Summary Background The optimum duration of androgen deprivation combined with high-dose radiotherapy in prostate cancer remains undefined. We aimed to determine whether long-term androgen deprivation ...was superior to short-term androgen deprivation when combined with high-dose radiotherapy. Methods In this open-label, multicentre, phase 3 randomised controlled trial, patients were recruited from ten university hospitals throughout Spain. Eligible patients had clinical stage T1c–T3b N0M0 prostate adenocarcinoma with intermediate-risk and high-risk factors according to 2005 National Comprehensive Cancer Network criteria. Patients were randomly assigned (1:1) using a computer-generated randomisation schedule to receive either 4 months of androgen deprivation combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76–82 Gy; short-term androgen deprivation group) or the same treatment followed by 24 months of adjuvant androgen deprivation (long-term androgen deprivation group), stratified by prostate cancer risk group (intermediate risk vs high risk) and participating centre. Patients assigned to the short-term androgen deprivation group received 4 months of neoadjuvant and concomitant androgen deprivation with subcutaneous goserelin (2 months before and 2 months combined with high-dose radiotherapy). Anti-androgen therapy (flutamide 750 mg per day or bicalutamide 50 mg per day) was added during the first 2 months of treatment. Patients assigned to long-term suppression continued with the same luteinising hormone-releasing hormone analogue every 3 months for another 24 months. The primary endpoint was biochemical disease-free survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT02175212. Findings Between Nov 7, 2005, and Dec 20, 2010, 178 patients were randomly assigned to receive short-term androgen deprivation and 177 to receive long-term androgen deprivation. After a median follow-up of 63 months (IQR 50–82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term androgen deprivation than among those receiving short-term treatment (90% 95% CI 87–92 vs 81% 78–85; hazard ratio HR 1·88 95% CI 1·12–3·15; p=0·01). 5-year overall survival (95% 95% CI 93–97 vs 86% 83–89; HR 2·48 95% CI 1·31–4·68; p=0·009) and 5-year metastasis-free survival (94% 95% CI 92–96 vs 83% 80–86; HR 2·31 95% CI 1·23–3·85; p=0·01) were also significantly better in the long-term androgen deprivation group than in the short-term androgen deprivation group. The effect of long-term androgen deprivation on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. Grade 3 late rectal toxicity was noted in three (2%) of 177 patients in the long-term androgen deprivation group and two (1%) of 178 in the short-term androgen deprivation group; grade 3–4 late urinary toxicity was noted in five (3%) patients in each group. No deaths related to treatment were reported. Interpretation Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation. Funding Spanish National Health Investigation Fund, AstraZeneca.
Little is known on how the domain and intensity of physical activity (PA) associates with metabolic syndrome (MetS). The aim of this study was to examine associations between PA domains ...(leisure-time, domestic, active transport, total walking and total PA), PA intensities (light, moderate and vigorous) and PA levels with MetS in the general adult population.
Cross-sectional study. Anthropometry, blood biochemistry, 79-item PA-questionnaire, lifestyle and medical history were evaluated in a representative sample of Canary Island adults (n = 6,729). MetS was diagnosed using the harmonized IDF-NHLBI-AHA criteria. T-test and multivariable logistic regression was used to analyse associations between PA domains and intensities with MetS vs. no MetS, controlling for socio-demographic, lifestyle, family antecedents and body mass index (BMI).
For each MET-h/day spent in moderate-vigorous PA intensities, as well as in recreational domain, active transport, total walking and total PA, the odds of MetS decreased between 3-10%. Energy expenditure exclusively in light and domestic PAs was not associated with MetS, however it was important to achieve a total PA level of 3 MET-h/day, which reduced the odds of MetS by 23%. This reduction was blunted in those with more than 2 h/d of TV watching time. A PA level of 3 MET-h/d also nullified the risk of MetS in those with low PA and high TV consumption.
Some types of leisure time PAs may contribute more than others to reducing MetS. Light and domestic PA play a complementary role in enhancing energy expenditure in the general population. TV watching time above 2 h/d counteracted the MetS risk reduction associated with PA level, but PA level also reduced the risk of METs presented by those with a low level of PA and an excess TV watching time. Physical activity explains a greater amount of the variance of MetS than any other factors of lifestyle, education, sex and family history, and substantially mitigates the strong association of age and BMI with MetS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and ...safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy.
Methods
In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1–2 months (M) apart 4–18M posttransplant. Anti–glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post–dose 1, and 1M and 12M post–dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post–dose 2.
Results
Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post–dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups.
Conclusions
RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose.
Clinical Trials Registration
NCT02058589.
The adjuvanted recombinant zoster vaccine was immunogenic in renal transplant recipients receiving daily immunosuppressive treatment. Humoral and cell-mediated immune responses persisted through 1 year postvaccination. Vaccination had no impact on renal function or rejection rate. No safety concerns arose.
In semiarid regions is important to use native strains best adapted to these environments to optimize plant-PGPR interaction. We aimed to isolate and characterize PGPR from roots and rhizosphere of a ...tomato crop, as well as studying the effect of its inoculation on tomato seedlings growth. We selected four strains considering their effectiveness of fixing nitrogen, solubilizing phosphate, producing siderophores and indole acetic acid. They belong to the genera Enterobacter, Pseudomonas, Cellulosimicrobium, and Ochrobactrum. In addition, we also analyzed the ability to solubilize Ca
(PO
)
, FePO
and AlPO
and the presence of one of the genes encoding the cofactor PQQ in their genome. Enterobacter 64S1 and Pseudomonas 42P4 showed the highest phosphorus solubilizing activity and presence of pqqE gene. Furthermore, in a tomato-based bioassay in speed-bed demonstrated that a sole inoculation at seedling stage with the strains increased dry weight of roots (49-88%) and shoots (39-55%), stem height (8-13%) and diameter (5-8%) and leaf area (22-31%) and were equal or even higher than fertilization treatment. Leaf nitrogen and chlorophyll levels were also increased (50-80% and 26-33%) compared to control. These results suggest that Enterobacter 64S1 and Pseudomonas 42P4 can be used as bio-inoculant in order to realize a nutrient integrated management.
Checkpoint inhibitors are being added to standard-of-care chemotherapy in multiple clinical trials. Success has been reported in non-small and small cell lung carcinomas and urothelial, head and ...neck, gastric, and esophageal cancers, and promising results are already available in triple-negative breast and pancreatic malignancies. The potential mechanisms of synergy include immunogenic tumor cell death, antiangiogenesis, selective depletion of myeloid immunosuppressive cells, and lymphopenia, which reduces regulatory T cells and makes room for proliferation of effector T cells. However, chemotherapy regimens have not been optimized for such combinations, perhaps explaining some recent clinical trial disappointments. Approaches to make the most of chemoimmunotherapy include neoadjuvant and adjuvant schemes.
Immunotherapy of cancer based on PD-1/PD-L1 blockade has prompted a revolution in cancer clinical management. Evidence in phase III clinical trials already supports combinations of immunotherapy with standard-of-care chemotherapy for a number of malignant diseases. This review focuses on such evidence and provides an overview of the potential synergistic mechanisms of action and the opportunities to optimize chemoimmunotherapy regimens.
From the conceptualization to the evaluation of computer‐supported collaborative learning (CSCL) scenarios, teachers address multiple tasks, sometimes being overwhelmed on account of the required ...time and associated burden. To support teachers in this endeavor, we propose to connect the pedagogical decisions made at design time with the analysis of the participants' interactions. Thus, teachers would be provided with relevant and coarse‐grained information that could help them manage their CSCL scenarios. This paper synthesizes the main contributions obtained from a 3‐year design‐based research process, and presents the findings obtained from the evaluation of the current proposal in two authentic CSCL scenarios. The participant teachers valued the proposal positively and stated that it was helpful for their orchestration of CSCL scenarios.
Experience in real clinical practice with ceftazidime/avibactam is limited, and there are even fewer data on infections due to OXA-48-producing Enterobacteriaceae.
We designed an observational study ...of a prospectively collected cohort of adult patients receiving ceftazidime/avibactam in our centre. Only the first treatment course of each patient was analysed. Efficacy and safety were evaluated as 14 and 30 day mortality, recurrence rate at 90 days, resistance development and occurrence of adverse effects.
Fifty-seven patients were treated with ceftazidime/avibactam. The median age was 64 years (range 26-86), 77% were male and the median Charlson index was 3. The most frequent sources of infection were intra-abdominal (28%), followed by respiratory (26%) and urinary (25%). Thirty-one (54%) patients had a severe infection (defined as presence of sepsis or septic shock). Most patients received ceftazidime/avibactam as monotherapy (81%) and the median duration of treatment was 13 days. Mortality at 14 days was 14%. In multivariate analysis, the only mortality risk factor was INCREMENT-CPE score >7 (HR 11.7, 95% CI 4.2-20.6). There was no association between mortality and monotherapy with ceftazidime/avibactam. The recurrence rate at 90 days was 10%. Ceftazidime/avibactam resistance was not detected in any case and only two patients developed adverse events related to treatment.
Ceftazidime/avibactam shows promising results, even in monotherapy, for the treatment of patients with severe infections due to OXA-48-producing Enterobacteriaceae and limited therapeutic options. The emergence of resistance to ceftazidime/avibactam was not observed.
Poly I:C is a powerful immune adjuvant as a result of its agonist activities on TLR-3, MDA5 and RIG-I. BO-112 is a nanoplexed formulation of Poly I:C complexed with polyethylenimine that causes tumor ...cell apoptosis showing immunogenic cell death features and which upon intratumoral release results in more prominent tumor infiltration by T lymphocytes. Intratumoral treatment with BO-112 of subcutaneous tumors derived from MC38, 4 T1 and B16-F10 leads to remarkable local disease control dependent on type-1 interferon and gamma-interferon. Some degree of control of non-injected tumor lesions following BO-112 intratumoral treatment was found in mice bearing bilateral B16-OVA melanomas, an activity which was enhanced with co-treatment with systemic anti-CD137 and anti-PD-L1 mAbs. More abundant CD8
T lymphocytes were found in B16-OVA tumor-draining lymph nodes and in the tumor microenvironment following intratumoral BO-112 treatment, with enhanced numbers of tumor antigen-specific cytotoxic T lymphocytes. Genome-wide transcriptome analyses of injected tumor lesions were consistent with a marked upregulation of the type-I interferon pathway. Inspired by these data, intratumorally delivered BO-112 is being tested in cancer patients (NCT02828098).
Highlights • Immunity against cancer is negatively regulated by lymphocyte surface receptors. • Cellular immunity against cancer can be unleashed by mAbs acting on such receptors. • Clinical trial ...evidence has shown efficacy with ipilimumab (a CTLA-4-blocking mAb). • Blockade of the PD-1/PD-L1 axis shows very promising activity in cancer patients. • Combination strategies under development attain synergistic effects.
Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect ...mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor‐suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib‐desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low‐dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
What's new?
Sunitinib, a tyrosine kinase inhibitor, is one of the most commonly used targeted therapeutics for treatment of metastatic renal cell carcinoma (mRCC). However, the majority of patients who initially respond eventually develop acquired resistance. In the present study, by analyzing sequential tumor biopsies from an mRCC patient who developed acquired resistance to sunitinib, the authors identified mutations in genes whose loss of function conferred sunitinib resistance to tumor cell lines and xenografted mice and went on to identify critical downstream action mechanisms. The findings may be relevant for the development of predictive biomarkers and new therapeutic strategies in mRCC.
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