Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma : Final results of the MARC-2 trial

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs 25 vs ≤25 kg/m2. A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most

Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)

There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progressionfree survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC

Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma

Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months' follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months' follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085

Polysaccharide-Based Composite Hydrogels as Sustainable Materials for Removal of Pollutants from Wastewater

Nowadays, pollution has become the main bottleneck towards sustainable technological development due to its detrimental implications in human and ecosystem health. Removal of pollutants from the surrounding environment is a hot research area worldwide; diverse technologies and materials are being continuously developed. To this end, bio-based composite hydrogels as sorbents have received extensive attention in recent years because of advantages such as high adsorptive capacity, controllable mechanical properties, cost effectiveness, and potential for upscaling in continuous flow installations. In this review, we aim to provide an up-to-date analysis of the literature on recent accomplishments in the design of polysaccharide-based composite hydrogels for removal of heavy metal ions, dyes, and oxyanions from wastewater. The correlation between the constituent polysaccharides (chitosan, cellulose, alginate, starch, pectin, pullulan, xanthan, salecan, etc.), engineered composition (presence of other organic and/or inorganic components), and sorption conditions on the removal performance of addressed pollutants will be carefully scrutinized. Particular attention will be paid to the sustainability aspects in the selected studies, particularly to composite selectivity and reusability, as well as to their use in fixed-bed columns and real wastewater applications

Preparation and Characterization of Semi-IPN Cryogels Based on Polyacrylamide and Poly(<i>N</i>,<i>N</i>-dimethylaminoethyl methacrylate); Functionalization of Carrier with Monochlorotriazinyl-β-cyclodextrin and Release Kinetics of Curcumin

Curcumin (CCM) is a natural hydrophobic polyphenol known for its numerous applications in the food industry as a colorant or jelly stabilizer, and in the pharmaceutical industry due to its anti-inflammatory, antibacterial, antioxidant, anti-cancer, and anti-Alzheimer properties. However, the large application of CCM is limited by its poor solubility in water and low stability. To enhance the bioavailability of CCM, and to protect it against the external degradation agents, a novel strategy, which consists in the preparation of semi-interpenetrating polymer networks, (s-IPNs) based on poly(N,N-dimethylaminoethyl methacrylate) entrapped in poly(acrylamide) networks, by a cryogelation technique, was developed in this work. All s-IPN cryogels were characterized by SEM, EDX, FTIR, and swelling at equilibrium as a function of pH. Functionalization of semi-IPN cryogel with monochlorotriazinyl-β-cyclodextrin (MCT-β-CD) led to IPN cryogel. The release profile of CCM from the composite cryogels was investigated at 37 °C, in pH 3. It was found that the cumulative release increased with the increase of the carrier hydrophobicity, as a result of increasing the cross-linking degree, the content and the molar mass of PDMAEMA. Fitting Higuchi, Korsmeyer–Peppas, and first order kinetic models on the CCM release profiles indicated the diffusion as the main driving force of drug release from the composite cryogels

Geriatric Assessment of Older Patients Receiving Trabectedin in First-Line Treatment for Advanced Soft Tissue Sarcomas: The E-TRAB Study from The German Interdisciplinary Sarcoma Group (GISG-13).

E-TRAB was a non-interventional, prospective trial investigating the feasibility and predictive value of geriatric assessments (GA) in older STS patients treated with trabectedin as first-line therapy. Primary endpoints were overall survival (OS), quality of life and individual clinical benefit assessed by the patient-reported outcome measures QLQ-C30 and PRO-CTCAE. Further, several GA tools were applied and correlated with clinical outcomes and treatment-related toxicities. The final analyses included 69 patients from 12 German-speaking sites. The median age of patients was 78 years (range: 55 to 88). Baseline data on PROs and GA identified a diverse population of older patients with respect to their global health status, although a large proportion of them suffered from limitations, required geriatric help and had a high risk of morbidity. The Cancer and Age Research Group (CARG) score classified 38%, 29% and 23% of the patients with low, intermediate and high risks for therapy-related side effects, respectively. Median OS was 11.2 months [95%CI: 5.6; 19.4]. The study confirmed that trabectedin as first-line treatment in older patients with STS has an acceptable and manageable safety profile. Potential prognostic factors for clinical outcome and therapy-related toxicity were identified among the GA tools. Long Timed Up and Go (TUG) showed a significant correlation to OS and early death, whereas a high CARG score (>9) was associated with an increase in unplanned hospitalizations and the incidence of toxicities grade ≥ 3

Trabectedin for Patients with Advanced Soft Tissue Sarcoma: A Non-Interventional, Prospective, Multicenter, Phase IV Trial

Simple Summary Active therapeutic options in advanced soft tissue sarcoma (STS), able to induce durable objective responses, are limited beyond first-line chemotherapy. Although results obtained in clinical trials suggest there is a high probability for patients with STS to benefit from treatment with trabectedin (Yondelis®), there is still a paucity of robust real-life data in more diverse patient populations. The prospective, non-interventional phase IV YON-SAR trial (NCT02367924) was designed to evaluate treatment effects of trabectedin in patients with advanced STS in real-life clinical practice across Germany. The efficacy results of this trial, conducted in 128 patients from 19 sites across Germany, further support trabectedin as a standard of care for a second- or further-line treatment of patients with advanced STS in routine clinical practice (median progression-free survival: 5.2 months; median overall survival: 15.2 months). The safety profile of trabectedin was manageable and in line with those observed in previous studies. Abstract This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile