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Background Resistance to osimertinib in advanced EGFR- mutated non-small cell lung cancer (NSCLC) constitutes a significant challenge for clinicians either in terms of molecular diagnosis and subsequent therapeutic implications. Methods This is a prospective single-centre study with the primary objective of characterising resistance mechanisms to osimertinib in advanced EGFR- mutated NSCLC patients treated both in first- and in second-line. Next-Generation Sequencing analysis was conducted on paired tissue biopsies and plasma samples. A concordance analysis between tissue and plasma was performed. Results Sixty-five advanced EGFR -mutated NSCLC patients treated with osimertinib in first- ( n  = 56) or in second-line ( n  = 9) were included. We managed to perform tissue and liquid biopsies in 65.5% and 89.7% of patients who experienced osimertinib progression, respectively. Acquired resistance mechanisms were identified in 80% of 25 patients with post-progression samples, with MET amplification ( n  = 8), EGFR C797S ( n  = 3), and SCLC transformation ( n  = 2) the most frequently identified. The mean concordance rates between tissue and plasma for the EGFR activating mutation and for the molecular resistance mechanisms were 87.5% and 22.7%, respectively. Conclusions Resistance to osimertinib demonstrated to be highly heterogeneous, with MET amplification the main mechanism. Plasma genotyping is a relevant complementary tool which might integrate tissue analysis for the study of resistance mechanisms.

The benefit of adjuvant immunotherapy after nephrectomy in renal cell carcinoma (RCC) is controversial. The present study aimed to examine the possible benefit of adjuvant immunotherapy in various clinical settings. We retrospectively reviewed 436 patients with pT1-3N0-2M0 RCC who underwent radical or partial nephrectomy with curative intent at our institution between 1981 and 2009. Of them, 98 (22.5%) patients received adjuvant interferon-α (IFN-α) after surgery (adjuvant IFN-α group), while 338 (77.5%) did not (control group). The primary endpoint was cancer-specific survival (CSS). Univariate and multivariate analyses were conducted using log-rank tests and Cox proportional hazards models, respectively. Fifty-two (11.9%) patients died from RCC with a median follow-up period of 96 months. Preliminary univariate analyses comparing CSS among treatment groups in each TNM setting revealed that CSS in the control group was equal or superior to that in the adjuvant IFN-α group in earlier stages, while the opposite trend was observed in more advanced stages. We evaluated the TNM cutoffs and demonstrated maximized benefit of adjuvant IFN-α in patients with pT2b-3cN0 (P = 0.0240). In multivariate analysis, ≥pT3 and pN1-2 were independent predictors for poor CSS in all patients. In the subgroups with ≥pT2 disease (n = 123), pN1-2 and no adjuvant treatment were significant poor prognostic factors. Adjuvant immunotherapy after nephrectomy may be beneficial in pT2b-3cN0 RCC. Careful consideration is, however, required for interpretation of this observational study because of its selection bias and adverse effects of IFN-α.

The objective of this research was to investigate the effect of a cyanobacterial (Spirulina platensis) biomass on the microflora of a probiotic fermented dairy product during storage at two temperatures. Spirulina-enriched and control (plain) fermented acidophilusbifidus-thermophilus (ABT) milks were produced using a fast fermentation starter culture (ABT-4) as the source of Lactobacillus acidophilus (A), bifidobacteria (B), and Streptococcus thermophilus (T). Incubation took 6 h at 40°C. As for the cyanobacterial product, the S. platensis biomass was added to the process milk during stirring at pH 4.5 to 4.6. Thereafter, the ABTtype fermented milks were cooled to 25°C in ice water, filled into sterile, tightly capped centrifuge tubes, further cooled at 4°C for 24 h, and then stored either at 15°C for 18 d or at 4°C for 42 d. Microbiological analyses and acidity measurements were performed at regular intervals. Our results showed that the counts of the starter organisms were satisfactory during the entire storage period at both temperatures applied in this research. The S. platensis biomass had a beneficial effect on the survival of ABT starter bacteria regardless of storage temperature. Postacidification was observed at 15°C, whereas pH remained stable during refrigerated storage at 4°C. The abundance of bioactive substances in S. platensis is of great importance from a nutritional point of view because thus the cyanobacterial biomass provides a new opportunity for the manufacture of functional dairy foods.

Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo. The double-blind, randomised, phase 3 CheckMate 914 trial enrolled patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4–12 weeks before random assignment. Part A, reported herein, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays. Randomisation was stratified by TNM stage and nephrectomy (partial vs radical). The primary endpoint was disease-free survival according to masked independent central review; safety was a secondary endpoint. Disease-free survival was analysed in all randomly assigned patients (intention-to-treat population); exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug (all-treated population). This study is registered with ClinicalTrials.gov, NCT03138512. Between Aug 28, 2017, and March 16, 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female. With a median follow-up of 37·0 months (IQR 31·3–43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71–1·19; p=0·53). The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group). 155 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had grade 3–5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo. Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival versus placebo in patients with localised renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma. Bristol Myers Squibb and Ono Pharmaceutical.

Anthocyanins are water-soluble polyphenolic compounds with a high nutraceutical value. Despite the fact that cultivated tomato varieties do not accumulate anthocyanins in the fruit, the biosynthetic pathway can be activated in the vegetative organs by several environmental stimuli. Little is known about the molecular mechanisms regulating anthocyanin synthesis in tomato. Here, we carried out a molecular and functional characterization of two genes, SlAN2 and SlANT1, encoding two R2R3-MYB transcription factors. We show that both can induce ectopic anthocyanin synthesis in transgenic tomato lines, including the fruit. However, only SlAN2 acts as a positive regulator of anthocyanin synthesis in vegetative tissues under high light or low temperature conditions.

