A novel rapamycin analog is highly selective for mTORC1 in vivo.

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs

SAUL, a single-arm study of atezolizumab for chemotherapy-pretreated locally advanced or metastatic carcinoma of the urinary tract: outcomes by key baseline factors, PD-L1 expression and prior platinum therapy

Background The impact of pretreatment factors on immune checkpoint inhibition in platinum-refractory advanced urothelial cancer (aUC) deserves further evaluation. The aim was to study the association of Bellmunt risk factors, time from last chemotherapy (TFLC), previous therapy and PD-L1 expression with atezolizumab efficacy in platinum-refractory aUC. Patients and methods This was a post-hoc analysis of patients who had received prior cisplatin or carboplatin in the prospective, single-arm, phase IIIb SAUL study (NCT02928406). Patients were treated with 3-weekly atezolizumab 1200 mg intravenously. The primary outcome was overall survival (OS). Relationships were analysed using Cox regression and long-rank test. Results Of 997 patients in SAUL, 969 were eligible for this analysis. The number of Bellmunt risk factors was associated with OS (P 6 months, 7.75 versus 11.6 months for PD-L1 expression on <1% of tumour-infiltrating immune cells (ICs) (IC0)/expression on 1% to <5% of tumour-infiltrating ICs (IC1) versus expression on ≥5% of tumour-infiltrating ICs (IC2/3) and 10.2 versus 7.8 months for prior versus no prior perioperative chemotherapy, respectively. The type of platinum compound and number of previous treatment lines were not associated with outcomes. Conclusions Post-platinum atezolizumab is active in aUC, irrespective of previous platinum compound and lines of therapy. Bellmunt risk stratification, PD-L1 expression, TFLC and perioperative chemotherapy were identified as prognostic factors for OS with second-line atezolizumab, indicating the need for novel prognostic signatures for immunotherapy-treated patients with aUC

Preparation of Active Proteins, Vaccines and Pharmaceuticals as Fine Powders using Supercritical or Near-Critical Fluids

Supercritical or near-critical fluid processes for generating microparticles have enjoyed considerable attention in the past decade or so, with good success for substances soluble in supercritical fluids or organic solvents. In this review, we survey their application to the production of protein particles. A recently developed process known as CO2-assisted nebulization with a Bubble Dryer® (CAN-BD) has been demonstrated to have broad applicability to small-molecule as well as macromolecule substances (including therapeutic proteins). The principles of CAN-BD are discussed as well as the stabilization, micronization and drying of a wide variety of materials. More detailed case studies are presented for three proteins, two of which are of therapeutic interest: anti-CD4 antibody (rheumatoid arthritis), α1-antitrypsin (cystic fibrosis and emphysema), and trypsinogen (a model enzyme). Dry powders were formed in which stability and activity are maintained and which are fine enough to be inhaled and reach the deep lung. Enhancement of apparent activity after CAN-BD processing was also observed in some formulation and processing conditions

Current clinical practice guidelines on chemotherapy and radiotherapy for the treatment of non-metastatic muscle-invasive urothelial cancer: A systematic review and critical evaluation by the Hellenic Genito-Urinary Cancer Group (HGUCG)

Radical cystectomy is the treatment of choice in localized muscle-invasive urothelial cancer. Nevertheless, relapses are frequent and systemic chemotherapy has been employed in order to reduce this risk. In addition, bladder preservation strategies are appealing. During the last decade, there has been a difficulty in conducting and completing large-scale trials in urothelial cancer. This has resulted in relatively few changes in the existing guidelines. Recent studies have created renewed interest in certain fields, such as the role of chemo-radiotherapy and management of unfit patients. In addition, application of certain guidelines has been limited in everyday practice. We conducted a systematic review of the existing guidelines and recent randomized trials not included in these guidelines, and developed a treatment algorithm, regarding non-surgical therapies for non-metastatic, muscle-invasive urothelial cancer based predominantly on patients&apos; fitness for the available therapeutic modalities. © 2014 Elsevier Ireland Ltd

Management of stent-related symptoms with the use of α-blockers: A meta-analysis

Objectives: To assess the effectiveness of α-blockers at reducing stent-related morbidity compared to placebo using the Ureteric Symptom Score questionnaire (USSQ) at particular time points as originally set by the developers of the USSQ. Materials and methods: We conducted the study following the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines. Eligible articles were identified by a search of the Medical Literature Analysis and Retrieval System Online (MEDLINE) database for the period from 1 January 2006 to 30 November 2018. The search strategy included specific keywords and only articles in English were considered eligible. A meta-analysis of randomised controlled trials was done according to methodological quality, placebo-control use, and USSQ completion at the time points of 1 and 4 weeks after insertion, and 4 weeks after stent removal. The mean differences with 95% confidence intervals were calculated for outcomes, with a P &lt; 0.05 considered statistically significant. Results: In all, eight papers were included for analysis. At 1 week after stent insertion, α-blockers were associated with a significant decrease in the USSQ Urinary Index score (UIS), Pain Index score, General Health Index score (GHIS), Sex Index score, and Work Index score (WIS). At 4 weeks after stent insertion, α-blockers were associated with a significant decrease in the UIS, GHIS and WIS only, whilst at 4 weeks after stent removal, α-blockers were associated with a significant decrease in the UIS and GHIS. Conclusions: The oral administration of α-blockers or their combinations have been shown to relieve stent morbidity, especially during the early period of stenting. The use of selective agents can therefore be considered; however, there is still the need for uniformly designed multi-centre randomised studies. Abbreviations: MD: mean difference; QoL: quality of life; RCT: randomised controlled trial; SRS: stent-related symptoms; USSQ: Ureteric Symptom Score questionnaire. © 2019, © 2019 The Author(s). Published by Informa UK Limited, trading as Taylor &amp; Francis Group

