First-line avelumab for patients with PD-L1-positive metastatic or locally advanced urothelial cancer who are unfit for cisplatin.

BACKGROUND: Cisplatin-based chemotherapy is the most recommended treatment for metastatic urothelial cancer (mUC). However, about 50% of patients are considered to be cisplatin ineligible. Anti-programmed cell death protein 1/programmed death-ligand 1 (PD-L1) therapies have, nevertheless, increased the options available to clinicians and are especially valuable for treating these patients. This study therefore tested the activity and safety of avelumab as first-line therapy for mUC. PATIENTS AND METHODS: Patients with mUC who were ineligible for cisplatin-based chemotherapy were screened centrally for PD-L1 expression and only those with a tumour proportion score ≥ 5% were enrolled in the trial. The primary endpoint was 1-year overall survival (OS), and the secondary endpoints were median OS, median progression-free survival, overall response rate, duration of the response, safety and tolerability. All the survival rates were estimated with the Kaplan-Meier product-limit methodology and compared across groups using the log-rank test. RESULTS: A total of 198 patients were screened, with 71 (35.9%) whose PD-L1 expression was ≥5% enrolled in the study. The median age was 75 years, bladder cancer was the primary tumour in 73.2% of cases and 25.3% had liver metastases. The main reasons for the cisplatin ineligibility were a low rate of creatinine clearance (<60 ml/min), present in 70.4% of patients, and an Eastern Cooperative Oncology Group performance status of 2, which affected 31%. The median OS was 10.0 months (95% confidence interval 5.5-14.5 months) and 43% of patients were alive at 1 year. A complete response was achieved in 8.5% of cases, and 15.5% had a partial response. Adverse any-grade and high-grade events occurred in 49.3% and 8.5% of patients, respectively. A grade 3 infusion reaction was the only high-grade treatment-related adverse event. No treatment-related deaths were reported. CONCLUSIONS: This ARIES trial confirmed the activity and safety of avelumab for treating mUC, adding a new therapy option to the armamentarium of checkpoint inhibitors already approved for platinum-ineligible, locally advanced/mUC.

Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains.

The extensive use of amphetamines to treat attention deficit hyperactivity disorders in children provides a compelling rationale for understanding the mechanisms of action of amphetamines and amphetamine-related drugs. We have previously shown that acute amphetamine (AMPH) regulates the trafficking of both dopamine and glutamate transporters in dopamine neurons by increasing activation of the small GTPase RhoA and of protein kinase A. Here we demonstrate that these downstream signaling events depend upon the direct activation of a trace amine-associated receptor, TAAR1, an intracellular G-protein coupled receptor (GPCR) that can be activated by amphetamines, trace amines, and biogenic amine metabolites. Using cell lines and mouse lines in which TAAR1 expression has been disrupted, we demonstrate that TAAR1 mediates the effects of AMPH on both RhoA and cAMP signaling. Inhibition of different Gα signaling pathways in cell lines and in vivo using small cell-permeable peptides confirms that the endogenous intracellular TAAR1 couples to G13 and to GS α-subunits to increase RhoA and PKA activity, respectively. Results from experiments with RhoA- and PKA-FRET sensors targeted to different subcellular compartments indicate that AMPH-elicited PKA activation occurs throughout the cell, whereas G13-mediated RhoA activation is concentrated near the endoplasmic reticulum. These observations define TAAR1 as an obligate intracellular target for amphetamines in dopamine neurons and support a model in which distinct pools of TAAR1 mediate the activation of signaling pathways in different compartments to regulate excitatory and dopaminergic neurotransmission.

Daratumumab in multiple myeloma: experience of the multiple myeloma GIMEMA Lazio group.

Daratumumab (DARA) is a human IgG-K monoclonal antibody (MoAb) targeting CD38 that is approved alone or in combination with bortezomib and dexamethasone or lenalidomide and dexamethasone for relapsed or refractory MM (RRMM) in patients previously exposed or double refractory to proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs). However, there are limited data on its clinical activity and tolerability in real-world patients. Therefore, in the present study, we aim to determine the efficacy and toxicity profile of daratumumab in a real-life setting. In this study, we report the experience of the multiple myeloma GIMEMA Lazio Group in 62 relapsed/refractory MM patients treated with daratumumab as monotherapy who had previously received at least two treatment lines including a PI and an IMiDs or had been double refractory. Patients received DARA 16 mg/kg intravenously weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks until disease progression or unacceptable toxicity. The overall response rate to daratumumab was 46%. Median progression-free survival (PFS) and overall survival reached 2.7 and 22.4 months, respectively. DARA was generally well tolerated; however, 2 patients interrupted their therapy due to adverse events. Present real-life experience confirms that DARA monotherapy is an effective strategy for heavily pre-treated and refractory patients with multiple myeloma, with a favorable safety profile.