The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.

The purpose of the study is to explore the deteriorating situations of SMEs in Qatar. The purpose is to suggest a quantitative model to be evaluated because the government is paying special attention towards the promotion of SMEs but hardly any significant improvement has been seen. Based on the reviewed literature over the entrepreneurial performance of SMEs, it has been seen that entrepreneurial orientation and knowledge management has a significant role, meanwhile big data has the capability to bridge the impact of entrepreneurial orientation and knowledge management over entrepreneurial performance of SMEs in Qatar. Moreover, considering the dynamic nature of the country and continuously changing technological advancements, technological turbulence has been proposed as a moderator between the same relationship. The framework is built over the theoretical underpinning of resources-based view with the support of contingency theory. The model is suggested to be evaluated through SPSS for initial diagnosis of the collected data and afterwards SMART PLS is proposed.

Abstract Background Despite advances with immune checkpoint inhibitors (ICIs) in metastatic renal cell carcinoma (mRCC), many patients do not achieve durable responses. The CHOMET study aimed to evaluate prognostic factors in patients receiving first-line ICIs, focusing on tumor expression of cholesterol transporters (ABCA1/ABCG1), lipid and nutritional status, and the role of nephrectomy. Methods CHOMET was a single-center retrospective study of patients with mRCC treated with first-line ICI-based combinations. Immunohistochemistry assessed ABCA1 and ABCG1 expression. Baseline data included serum lipids, albumin, CONUT score, neutrophil-to-lymphocyte ratio (NLR), and nephrectomy status. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression. Associations were tested with linear regression and Mann–Whitney tests. Results Among 86 patients (median follow-up: 30 months), median PFS was 25.6 months and OS was not reached. High ABCA1/ABCG1 expression correlated with shorter PFS and OS. Better outcomes were observed in patients with lower CONUT score, cholesterol ≥200 mg/dL, and triglycerides ≥150 mg/dL. Nephrectomy, performed in 59% of patients, was associated with significantly better survival and favorable baseline lipid and nutritional profiles. A combined nephrectomy-cholesterol score (0-2 points) stratified prognosis: higher scores predicted longer survival (Table 1). In multivariable analysis, both nephrectomy and high cholesterol were independently associated with reduced risk of progression and death. Table 1. Oncological outcomes according to ABCA1/G1 staining intensity, cholesterol and triglycerides levels, CONUT, and nephrectomy-cholesterol scores. mPFS months (95%CI) mOS months (95%CI) ABCA1 1+ 30 (26-NR) NR 3+ 5 (3-NR) 13 (8-NR) P  value .261 .014 ABCG1 1+ 63 (NR-NR) NR 3+ 9 (3-NR) 12 (7-NR) P value .005 .008 CONUT score <3 30 (26-NR) NR ≥3 10 (3-34) 23 (13-NR) P  value .005 .003 Nephrectomy-Cholesterol score 0 10 (6-NR) 23 (12-NR) 1 27 (24-NR) NR 2 33 (26-NR) NR P  value .003.029 .003.028 Abbreviations; mOS, median overall survival; mPFS, median progression-free survival; NR, not reached. Conclusions In mRCC, high tumor expression of ABCA1/ABCG1 predicted poorer outcomes, while favorable metabolic and nutritional profiles and nephrectomy predicted improved survival. The nephrectomy-cholesterol score may serve as a prognostic tool and highlight the relevance of host metabolic status in ICI response.

Renal cell carcinoma (RCC) represents 2%-3% of all cancers in adults, and its pathogenesis is mainly related to altered cellular response to hypoxia. Lenvatinib, a novel multitarget tyrosine kinase inhibitor (TKI), represents a therapeutic option, in combination with mammalian target of rapamycin (mTOR) inhibitor everolimus, for the treatment of metastatic RCC (mRCC). The objective of this article is to review the evidence about the treatment of mRCC with combination of lenvatinib plus everolimus. Phase I studies supported clinical activity of lenvatinib in mRCC. A randomized, Phase II, open-label, multicenter trial demonstrated the clinical efficacy of combination treatment with lenvatinib plus everolimus in patients with progressive mRCC after prior therapy with TKI. Median progression-free survival was improved by 9 months with the combination therapy compared to the single-agent everolimus, with an overall response rate of 43% for the experimental regimen. Lenvatinib plus everolimus appeared to be slightly less toxic than single-agent lenvatinib and more toxic than single-agent everolimus; grade 3-4 adverse events occurred in 71% of patients. Currently, lenvatinib plus everolimus has US Food and Drug Administration approval for its use in mRCC after failure of previous treatment with TKI. The combination therapy with lenvatinib plus everolimus might be a promising choice for second-line treatment of mRCC patients. Based on the results of the Phase II trial, it is possible to speculate that the combination therapy could be appropriate for patients with high disease burden or strongly symptomatic patients.

Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p  < 0.001) with a longer median overall survival (OS) (35.9 months vs 12.1 months), 1-year OS of 71.6% vs 50.5% and 2-years OS of 56.5% vs 22.0% compared to those who did not. No significant interaction between nephrectomy and the overall five Meet-URO score risk groups was observed ( p  = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 ( p  = 0.038) and associated with a longer OS for the first three prognostic groups ( p  < 0.001), but not for groups 4 and 5 ( p  = 0.54). Conclusions Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.