risk pts, ORR was 77%, ≥VGPR 46% and ≥nCR 17% as compared to 71%, 36% and 18% in standard risk pts (p=0.53, p=0.33 and p=1, respectively). Response rates were also comparable according to frailty status: in frail pts, ORR was 73%, ≥VGPR 36% and ≥nCR 11% as compared to 75%, 40% and 17% in intermediate and 70%, 40% and 22% in fit pts (p=0.78, p=0.90 and p=0.32, respectively). Median number of induction cycles was 9 (IQR 5-9); 93 (53%) pts completed induction treatment and 14 (8%) pts are still on induction treatment. During the first 4 cycles, hematologic toxicity was limited, and non-hematologic toxicity manageable. The most frequent G3-4 adverse event (AE) was rash in ITd arm (11%); discontinuation rate due to toxicity was 6%. During induction, the rate of at least 1 hematologic G≥3 AE was 11% and at least 1 non-hematologic G≥3 AE was 44%. The most frequent G≥3 AEs were neutropenia (8%), gastrointestinal (9%), infections (11%), neurologic (11%) and dermatologic (6%). G3-4 thrombocytopenia (3%) and PN (5%) were limited. Ixazomib dose reduction due to AEs was required in 15% of pts. The rate of non-hematologic AEs was slightly higher in ITd arm (37% in Id, 37% in ICd, 53% in ITd, 55% in IBd). Early death rate ( 〈 60 days from start therapy) was 1%. CONCLUSIONS. ITd and ICd are convenient all-oral induction regimens for ASCT-ineligible NDMM, confirming an improved efficacy of a triplet vs a doublet combination, also in intermediate and frail patients. Id showed lower efficacy, thus suggesting a possible effect of the dose of Ixazomib or the absence of a third drug. Treatment was feasible, with limited toxicity and low discontinuation rate due to AEs, although ITd induced a slightly higher toxicity, but mainly attributable to Thalidomide. Disclosures Larocca: Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Corradini:Servier: Honoraria; Amgen: Honoraria; Gilead: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; KiowaKirin: Honoraria; Jazz Pharmaceutics: Honoraria; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Celgene: Honoraria, Other: Travel Costs. Mina:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Liberati:Bristol-Myers Squibb: Honoraria; Roche: Other: Clinical trial support; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Honoraria, Other: Clinical trial support; Novartis: Other: Clinical trial support. Petrucci:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Patriarca:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cellini:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Janssen: Honoraria. Galli:Takeda: Honoraria; Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria. Aquino:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. De Sabbata:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ballanti:Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Offidani:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boccadoro:Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Bringhen:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Abstract: Background. Approximately 70% of newly diagnosed chronic lymphocytic leukemia (CLL) patients present in early Binet or Rai stage, may never require treatment, and may have a life expectancy similar to that of the general population. Two independent and recent studies have identified the clinical and immunogenetic variables associated with shorter time to first treatment (TTFT) in Binet A and Rai 0 CLL (Condoluci et al., Blood 2020; Cohen et al., Haematologica 2020). However, the clinical impact of gene mutations in predicting TTFT is not completely understood. Purpose. Using a training/validation approach, we aimed at identifying new molecular biomarkers that may predict early treatment requirement and may help clinicians to better plan the watch and wait strategy in asymptomatic early stage CLL patients. Methods. The training cohort included 295 CLL in Binet A stage who did not require treatment for at least 3 months after diagnosis. The two validation multicenter cohorts included 402 treatment-naïve Binet A CLL patients (Binet A validation cohort) and 395 untreated Rai 0 CLL patients (Rai 0 validation cohort), respectively. In the training cohort, tumor genomic DNA was isolated from peripheral blood mononuclear cells at the time of diagnosis and was analyzed in the coding exons plus splice sites of the most frequently mutated genes in CLL with a next-generation-sequencing (NGS) approach using a variant allele frequency (VAF) threshold of 5%. In the validation series, the XPO1 gene (exons 15 and 16) was analyzed by NGS or by Sanger sequencing. The primary endpoint was TTFT defined as the time interval between the date of CLL diagnosis and the date of first CLL treatment. Results. In the training cohort, NGS mutational analysis showed that XPO1 was mutated in 7 (2.4%) patients. In univariate analysis, trisomy 12 (HR 2.42; 95% CI 1.43-4.15; p=0.001), unmutated IGHV genes (HR 4.51; 95% CI 2.83-7.05; p & lt;0.0001) and mutations of XPO1 (HR 8.88; 95% CI 3.77-20.95; p & lt;0.0001) (Fig. 1A), NOTCH1 (HR 3.02; 95% CI 1.66-5.51; p & lt;0.001) and SF3B1 (HR 2.65; 95% CI 1.15-6.10; p=0.022) were associated with a shorter TTFT. By multivariate analysis, XPO1 mutations (HR 4.24; 95% CI 1.72-10.44; p=0.002) and unmutated IGHV genes (HR 3.43; 95% CI 2.08-5.67; p & lt;0.0001) maintained an independent association with a shorter TTFT. XPO1 mutational analysis was subsequently investigated in 2 independent multicenter cohorts of early stage CLL patients. In the Binet A validation cohort (N=402 patients), XPO1 was mutated in 15 (3.7%) patients and was associated with a shorter TTFT (HR 2.59; 95% CI 1.36-4.96; p=0.004) (Fig. 1B). Similarly, also in the Rai 0 validation cohort, (N=395 patients), XPO1was mutated in 8 (2.0%) patients and was associated with a shorter TTFT (HR 6.02; 95% CI 15.03-4.96; p & lt;0.001) (Fig. 1C). Moreover, in the Rai 0 validation cohort, XPO1 mutations maintained an independent association with a shorter TTFT when corrected in multivariate analysis by the IGHV mutational status (HR 3.31; 95% CI 1.30-8.44; p=0.012). By combining the training and the validation cohorts (N=1092 patients), a total of 30 somatically acquired XPO1 mutations were identified (2.7% of patients). More precisely, 27 (90.0%) mutations affected XPO1 codon E571 and 3 (10.0%) codon D624. This finding suggests that a target sequencing or an allele-specific polymerase chain reaction based method may be used to identify XPO1 mutations in a simple and time-effective manner. From a clinical perspective, patients carrying either XPO1 E571 or D624 mutations showed superimposable outcome in terms of TTFT (p=0.345) (Fig. 1D). Conclusions. Mutations of the XPO1 gene, encoding for exportin 1 which mediates the nuclear export of proteins and RNAs, are an independent predictor of shorter TTFT validated in independent series of early stage treatment-naïve CLL patients. XPO1 mutations are conceivably gain-of-function and may enhance cell proliferation by exporting out of the nucleus with a greater extent proteins that physiologically downregulate cell proliferation. Based on these results, XPO1 mutational analysis might be incorporated in other prognostic scores and help clinicians to refine the management of the watch and wait strategy for early stage CLL. In addition, XPO1 inhibitors are particularly active in XPO1E571 mutated cells (Taylor et al., Cancer Discov 2019) providing initial pre-clinical rational for their usage in XPO1 mutated CLL patients. Figure Disclosures Scarfo: AstraZeneca: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Del Giudice:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Other: grant for meeting partecipation; Janssen: Other: grant for meeting participation; Tolero: Membership on an entity's Board of Directors or advisory committees. Sportoletti:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Marasca:Shire: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Ghia:Acerta/AstraZeneca: Consultancy, Honoraria; ArQule: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Research Funding; Celgene/Juno: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; MEI: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Adaptive, Dynamo: Consultancy, Honoraria. Foà:Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gaidano:Sunesys: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees. Rossi:AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.