Two nasal swabs may not be enough to exclude SARS-CoV-2 infection in symptomatic patients.

Abstracts: The spread of COVID-19 (COronaVIrus Disease 2019), due to SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2) has taken on dramatic pandemic proportions, affecting over 100 countries in a matter of weeks. Italy has had 237,828 confirmed cases according to the Istituto Superiore di Sanità as of May 13, and 34,448 deaths (1).

Preclinical study for treatment of hypospadias by advanced therapy medicinal products.

PURPOSE: This paper explores the feasibility of a new therapy for the treatment of hypospadias patients. Hypospadias is a very common congenital malformation of male genitals, with very high rate of recurrences after surgery. The field of regenerative medicine, which offers innovative solutions for many pathologies, still does not offer reliable solution for this pathology. Here, we propose quality, safety, and clinical feasibility assessment for an oral mucosa advanced therapy medicinal product (ATMP) grown on a biocompatible scaffold for a clinical study on urethral reconstruction of hypospadias patients. METHODS: Urethral and oral mucosal epithelia from donor biopsies were cultivated between two fibrin layers, under clinical-grade conditions for cell and tissue characterization and comparison, aimed at tissue engineering. In addition, single-clone analyses were performed to analyze gene expression profiles of the two epithelia by microarray technology. RESULTS: Oral mucosa appeared suitable for urethral reconstruction. The resulting ATMP was proven to maintain stem cells and regenerative potency. The preclinical safety studies were performed on human tissues to assess abnormalities and tumorigenicity, and confirmed the safety of the ATMP. Finally, the patient selection and the clinical protocol for the upcoming clinical trial were defined. CONCLUSIONS: Against this backdrop, in this paper, we are proposing a new reproducible and reliable ATMP for the treatment of hypospadias.

A comparative study of combined intravenous and topical administration of tranexamic acid with topical tranexamic acid alone for blood loss reduction after primary uncemented total hip arthroplasty.

The aim of the present study was to evaluate the efficacy of topical versus combined (intravenous + topical) tranexamic acid (TXA) to reduce perioperative blood loss after uncemented primary total hip arthroplasty (THA). Seventy-five patients were randomized in three comparable experimental groups: 1) topical TXA (3 g in 50 ml of saline solution); 2) intravenous + topical TXA (3 g topical + 2 g in 100 ml of saline solution intravenously); 3) controls. Pre- and post-operative hemoglobin (Hb) levels and hematocrit (Hct) values along with the rate of blood transfusion in the 3 groups were compared. The intravenous + topical TXA group demonstrated higher Hb levels and Hct values at postoperative day one (Hb = p <0.05, Hct = p <0.001), postoperative day three (Hb = p <0.05, Hct = p <0.001), and discharge (Hct = p <0.01) compared to the control group. The intravenous + topical group had a lower transfusion rate compared to the control group (0% vs 20%, p = 0.014). With the numbers available, no difference in postoperative Hb level and transfusion rate emerged between topical TXA and control group.

Use of synthetic cartilage implant (Cartiva®) for degeneration of the first and second metatarsophalangeal joint: what is the current evidence?

Polyvinyl alcohol hydrogel implants (also known as Synthetic Cartilage Implant or Cartiva® have been described in the treatment of degeneration of the first and second metatarsophalangeal joint (MTPJ). We reviewed literature to report characteristics of devices on the market and investigate their efficacy and safety. Following the PRISMA checklist, the Medline and Scopus databases were searched, including studies reporting use of Cartiva® for treating joint degeneration of the first and second MPTJ. Studies were searched for surgical technique, postoperative protocol, clinical scores, complications and reoperations. We found that, although some studies suggest that the use of Synthetic Cartilage Implant (Cartiva® is effective in the treatment of hallux rigidus in providing symptoms relief without sacrifice of joint motion, the redundancy of cohorts reported in studies and the frequency of conflict of interest reported by authors weaken the strength of evidence available and warrant further studies. Regarding the treatment of the second MTPJ ailments, no recommendation can be formulated to date due to the lack of primary studies.

Thumb basal joint interpositional arthroplasty: a systematic review.

The aim of this systematic review was to analyze the failure rates among different trapeziometacarpal interposition implants used to treat thumb basal joint osteoarthritis. We searched Medline (PubMed), Web of Science and Scopus databases, to identify articles reporting on thumb interpositional arthroplasty, in English literature. We excluded studies with less than 35 cases and with a follow-up shorter than 24 months. Twenty-one studies were included. We assessed the quality of the studies using the Coleman Methodological Score. The mean quality of the studies was moderate. The total number of procedures included in this review was 1205. The failure rate for interposition implants was 11%. The main longterm complication was dislocation, which is also the major reason for revision.