Epidemiologic risk factors of basal cell carcinoma development and age at onset in a Southern European population from Greece

Background: Basal cell carcinoma (BCC) is the most common form of skin cancer with increasing incidence rates worldwide. Methods: To assess the association of BCC with epidemiologic risk factors in a Southern European population from Greece, we conducted a hospital-based case-control study of 199 patients with BCC and 200 controls. Results: In the multivariate analysis, fair skin colour was associated with increased risk of BCC (OR: 4.9, 95% CI: 2.4-10.0). However, darker skin phototypes III/IV (patient&apos;s reported sun sensitivity/tanning ability) showed a higher BCC risk (OR: 3.9, 95% CI: 1.8-8.5). Persons with occupational UV exposure of 5years or more had a 2.7-fold increased risk (95% CI:1.4-5.3). There was an increased risk of BCC related to the number of sunburns after the age of 20years (OR: 3.2, 95% CI: 1.4-7.3) and solar lentigines (OR: 6.8, 95% CI: 3.6-12.8). Subgroup analysis showed that different risk factors are associated with early onset BCC including the presence of dysplastic nevi (OR: 6.4, 95% CI: 1.5-27.2), the number of weeks per year spent at the beach during childhood (OR: 8.9, 95% CI: 3.3-24.1) and the history of sunburns during childhood (OR:5.0, 95% CI: 1.3-19.1). Conclusions: Fair skin colour was significantly associated with BCC risk. The relation of sunburns during adulthood with BCC underlies the importance of sunburn prevention throughout life time. Early onset BCCs seem to have a different pathogenetic background and were associated with dysplastic nevi as well as intermittent sun exposure and sunburns during the early years of life. © 2011 John Wiley &amp; Sons A/S

Real-world experience of everolimus as second-line treatment in metastatic renal cell cancer after failure of pazopanib

Konstantinos Koutsoukos,1,2 Aristotelis Bamias,1,2 Kimon Tzannis,1 Marta Espinosa Monta&ntilde;o,3 Vasiliki Bozionelou,4 Christos Christodoulou,5 Dimitra Stefanou,6 Haralabos Kalofonos,7 Ignacio Duran,3 Konstantinos Papazisis1,8 1Hellenic Genito-Urinary Cancer Group, 2Oncology Unit, Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece; 3Medical Oncology Department, Hospital Universitario Virgen del Roc&iacute;o, Sevilla, Spain; 4Department of Medical Oncology, University Hospital of Heraklion, Heraklion, 52nd Oncology Clinic, Metropolitan Hospital, Piraeus, 61st Department of Medical Oncology, Saint Savvas Anticancer Hospital, Athens, 7Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, 8Euromedica General Clinic, Thessaloniki, Greece Aim: We aimed to provide real-life data on the outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus as second-line treatment after failure of first-line pazopanib.Patients and methods: Data from the medical charts of mRCC patients from 8 centers in Greece and Spain were reviewed. All patients had received or were continuing to receive second-line everolimus treatment after failure of first-line treatment with pazopanib. No other previous therapies were allowed. The primary end point was the determination of progression-free survival (PFS).Results: In total, 31 patients were enrolled. Of these, 26% had performance status (PS) &gt;0, 88% were of intermediate/poor Memorial Sloan-Kettering Cancer Center (MSKCC) risk group, and only 61% had undergone prior nephrectomy. Median PFS was 3.48&nbsp;months (95%&nbsp;CI: 2.37&ndash;5.06&nbsp;months). Median overall survival (OS) from everolimus initiation was 8.9&nbsp;months (95%&nbsp;CI: 6.47&ndash;13.14 months). Median OS from pazopanib initiation was 14.78&nbsp;months (95%&nbsp;CI: 10.54&ndash;19.08&nbsp;months). Furthermore, 32% of patients temporarily discontinued everolimus due to adverse events (AEs), and 22% of patients discontinued everolimus permanently due to toxicity. Most common toxicities were anemia (29%), stomatitis (26%), pneumonitis (19%), and fatigue (10%). Moreover, 14 AEs (27%) were graded as 3 or 4 and were reported by 13&nbsp;patients (42%).Conclusion: This study provides data exclusively on the sequence pazopanib&ndash;everolimus in mRCC. Everolimus has a favorable safety profile and is active. The short PFS and OS could be attributed to the fact that the pazopanib&ndash;everolimus sequence was mainly offered to patients with adverse prognostic features, resulting in a modest increase in the combined OS of our population. Keywords: pazopanib, everolimus, renal cell carcinom