Sopravvivenza e mortalità per causa

Analisi della mortalità generale e per causa nelle regioni italian

Case Report: REL-1017 Reduces Abnormal Clinician Administered Dissociative States Scale Scores in Patients with Major Depressive Disorder

BACKGROUND: Dissociative symptoms may be found in a subset of patients with major depressive disorders (MDD). The Clinician-Administered Dissociative States Scale (CADSS) is a 23-item scale for the measurement of present-state dissociative symptoms with good inter-rater reliability and construct validity that can discriminate patients with dissociative disorders. The total CADSS score is derived by adding the score for each of the 23 items. A score of 4 or more on the CADSS is considered abnormal and clinically meaningful. Uncompetitive N-methyl-d-aspartic acid receptor (NMDAR) channel blockers have been proposed as a treatment for post-traumatic stress disorder (PTSD). REL-1017 is a novel, low potency, NMDAR channel blocker currently in Phase 3 studies for MDD. METHODS: This retrospective case series describes a subset of patients from a double-blind, randomized, placebo-controlled, in-patient 7-day, phase 2 trial of oral, once daily, 25 mg (75 mg loading dose on day 1, first dose) and 50 mg REL-1017 (100 mg loading dose on day 1, first dose) as an adjunctive treatment for MDD. This subset of patients was selected based on abnormal CADSS score at baseline, pre-treatment with the study drug. As part of REL-1017 safety evaluation, the CADSS was administered at four timepoints to all study patients: (a) 30 to 60 minutes pre-treatment at baseline on day 1; (b) 2 hours post-treatment on day 1 (after the first dose of study drug); (c) 2 hours post-treatment on day 7 (after the last dose); and (d) prior to discharge on day 9 (2 days after the last dose). RESULTS: Among the 62 randomized patients, four patients had a CADSS score of at least 4 on day 1 before study drug administration (2 patients in the 25 mg arm [CADSS score 22 and 4]; 1 patient in the 50 mg arm [CADSS score 35]; 1 patient in the placebo arm [CADSS score 6]). Among these 4 patients, starting on day 1, 2 hours post-treatment, the 2 subjects in the 25 mg subgroup (75 mg loading dose) and 1 subject in the 50 mg subgroup (100 mg loading dose) showed a clinically meaningful decrease in their CADSS score, while the single patient in the placebo group showed no change. CADSS scores on Day 1 pre-treatment, day 1 post-treatment, day 7 post last treatment, and on day 9 prior to discharge were 22-2-6-0; 4-0-0-0; 35-14-9-0, and 6-6-n/a-n/a, for the two patients in the 25 mg REL-1017 subgroup, the single patient in the 50 mg REL-1017 subgroup, and the single patient in the placebo group, respectively. CONCLUSIONS: These retrospective case report data potentially signal that REL-1017 may determine rapid and sustained improvement in patients with MDD and concurrent clinically meaningful dissociative symptoms assessed by a CADSS score of 4 or above. Ongoing phase 3 trials with REL-1017 are expected to enroll a total of 1200 outpatients with MDD. These studies will potentially generate additional data that may support the initiation of controlled studies with REL-1017 for the treatment of PTSD. FUNDING: Relmada Therapeutics

Emetogenicity of Antibody-Drug Conjugates (ADCs) in Solid Tumors with a Focus on Trastuzumab Deruxtecan: Insights from an Italian Expert Panel

In the past decade, nine antibody-drug conjugates (ADCs) have been approved for the treatment of various tumors, four of which specifically for solid malignancies. ADCs deliver the cytotoxic payload to the cancer site, thereby improving chemotherapy efficacy while reducing systemic drug exposure and toxicity. With their high selectivity, ADCs are associated with a manageable side-effect profile, with nausea and vomiting being among the most frequent toxicities, although this may vary according to the respective ADC and the associated payload. Information about the emetic risk of the new ADC compounds is limited. Three virtual focus groups of Italian oncologists were held to raise awareness on the importance of an antiemetic prophylaxis regimen to prevent and mitigate ADC-associated emesis and its sequelae. After reviewing published evidence and guidelines, the three expert panels shared their experience on the early use of ADCs gained through the participation in specific clinical trials and their clinical practice. The following issues were discussed: antiemetic therapy during trastuzumab deruxtecan treatment, with a protocol adopted at the San Raffaele Hospital (Milan, Italy); the use of steroids; the management of anticipatory nausea during trastuzumab deruxtecan therapy; nutritional counselling; and effective doctor\u2013patient communication. The experts acknowledged that recommendations should be drug-specific, and formulated opinion-based advice intended to guide physicians in their daily practice until further evidence emerges

