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As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0–2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1–14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled. Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9–21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66–13·73] vs 7·10 months [5·88–8·48]; hazard ratio 0·61, 95% CI 0·49–0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]). Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide. Celgene.

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib and dexamethasone (PVd) significantly improved the progression‐free survival (PFS) and the overall response rate (ORR) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. All patients were previously treated with lenalidomide (70% refractory to lenalidomide) and had received one to three prior regimens. Here we report the first efficacy and safety analysis of PVd vs Vd in Japanese patients with relapsed or refractory multiple myeloma. Seventeen patients enrolled in the OPTIMISMM trial in Japan. With a median follow‐up of 14.8 months, the median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and the ORR was 100% vs 60.0%, respectively. The safety profile was as expected for PVd. Toxicities were managed with dose reductions and interruptions, and no patients discontinued PVd due to treatment‐emergent adverse events. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients. Here we report the efficacy and safety of PVd vs Vd in 17 patients with relapsed refractory multiple myeloma enrolled in the OPTIMISMM trial in Japan. With a median follow‐up of 14.8 months, median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and ORR was 100% vs 60.0%, respectively; the safety profile with PVd was as expected. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients.

This study aims to compare the effects of some chemical agents on the removal of calcareous encrustations, which are characterized by the presence of both calcium and silicon. The experimentation was conducted during the conservation treatments of Cerriglio’s nymphaeum (Massa Lubrense, Naples, Italy). Tests were carried out in the laboratory on specimens and in situ to define the most efficient choice between several chelant agents, in the recovery of calcium and silicon, using ICP/OES and spectrocolorimetric and microscopic analyses.

Early prognosis of clinical efficacy is an urgent need for oncology drug development. Herein, we systemically examined the quantitative approach of tumor growth inhibition (TGI) and survival modeling in the space of relapsed and refractory multiple myeloma (MM), aiming to provide insights into clinical drug development. Longitudinal serum M‐protein and progression‐free survival (PFS) data from three phase III studies (N = 1367) across six treatment regimens and different patient populations were leveraged. The TGI model successfully described the longitudinal M‐protein data in patients with MM. The tumor inhibition and growth parameters were found to vary as per each study, likely due to the patient population and treatment regimen difference. Based on a parametric time‐to‐event model for PFS, M‐protein reduction at week 4 was identified as a significant prognostic factor for PFS across the three studies. Other factors, including Eastern Cooperative Oncology Group performance status, prior anti‐myeloma therapeutics, and baseline serum ß2‐microglobulin level, were correlated with PFS as well. In conclusion, patient disease characteristics (i.e., baseline tumor burden and treatment lines) were important determinants of tumor inhibition and PFS in MM patients. M‐protein change at week 4 was an early prognostic biomarker for PFS.

Since the beginning of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, it has been clear that testing large groups of the population was the key to stem infection and prevent the effects of the coronavirus disease of 2019, mostly among sensitive patients. On the other hand, time and cost-sustainability of virus detection by molecular analysis such as reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) may be a major issue if testing is extended to large communities, mainly asymptomatic large communities. In this context, sample-pooling and test grouping could offer an effective solution. Here we report the screening on 1195 oral-nasopharyngeal swabs collected from students and staff of the Università degli Studi del Sannio (University of Sannio, Benevento, Campania, Italy) and analyzed by an in-house developed multiplex RT-qPCR for SARS-CoV-2 detection through a simple monodimensional sample pooling strategy. Overall, 400 distinct pools were generated and, within 24 h after swab collection, five positive samples were identified. Out of them, four were confirmed by using a commercially available kit suitable for in vitro diagnostic use (IVD). High accuracy, sensitivity and specificity were also determined by comparing our results with a reference IVD assay for all deconvoluted samples. Overall, we conducted 463 analyses instead of 1195, reducing testing resources by more than 60% without lengthening diagnosis time and without significant losses in sensitivity, suggesting that our strategy was successful in recognizing positive cases in a community of asymptomatic individuals with minor requirements of reagents and time when compared to normal testing procedures.

Oral mezigdomide is a cereblon-modifying agent that results in degradation of transcription factors essential for myeloma cell survival. Given with dexamethasone, it induced responses in 40% of heavily pretreated patients.

