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Plitidepsin (P) is a marine-derived anticancer compound isolated from the tunicate Aplidium albicans . P plus low-dose dexamethasone (LD-DXM) was evaluated versus LD-DXM alone in patients with relapsed/refractory multiple myeloma (r/r MM) in the randomized phase III ADMYRE trial. In absence of a randomized study with P + LD-DXM vs. POM + LD-DXM, a direct matched comparison between P + LD-DXM (ADMYRE data) and pomalidomide (POM) + LD-DXM as an External Control Arm (ECA) was conducted using individual patient-level data from several contemporary POM + LD-DXM trials with a similar design. A first analysis (ECA1) showed that P + LD-DXM was non-inferior to POM + LD-DXM in terms of median overall survival (OS): 11.8 vs. 13.9 months; HR = 1.009 (95%CI, 0.812–1.254; p  = 0.9336). Safety profile showed a lower rate of grade ≥ 3 hematological treatment-related adverse events (TRAEs) (neutropenia 2.5% vs. 37.1%; thrombocytopenia 2.5% vs. 13.2%) and infections (8.1% vs. 18.7%) for P + LD-DXM, and a higher rate of grade ≥ 1 gastrointestinal TRAEs (52.8% vs. 27.4%), grade ≥ 3 blood creatine phosphokinase (14.3% v s. 0%) and grade ≥ 3 myalgia (5.6% vs. 0%). A second analysis (ECA2) compared POM + LD-DXM with the LD-DXM alone arm included in ADMYRE and showed a treatment effect in OS (HR = 0.762; 95%CI, 0.566–1.026) similar to that observed in ADMYRE (HR = 0.797, 95%CI, 0.596–1.067). Safety profile of POM + LD-DXM was associated to a higher rate of TRAEs, as expected for a combination. In conclusion, P + LD-DXM can be an alternative therapeutic option in r/r MM as this comparison shows that P + LD-DXM is non-inferior in OS to POM + LD-DXM with an advantageous safety profile in terms of hematological and infection events.

Background: The phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma (r/r MM). ADMYRE met its primary endpoint, showing a 35% reduction in the risk of progression or death. Methods: Results from a pre-planned subgroup of patients aged <75 years are shown here. This subgroup includes most of the patients evaluated in the ADMYRE study: 145/171 patients (84.8%) in the plitidepsin + DXM arm and 71/84 (84.5%) patients in the DXM alone arm. Results: Compared to the overall ADMYRE population, a higher reduction was found with plitidepsin plus DXM for the risk of progression or death in the primary endpoint: 47.7% vs. 35.0% (Hazard ratio [HR] = 0.523 vs. HR = 0.6509). Higher reduction in the risk of death was also found (28.9% vs. 20.3%; HR = 0.711 vs. HR = 0.797), with a clinically meaningful 5-month difference in median overall survival (13.0 months vs. 8.1 months; p = 0.0350). The safety profile of plitidepsin plus DXM in patients aged <75 years was similar to that observed in the overall population of patients treated in the ADMYRE study. The most common adverse events (all grades) related to the study treatment in patients < 75 years were fatigue (39.2% of patients), gastrointestinal (nausea, 39.2%; vomiting, 19.6%; diarrhea, 14.7%), and myalgia (14.0%). Conclusions: Larger differences in efficacy outcomes while maintaining a similar safety profile, together with a novel mechanism of action, suggest that this combination can be a valid option for patients with r/r MM aged <75 years.

Plitidepsin is a cyclic depsipeptide of marine origin in clinical development in cancer patients. Previously, some depsipeptides have been linked to increased cardiac toxicity. Clinical databases were searched for cardiac adverse events (CAEs) that occurred in clinical trials with the single-agent plitidepsin. Demographic, clinical and pharmacological variables were explored by univariate and multivariate logistic regression analysis. Forty-six of 578 treated patients (8.0%) had at least one CAE (11 patients (1.9%) with plitidepsin-related CAEs), none with fatal outcome as a direct consequence. The more frequent CAEs were rhythm abnormalities (n = 31; 5.4%), mostly atrial fibrillation/flutter (n = 15; 2.6%). Of note, life-threatening ventricular arrhythmias did not occur. Myocardial injury events (n = 17; 3.0%) included possible ischemic-related and non-ischemic events. Other events (miscellaneous, n = 6; 1.0%) were not related to plitidepsin. Significant associations were found with prostate or pancreas cancer primary diagnosis (p = 0.0017), known baseline cardiac risk factors (p = 0.0072), myalgia present at baseline (p = 0.0140), hemoglobin levels lower than 10 g/dL (p = 0.0208) and grade ≥2 hypokalemia (p = 0.0095). Treatment-related variables (plitidepsin dose, number of cycles, schedule and/or total cumulative dose) were not associated. Electrocardiograms performed before and after plitidepsin administration (n = 136) detected no relevant effect on QTc interval. None of the pharmacokinetic parameters analyzed had a significant impact on the probability of developing a CAE. In conclusion, the most frequent CAE type was atrial fibrillation/atrial flutter, although its frequency was not different to that reported in the age-matched healthy population, while other CAEs types were rare. No dose-cumulative pattern was observed, and no treatment-related variables were associated with CAEs. Relevant risk factors identified were related to the patient’s condition and/or to disease-related characteristics rather than to drug exposure. Therefore, the current analysis supports a safe cardiac risk profile for single-agent plitidepsin in cancer patients.

The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m2) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting ≥6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator’s assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines.

SummaryPlocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies. This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors. Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62 years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5 mg/m2/Gem 1000 mg/m2) was the MTD. Accrual into DL7 (Plo 10.0 mg/m2/Gem 1000 mg/m2) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4 months occurred among 13 pts with ovarian cancer. The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5 mg/m2/Gem 1000 mg/m2. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

[This corrects the article DOI: 10.1371/journal.pone.0132546.].

The objective of this study was to establish and analyze the relationship between resilience, anxiety states and sports injuries, taking in account the level of competition. 185 soccer players of various clubs and categories participated, using diversity questionnaires such as: CD-RISC and STAI-RASGO, as well as an injuries register. Analysis with structural equations was carried out. Results showed that competitive level directly affects the capacity of confronting future injuries independently of the anxiety states players have. El objetivo de este estudio fue determinar y analizar las relaciones existentes entre la resiliencia, los niveles de ansiedad (estado y rasgo) y las lesiones deportivas en base al nivel competitivo. Para ello se analizaron a 185 futbolistas de diversos clubes y categorías, mediante los cuestionarios CD-RISC y STAI-RASGO, así como una hoja de autoregistro de lesiones. Se realizó un análisis mediante ecuaciones estructurales y los resultados depararon que a mayor nivel de profesionalidad mayor capacidad de resiliencia, concluyéndose que el nivel competitivo afecta de una manera directa a la capacidad de afrontar las lesiones independientemente de los niveles de ansiedad que tengan los futbolistas.

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.