Foot and ankle measurements on cone beam weightbearing computed tomography.

Over the last years, an increased number of studies have reported the use of cone beam weightbearing computed tomography (WBCT) in the assessment of foot and ankle pathology. This new technology has enabled to overcome the limits inherently related to two-dimensional radiographs (superimposition bias, operator-related bias, rotation bias) and to obtain images reproducing the bones and joints anatomy during physiological standing with a low radiation dose. We performed a review of the current literature to summarize the evidence about the use of 2D or 3D measurements on WBCT images in various foot and ankle conditions. Our aims were to describe measurements proposed so far and to report data on reliability and validity from primary authors.

Blood loss and transfusion rate in patients undergoing two-stage exchange in infected total knee arthroplasty.

Two-stage exchange in infected total knee arthroplasty is a reliable technique, but it has a high rate of blood loss. The study aims to compare the pre-operative and post-operative haemoglobin levels, the rate of transfusion, and the blood loss in two-stage exchange. From July 2018 to July 2019, eighteen patients underwent two-stage exchange of their infected total knee arthroplasty. Local and systemic tranexamic acid was administered in both surgical stages. Calculated blood loss was 2246 mL (range 1528 - 2850) in the first stage and 2388 mL (1873 - 2829) during reimplantation, respectively. The corresponding transfusion rate was 55 % and 67%, respectively. With the numbers available, these differences were not significant. In conclusion, this study shows that the blood loss and transfusion rate are similar during the two stages of exchange knee arthroplasty for infection.

Prevention and treatment of peri-prosthetic joint infection using surgical wound irrigation.

Over the past decade, the incidence of revision arthroplasty due to infection has increased substantially, often resulting in multiple surgical interventions with variable success rates and poor clinical outcome. Intraoperative wound irrigation has been proposed to reduce bacterial bioburden and contamination, but currently there is no widely accepted recommendation for the use of topical antiseptics, whether as separate molecules or as a mixed solution. We reviewed studies regarding the use of intraoperative topical antiseptics, their security profile and efficacy in preventing and treating infections of orthopedic implants and introduced a possible combination that may prove valuable in the future.

Assessing forest availability for wood supply in Europe.

The quantification of forests available for wood supply (FAWS) is essential for decision-making with regard to the maintenance and enhancement of forest resources and their contribution to the global carbon cycle. The provision of harmonized forest statistics is necessary for the development of forest associated policies and to support decision-making. Based on the National Forest Inventory (NFI) data from 13 European countries, we quantify and compare the areas and aboveground dry biomass (AGB) of FAWS and forest not available for wood supply (FNAWS) according to national and reference definitions by determining the restrictions and associated thresholds considered at country level to classify forests as FAWS or FNAWS. FAWS represent between 75 and 95 % of forest area and AGB for most of the countries in this study. Economic restrictions are the main factor limiting the availability of forests for wood supply, accounting for 67 % of the total FNAWS area and 56 % of the total FNAWS AGB, followed by environmental restrictions. Profitability, slope and accessibility as economic restrictions, and protected areas as environmental restrictions are the factors most frequently considered to distinguish between FAWS and FNAWS. With respect to the area of FNAWS associated with each type of restriction, an overlap among the restrictions of 13.7 % was identified. For most countries, the differences in the FNAWS areas and AGB estimates between national and reference definitions ranged from 0 to 5 %. These results highlight the applicability and reliability of a FAWS reference definition for most of the European countries studied, thereby facilitating a consistent approach to assess forests available for supply for the purpose of international reporting.

Nitric Oxide Activates ß-Cell Glucokinase by Promoting Formation of the "Glucose-Activated" State.

The release of insulin from the pancreas is tightly controlled by glucokinase (GCK) activity that couples ß-cell metabolism to changes in blood sugar. Despite having only a single glucose-binding site, GCK displays positive glucose cooperativity. Ex vivo structural studies have identified several potential protein conformations with varying levels of enzymatic activity, yet it is unclear how living cells regulate GCK cooperativity. To better understand the cellular regulation of GCK activation, we developed a homotransfer Förster resonance energy transfer (FRET) GCK biosensor and used polarization microscopy to eliminate fluorescence crosstalk from FRET quantification and improve the signal-to-noise ratio. This approach enhanced sensor contrast compared to that seen with the heterotransfer FRET GCK reporter and allowed observation of individual GCK states using an automated method to analyze FRET data at the pixel level. Mutations known to activate and inhibit GCK activity produced distinct anisotropy distributions, suggesting that at least two conformational states exist in living cells. A high glucose level activated the biosensor in a manner consistent with GCK's enzymology. Interestingly, glucose-free conditions did not affect GCK biosensor FRET, indicating that there is a single low-activity state, which is counter to proposed structural models of GCK cooperativity. Under low-glucose conditions, application of chemical NO donors efficiently shifted GCK to the more active conformation. Notably, GCK activation by mutation, a high glucose level, a pharmacological GCK activator, or S-nitrosylation all shared the same FRET distribution. These data suggest a simplified model for GCK activation in living cells, where post-translational modification of GCK by S-nitrosylation facilitates a single conformational transition that enhances GCK enzymatic activity.

TLR-Stimulated Eosinophils Mediate Recruitment and Activation of NK Cells In Vivo.

Eosinophils like many myeloid innate immune cells can provide cytokines and chemokines for the activation of other immune cells upon TLR stimulation. When TLR-stimulated eosinophils were inoculated i.p. into wild-type mice, and NK cells were rapidly recruited and exhibited antitumour cytotoxicity. However, when mice depleted of CD11c+ cells were used, a marked decrease in the number of recruited NK cells was observed. We postulated that CpG or LPS from the injected eosinophils could be transferred to host cells, which in turn could recruit NK cells. However, by inoculating mice deficient in TLR4 or TLR9 with LPS or CpG-stimulated eosinophils respectively, NK cell recruitment was still observed alongside cytotoxicity and IFNγ production. CpG stimulation of eosinophils produced the pro-inflammatory cytokine IL-12 and the chemokine CXCL10, which are important for NK cell activation and recruitment in vivo. To demonstrate the importance of CXCL10 in NK cell recruitment, we found that CpG-stimulated eosinophils pretreated with the gut microbial metabolite butyrate had reduced expression and production of CXCL10 and IL-12 and concomitantly were poor at recruitment of NK cells and inducing IFNγ in NK cells. Therefore, eosinophils like other innate immune cells of myeloid origin can conceivably stimulate NK cell activity. In addition, products of the gut microbiota can be potential inhibitors of NK cell.

Oral manifestations of inflammatory bowel disease.

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, have important extraintestinal manifestations, notably in the oral cavity. These oral manifestations can constitute important clinical clues in the diagnosis and management of IBD, and include changes at the immune and bacterial levels. Aphthous ulcers, pyostomatitis vegetans, cobblestoning and gingivitis are important oral findings frequently observed in IBD patients. Their presentations vary considerably and might be well diagnosed and distinguished from other oral lesions. Infections, drug side effects, deficiencies in some nutrients and many other diseases involved with oral manifestations should also be taken into account. This article discusses the most recent findings on the oral manifestations of IBD with a focus on bacterial modulations and immune changes. It also includes an overview on options for management of the oral lesions of IBD.

Tea catechins induce crosstalk between signaling pathways and stabilize mast cells in ulcerative colitis.

It is well documented that nutraceuticals, in general, and Green tea catechins, in particular, possess a potential therapeutic value in inflammatory bowel diseases (IBD) due to their anti-oxidative and anti-inflammatory effects. This study aimed to investigate the possible mechanism of action of catechins in a rat model of colitis induced by 2.4.6 trinitrobenzene sulfonic acid (TNBS). Thirty-five young adult Sprague-Dawley rats were divided into four groups: normal control (n=5), catechins (n=9), TNBS (n=9) and TNBS plus catechins (n=12) treated. Catechin in the form of Epigallocatechin-3-gallate (EGCG) was administered daily by intraperitoneal injection, 1 week before the induction date of UC. Biopsies of the descending colon were collected on days 3, 10 and 17, and partly frozen for molecular studies or fixed for light microscopy. The status of intestinal tissue alterations and mast cells number were also assessed, as well as the mRNA expressions of IL-6, TNF-a and NF-kB, and determination of ROS expression. Histological data depicted a significant amelioration in the TNBS- and EGCG-treated rats compared to the non-treated animals. Catechin expressed strong anti-inflammatory and anti-oxidant effects, ameliorated ulcerative colitis and stabilized mast cells. The mechanism of action occurred basically through the NF-kB pathway and possibly through a crosstalk with other pathways.

Comparison between intrarticular injection of hyaluronic acid, oxygen ozone, and the combination of both in the treatment of knee osteoarthrosis.

This study aimed to compare short-term clinical outcomes between intra-articular injection of hyaluronic acid (HA), oxygen ozone (O2O3), and the combination of both, in patients affected by osteoarthrosis (OA) of the knee. Seventy patients (age 45-75 years) with knee OA were randomized to intra-articular injections of HA (n=23), or O2O3 (n=23) or combined (n=24) one per week for 5 consecutive weeks. KOOS questionnaire and visual analog scale (VAS), before treatment (pre) at the end (post), and at 2 months after treatment ended (follow-up) were used as outcome measures. Analysis showed a significant effect (P < 0.05) of the conditions (pre, post and follow-up) in all parameters of the KOOS score and a significant effect (P < 0.05) of groups (HA, O2O3 and combined) for pain, symptoms, activities of daily living and quality of life. The combined group scores were higher compared to the HA and O2O3 groups, especially at follow-up. The combination of O2O3 and HA treatment led to a significantly better outcome especially at 2-month follow-up compared to HA and O2O3 given separately to patients affected by OA of the knee.

Telemonitoring in heart failure patients treated by cardiac resynchronisation therapy with defibrillator (CRT-D): the TELECART Study.

AIM: Telemonitoring (TM) is a safe and efficient monitoring system for internal cardioverter defibrillator device (ICD) recipients. TM has been used to track info on the clinical status of heart failure patients treated by ICD and/or cardiac resynchronisation therapy defibrillator (CRT-D). The aim of this study was to investigate the impact of TM on clinical outcomes in a population of CRT-D patients with heart failure. METHODS: In a multicentre, randomised study, patients with chronic heart failure, New York Heart Association (NYHA) functional class II or III, left bundle branch block, severe left ventricle ejection fraction reduction (LVEF < 35%) have been identified and screened. RESULTS: One hundred and ninety-one patients have been randomised to receive either a CRT-D with TM or a CRT-D with traditional ambulatory monitoring (control group) and completed the 12-month study follow-up. Primary endpoints were all cause death, cardiac death and hospital admission for heart failure. Secondary endpoints were atrial fibrillation, sustained episodes, non-sustained and self terminated ventricular tachyarrhythmia, sustained ventricular tachycardia, and ventricular fibrillation, ICD shocks and percentage of CRT-D responder patients. Univariate analysis identified the following factors predicting hospitalisation: TM, age, chronic kidney disease, hypercholesterolaemia, LVEF and NYHA class. At multivariate analysis, TM was the only factor predicting heart failure hospitalisation (hazard ratio 0.6, 0.42-0.79, 95% CI, p = 0.002), without affecting overall mortality and cardiac deaths events. CONCLUSIONS: Taken together, our data indicate the importance of TM in predicting heart failure hospitalisation in patients treated with CRT-D.

Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis.

BACKGROUND: First-line sunitinib is recommended in metastatic renal cell carcinoma (mRCC), but it is frequently associated with relevant toxicities and subsequent dose reductions. Alternative schedules, such as 2-week-on treatment and 1-week-off (2/1 schedule), might improve tolerability. We evaluated the safety and outcomes of this schedule in a large multicenter analysis. PATIENTS AND METHODS: Retrospective, multicenter analysis of mRCC patients treated with first-line sunitinib on a 2/1 schedule. Data of 249 patients were reviewed: 208 cases who started sunitinib on the 4/2 schedule (full dosage: 188/208, 90.4%) and thereafter switched to the 2/1 schedule for toxicity (group 4/2 → 2/1) and 41 patients who started first-line sunitinib with the 2/1 schedule because of suboptimal clinical conditions (group 2/1). A total of 211 consecutive patients treated with the 4/2 schedule in another institution served as external controls. Safety was the primary end point. Treatment duration (TD), progression-free survival (PFS) and overall survival (OS) were also analyzed. RESULTS: In group 4/2 → 2/1, the overall incidence of grade ≥ 3 toxicities was significantly reduced (from 45.7% to 8.2%, P < 0.001) after the switch to 2/1 schedule. This advantage was maintained also in the 106/188 cases (56.4%) who maintained the full dosage. Fatigue, hypertension, hand-foot syndrome and thrombocytopenia were less frequent. The incidence of grade ≥ 3 adverse events in the negatively selected group 2/1 (only 73.2% starting at full dose) was 26.8%, similar to what observed in the external control group (29.4%). Median TD was 28.2 months in the 4/2 → 2/1 group (total time spent with both schedules), 7.8 months in the 2/1 group and 9.7 months in external controls. Median PFS was 30.2, 10.4 and 9.7 months, respectively. Median OS was not reached, 23.2 and 27.8 months, respectively. CONCLUSIONS: mRCC patients who moved to a modified 2/1 schedule of sunitinib experience an improved safety profile compared with that observed during the initial 4/2 schedule.