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib, and dexamethasone (PVd) demonstrated superior efficacy vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma previously treated with lenalidomide, including those refractory to lenalidomide. This analysis evaluated outcomes in patients at first relapse ( N  = 226) by lenalidomide-refractory status, prior bortezomib exposure, and prior stem cell transplant (SCT). Second-line PVd significantly improved PFS vs Vd in lenalidomide-refractory (17.8 vs 9.5 months; P  = 0.0276) and lenalidomide-nonrefractory patients (22.0 vs 12.0 months; P  = 0.0491), patients with prior bortezomib (17.8 vs 12.0 months; P  = 0.0068), and patients with (22.0 vs 13.8 months; P  = 0.0241) or without (16.5 vs 9.5 months; P  = 0.0454) prior SCT. In patients without prior bortezomib, median PFS was 20.7 vs 9.5 months ( P  = 0.1055). Significant improvement in overall response rate was also observed with PVd vs Vd in lenalidomide-refractory (85.9% vs 50.8%; P  < 0.001) and lenalidomide-nonrefractory (95.7% vs 60.0%; P  < 0.001) patients, with similar results regardless of prior bortezomib or SCT. No new safety signals were observed. These data demonstrate the benefit of PVd at first relapse, including immediately after upfront lenalidomide treatment failure and other common first-line treatments.

Early life exposure to Endocrine Disruptor Chemicals (EDCs), such as the organophosphate pesticide Chlorpyrifos (CPF), affects the thyroid activity and dependent process, including the glucose metabolism. The damage of thyroid hormones (THs) as a mechanism of action of CPF is underestimated because the studies rarely consider that TH levels and signaling are customized peripherally. Here, we investigated the impairment of metabolism/signaling of THs and lipid/glucose metabolism in the livers of 6-month-old mice, developmentally and lifelong exposed to 0.1, 1, and 10 mg/kg/die CPF (F1) and their offspring similarly exposed (F2), analyzing the levels of transcripts of the enzymes involved in the metabolism of T3 (Dio1), lipids (Fasn, Acc1), and glucose (G6pase, Pck1). Both processes were altered only in F2 males, affected by hypothyroidism and by a systemic hyperglycemia linked to the activation of gluconeogenesis in mice exposed to 1 and 10 mg/kg/die CPF. Interestingly, we observed an increase in active FOXO1 protein due to a decrease in AKT phosphorylation, despite insulin signaling activation. Experiments in vitro revealed that chronic exposure to CPF affected glucose metabolism via the direct modulation of FOXO1 activity and T3 levels in hepatic cells. In conclusion, we described different sex and intergenerational effects of CPF exposure on the hepatic homeostasis of THs, their signaling, and, finally, glucose metabolism. The data points to FOXO1-T3-glucose signaling as a target of CPF in liver.

Extracranial metastases from meningiomas are extremely rare, with an incidence of <1%, and their prognosis is poor. Moreover, there is currently no gold standard for their treatment; therefore, the decision-making process is strictly dependent on multidisciplinary discussions. In this report, we describe the case of a 73-year-old patient who was diagnosed with a solitary lung metastasis more than 20 years after the initial treatment for a low-grade meningioma. Molecular characterization of this metastasis was performed using the Oncomine Comprehensive Assay Plus, which identified multiple functional mutations in the beta2-microglobulin (β2M) and ATM genes, both of which may contribute to immune evasion and genomic instability. A short overview of the literature is also reported. To our knowledge, no previous reports exist on single pulmonary metastasis from low-grade meningioma occurring more than 20 years after diagnosis.

Real-time seismological applications are essential for monitoring active volcanoes, offering valuable tools for the early detection of volcanic unrest and eruption. Very Long Period (VLP) seismicity, commonly observed at open-vent volcanoes with mild and persistent explosive activity, is a key indicator of volcanic activity intensity as changes in the rate of occurrence and VLP event magnitude can be a signal of impending unrest. In this study, we introduce a new method for the automatic and near real-time detection and characterization of VLP seismicity. Our approach was tested on Stromboli Volcano (Italy), where VLP seismic activity has been well-documented for over two decades. The detection algorithm is based on three-component amplitude analysis, derived from waveform polarization and spectral characteristics of continuous seismic records. It extracts key parameters such as detection time, event duration, azimuth, and incidence (polarization) angles. VLP events are distinguished from other signals through a single-station statistical analysis of polarization parameters, providing a reliable near–real-time catalog of VLP detections. Optimal detection thresholds for each station were determined using a machine-learning hyperparameter optimization approach. Here, we focus on the year 2007, which was characterized by highly variable VLP activity, including a major effusive eruption at Stromboli. The algorithm’s performance was validated using an independent, manually inspected dataset from 2007, yielding a false alert rate of 23% and a missed alert rate of 27% for the best-performing station. The results show that the method accurately reproduces the temporal evolution of the different activity phases throughout the year, with clear implications for enhancing and integrating VLP detection into existing volcano monitoring strategies. We applied the method to 16 years of seismic data (2009–2024), successfully reconstructing the temporal evolution of the VLP event rate in close agreement with manual inspections. The automatic detections show a strong correlation with manually derived daily rates, demonstrating that our automatic VLP detection time series reliably captures long-term fluctuations in volcanic activity over the entire period of investigation.