A Phase 2a Double-Blind Randomized Trial of REL-1017 (Esmethadone) in Patients with MDD: Analysis of Subscales from the Symptoms of Depression Questionnaire

BACKGROUND: Major depressive disorder (MDD) is the second leading cause of disability and chronic disease burden in the United States. The importance of improving functional outcomes in MDD is increasingly recognized. The Symptoms of Depression Questionnaire (SDQ), a patient-reported measure, was developed to capture the heterogeneity of symptoms of MDD. REL-1017 (esmethadone HCl; d-methadone), is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and potential rapid antidepressant currently in Phase 3 development. In a Phase 2a trial, REL-1017 showed robust, rapid, and sustained antidepressant efficacy as adjunctive treatment in patients with MDD. The objective of this study was to assess the effects of REL-1017 on SDQ subscales to better characterize the functional implications of its therapeutic effects. METHODS: A double-blind, placebo-controlled, inpatient, two-doses, 25 and 50 mg, three-arm, 1:1:1, randomized, phase 2a trial of REL-1017 was conducted at 10 centers in the United States. Least square (LS) mean scores and Cohen's effect sizes of the total score of a 44-item of SDQ and its 5 subscales: lassitude, mood, cognitive/social functioning (SDQ-1); anxiety, agitation, anger, and irritability (SDQ-2); desire to be dead (SDQ-3); disruptions in sleep quality (SDQ-4); changes in appetite and weight (SDQ-5) were compared between REL-1017 and placebo. RESULTS: A total of 62 adult male and female patients (18-65 years of age) diagnosed with MDD participated in the trial. On day 14, the last day of efficacy measurement, the difference from placebo of the LS mean (90% CI) for REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed improvement for both tested doses on SDQ total score (-23.2; P = .0066 [effect size: 0.9]; -26.8 P = .0014 [effect size: 1.1]). Additionally, for SDQ subscales, REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed significant improvement as compared with placebo: SDQ-1 (-13.9; P = .0025 [effect size: 1.0]; -15.0; P = .0009 [effect size: 1.1]), SDQ-2 (-4.6; P = .0398 [effect size: 0.7]; -7.2; P = .0012 [effect size: 1.1]) and SDQ-4 (-2.7; P = .0055 [effect size: 1.0]; -2.8; P = .0029 [effect size: 1.0]). No significant differences were observed between the treated groups and placebo in the SDQ-3 and SDQ-5 subscales. CONCLUSIONS: In patients with MDD, aside from improving the overall CFB compared to placebo in SDQ total score, REL-1017 resulted in clinically meaningful and statistically significant improvements in cognitive/motivational, anxiety/irritability, and sleep-specific domains. The robust, rapid, and sustained efficacy of REL-1017 for MDD is not limited to improving mood, but potentially extends to cognitive, motivational, sleep, and social functions, with potentially meaningful therapeutic and socioeconomic implications. These results may signal disease-modifying effects of esmethadone for MDD that may offer potential advantages over symptomatic treatment with standard antidepressants. FUNDING: Relmada Therapeutics, Inc

Loco-regional adjuvant radiation therapy in breast cancer patients with positive axillary lymph-nodes at diagnosis (CN2) undergoing preoperative chemotherapy and with complete pathological lymph-nodes response. Development of GRADE (Grades of recommendation, assessment, Development and Evaluation) recommendation by the Italian Association of radiation therapy and Clinical Oncology (AIRO)

Objective: To perform a meta-analysis to determine the effect of loco-regional radiation therapy (RT) compared to no loco-regional RT for operated patients in clinical stage cN2 breast cancer at diagnosis and ypN0 after preoperative chemotherapy (PST). Material and Methods: Eligible studies were identified through a systematic search of the medical literature performed independently by two researchers using a validated search strategy. An electronic search of Medline via PubMed and Embase (Breast cancer AND preoperative chemotherapy AND radiation therapy) was conducted with no language or publication status restrictions. The effect of loco-regional RT on overall (OS), disease free (DFS), loco-regional recurrence-free (LRRFS) survival and local recurrence was evaluated. An electronic search of Medline via PubMed and Embase (Toxicity AND radiation therapy breast cancer AND preoperative therapy; toxicity AND breast surgery AND preoperative chemotherapy) was conducted for outcomes of harm: major acute and late skin toxicity, lymphedema and cardiac events. Results: Of 333 studies identified, 4 retrospective studies reporting on a total of 1107 patients were included in the meta-analysis. Six and 3 reported data of acute and late skin toxicity, while 2 studies provided information on cardiac events. Pooled results showed no difference in terms of hazard ratio for loco-regional RT versus no loco-regional RT [hazard ratio (HR) = 0.82, 95% confidence interval (CI) 0.63\u20131.68]. Loco-regional RT was associated with an OS benefit in the subgroup analysis: IIIB-C (loco-regional RT 79.3% vs no loco-regional RT 71.2%, p = 0.027) and T3-T4 (loco-regional RT 82.6% vs no loco-regional RT 76.6%, p = 0.025). No difference was shown in terms of 5-year DFS (loco-regional RT 91.2% vs no loco-regional RT 83%, p = 0.441) and LRRFS (loco-regional RT 98.1% vs no loco-regional RT 92.3%, p = 0.148). There was no significant difference between the groups in terms of acute and late skin toxicities, lymphedema and cardiac events. Conclusions: Because of the limitations due to the small number of studies and heterogeneity in the analysis, the present study does not allow to draw any definitive conclusion, highlighting the need for well-controlled trials to determine the effect of loco-regional RT in patients with cN2 having a pathological complete response in the axillary nodes after preoperative chemotherapy

We only die once... but from how many causes?

Analysing causes of death provides a betterunderstanding of long-term mortality trends. InFrance, the death certificates completed by physiciansgenerally mention several causes of death (2.4 onaverage in 2011). As a general rule, just one of them,the so-called underlying cause, is taken into account.As a result, the contribution of certain diseases-endocrine diseases for example-to mortality isseverely underestimated. In a context of rising lifeexpectancy where people increasingly die not from asingle cause of death but from several, it is importantto also take these contributing causes into account

Intermittent docetaxel chemotherapy as first-line treatment for metastatic castration-resistant prostate cancer patients

Aims: The intermittent administration of chemotherapy is a means of preserving patients' quality of life (QL). The aim of this study was to verify whether the intermittent administration of docetaxel (DOC) improves the patients' QL. Patients & methods: All patients received DOC 70 mg/m every 3 weeks for eight cycles. The patients were randomized to receive DOC continuously or with a fixed 3-month interval after the first four DOC courses. Results: The study involved 148 patients. There was no difference in QL between the groups receiving intermittent or continuous treatment. Intermittence had no detrimental effects on disease control. Conclusion: Although feasible and not detrimental, our results showed that true intermittent chemotherapy in metastatic castration-resistant prostate cancer patients failed to improve the patients' QL

Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer

Hormonal therapy is the preferred systemic treatment for recurrent or metastatic, post-menopausal hormone-receptor-positive breast cancer. Previous studies have shown that there is no cross-resistance between exemestane and reversible aromatase inhibitors. Exposure to hormonal therapy does not hamper later response to chemotherapy. Patients with locally advanced or metastatic, hormonal receptor positive or unknown, breast cancer were treated with oral anastrozole, until disease progression, followed by oral exemestane until new evidence of disease progression. The primary end point of the study was clinical benefit, defined as the sum of complete responses (CR), partial responses (PR) and > 24 weeks stable disease (SD). In all, 100 patients were enrolled in the study. Anastrozole produced eight CR and 19 PR for an overall response rate of 27% (95% CI: 18.6-36.8%). An additional 46 patients had long-term (> 24 weeks) SD for an overall clinical benefit of 73% (95% CI: 63.2-81.4). Median time to progression (TTP) was 11 months (95% CI: 10-12). A total of 50 patients were evaluated for the second-line treatment: exemestane produced one CR and three PR; 25 patients had SD which lasted ≥ 6 months in 18 patients. Median TTP was 5 months. Toxicity of treatment was low. Our study confirms that treatment with sequential hormonal agents can extend the period of time during which endocrine therapy can be used, thereby deferring the decision to use chemotherapy. © 2005 Cancer Research UK

Reversal of <i>MYB </i>-dependent suppression of <i>MAFB </i>expression overrides leukaemia phenotype in MLL-rearranged AML

Abstract The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias