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.
The protein kinase C (PKC) agonist bryostatin-1 has shown significant ex-vivo potency to revert HIV-1 latency, compared with other latency reversing agents (LRA). The safety of this candidate LRA ...remains to be proven in treated HIV-1-infected patients.
In this pilot, double-blind phase I clinical-trial (NCT 02269605), we included aviraemic HIV-1-infected patients on triple antiretroviral therapy to evaluate the effects of two different single doses of bryostatin-1 (10 or 20 μg/m) compared with placebo.
Twelve patients were included, four in each arm. Bryostatin-1 was well tolerated in all participants. Two patients in the 20 μg/m arm developed grade 1 headache and myalgia. No detectable increases of cell-associated unspliced (CA-US) HIV-1-RNA were observed in any study arm, nor differences in HIV-1 mRNA dynamics between arms (P = 0.44). The frequency of samples with low-level viraemia did not differ between arms and low-level viraemia did not correlate with CA-US HIV-1-RNA levels (P = 0.676). No changes were detected on protein kinase C (PKC) activity and in biomarkers of inflammation (sCD14 and interleukin-6) in any study arm. After the single dose of bryostatin-1, plasma concentrations were under detection limits in all the patients in the 10 μg/m arm, and below 50 pg/ml (0.05 nmol/l) in those in the 20 μg/m arm.
Bryostatin-1 was safe at the single doses administered. However, the drug did not show any effect on PKC activity or on the transcription of latent HIV, probably due to low plasma concentrations. This study will inform next trials aimed at assessing higher doses, multiple dosing schedules or combination studies with synergistic drugs.
Cocoa is a source of flavanols, and these phenolic compounds exert beneficial effects on health and aging, and reduce the risk of suffering chronic diseases (cardiovascular diseases, metabolic ...disorders, cancer). An increasing body of evidence has emerged to suggest that cocoa flavanols potentially are important chemopreventive natural agents. This review summarizes human studies from the past two decades, providing data related to the effects derived from cocoa intake on health and disease. Most human studies have reported beneficial effects of cocoa consumption on health and chronic diseases; however, outcomes are not unequivocal. Review of human studies enable to identify different mechanisms of action for cocoa, although they are not fully understood at present. In addition, it remains unclear whether cocoa consumption should be recommended to healthy subjects or to patients and what is the appropriate dosage or duration of cocoa consumption. Elucidation of information regarding these crucial issues could lead to cocoa use as an approach for decreasing the risk of certain chronic diseases, as well as improving health and quality of life.
-Most epidemiologic and interventional studies report benefits of cocoa intake on health.-Human studies mostly state protective effects of cocoa intake against chronic diseases.-Large controlled trials with longer follow-ups are needed to verify equivocal findings.-Well-designed studies in cells and animals will help to clarify cocoa molecular mechanisms.-Further human studies are needed before recommending specific cocoa dosages for the population.
Prevention of diabetes through the diet has recently received an increasing interest, and polyphenolic compounds, such as flavanols, have become important potential chemopreventive natural agents due ...to their proved benefits on health, with low toxicity and cost. Tea, red wine and cocoa are good sources of flavanols and these highly consumed foods might contribute to prevent diabetes. In this regard, there is increasing evidence for a protective effect of tea, red wine and cocoa consumption against this disorder. This review summarizes the available epidemiological and interventional human studies providing evidence for and against this effect. Overall observational data suggest a benefit, but results are still equivocal and likely confounded by lifestyle and background dietary factors. The weight of data indicate favourable effects on diabetes risk factors for tea, red wine and cocoa intake, and a number of plausible mechanisms have been elucidated in human studies. However, despite the growing evidence it remains uncertain whether tea, red wine and cocoa consumption should be recommended to the general population or to patients as a strategy to reduce the risk of diabetes.
•The current state-of-the-art on diabetes and tea, red wine and cocoa consumption is reviewed.•Epidemiologic and interventional studies mostly support a benefit of tea, red wine and cocoa intake against diabetes.•New human studies should be encouraged to clarify the equivocal evidences before giving any recommendation to the population.•The mechanisms behind potential tea, red wine and cocoa benefits against diabetes should be further investigated.
Antidiabetic actions of cocoa flavanols Martin, Maria Ángeles; Goya, Luis; Ramos, Sonia
Molecular nutrition & food research,
August 2016, Letnik:
60, Številka:
8
Journal Article
Recenzirano
Prevention of diabetes mellitus type 2 (DMT2) through the diet is receiving a growing interest and cocoa because of its polyphenolic compounds, mainly flavanols, has become an important potential ...chemopreventive natural agent. Cocoa and its main flavanols might contribute to prevent or delay diabetes mellitus type 2 by modulating insulin secretion in β‐pancreatic cells and targeting insulin‐sensitive tissues because of their insulin‐like activity or through the regulation of key proteins of the insulin signaling route. Among other actions, cocoa flavanols have been proved to enhance glucose uptake through the promotion of glucose transport, to repress glucose production, or to improve lipid metabolism. Nevertheless, the molecular mechanisms of action involved in these effects are not fully understood and many points remain to be clarified. This review provides insights into the molecular machinery of the chemopreventive activity of cocoa and its flavanols by compiling cell culture and animal models studies, as well as evidence from human interventional trials.
Mechanisms of action related to the chemopreventive activity of cocoa and its flavanols on insulin‐sensitive tissues in diabetes are reviewed.
The objective of this review was to assess, based on human data, the role of phenolic compounds in selected plant foods consumed as part of the Mediterranean diet in the prevention of chronic ...diseases (CDs) like cardiovascular disease, cancer and neurodegenerative conditions. Fruits and vegetables are rich sources of phenolic compounds and based on scientific data it would be expected that their consumption, as part of the diet, would be responsible for their documented preventive role of chronic diseases. The results of the review of scientific literature on human clinical trials revealed that in some studies polyphenols exert a positive effect in the prevention of cardiovascular disease, essentially blood pressure and arterial dilation, certain types of cancer and neurodegenerative disorders. However, such effects are not consistent with other clinical studies in which no effect has been found. Therefore, the level of evidence for a beneficial effect in humans of phenols on the prevention of CDs is weak and need to be strengthened by additional studies addressing potential confounding factors, such as interaction of phenols with other bioactive substances in foods and potential pro-oxidant effects.
Summary Background Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic ...effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects. Methods Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m2 on days 1–4) or daily thalidomide (100 mg), and prednisone (60 mg/m2 on days 1–4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m2 on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m2 on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00443235. Findings In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 31% vs 20 15%, p=0·01) and discontinuations (22 17% vs 15 12%, p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one 1% in the VTP group vs nine 7% in the VMP group), cardiac events (11 8% vs 0), and peripheral neuropathy (nine 7% vs 12 9%). After maintenance therapy, the complete remission rate was 42% (40 44% patients in complete remission in the bortezomib plus thalidomide group, 34 39% in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy. Interpretation Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma. Funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).
SummaryBackgroundExtraskeletal myxoid chondrosarcoma is a rare sarcoma with low sensitivity to cytotoxic chemotherapy. Retrospective evidence suggests that antiangiogenic drugs could be a treatment ...option. We aimed to investigate the activity of pazopanib, an antiangiogenic drug, in patients with advanced extraskeletal myxoid chondrosarcoma. MethodsIn this single-arm, open-label phase 2 trial, three parallel independent cohorts of different histotypes of advanced sarcomas were recruited (extraskeletal myxoid chondrosarcoma, typical solitary fibrous tumour, and malignant-dedifferentiated solitary fibrous tumour). In each cohort, patients received pazopanib. In this Article, we report the results of the cohort of patients with advanced extraskeletal myxoid chondrosarcoma. Separate reporting of the three cohorts was prespecified in the study protocol. In this cohort, adult patients (aged ≥18 years) with a diagnosis of NR4A3-translocated, metastatic, or unresectable extraskeletal myxoid chondrosarcoma, who had Response Evaluation Criteria in Solid Tumors (RECIST) progression in the previous 6 months, and had an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled at 11 study sites of the Spanish, Italian, and French sarcoma groups. Patients received oral pazopanib (800 mg/day) continuously, until disease progression, unacceptable toxicity, death, non-compliance, patient refusal, or investigator's decision. The primary endpoint was the proportion of patients achieving an objective response according to RECIST 1·1 in the modified intention-to-treat population (patients who provided consent and had a central molecularly confirmed diagnosis of extraskeletal myxoid chondrosarcoma). The safety analysis included all patients who received at least one dose of pazopanib. This study is registered with ClinicalTrials.gov, number NCT02066285. FindingsBetween June 24, 2014, and Jan 17, 2017, 26 patients entered the study and started pazopanib. Of these, 23 met the eligibility criteria for the modified intention-to-treat analysis. Median follow-up was 27 months (IQR 18–30). 22 patients (one patient died before the primary analysis) were evaluable for the primary endpoint: four (18% 95% CI 1–36) had a RECIST objective response. No deaths or grade 4 adverse events occurred. The most frequent grade 3 adverse events were hypertension (nine 35% of 26 patients), increased concentration of alanine aminotransferase (six 23%), and increased aspartate aminotransferase (five 19%). InterpretationPazopanib had clinically meaningful antitumour activity in patients with progressive and advanced extraskeletal myxoid chondrosarcoma, and could be considered a suitable option after failure to respond to first-line anthracycline-based chemotherapy in these patients. FundingSpanish Group for Research on Sarcomas, Italian Sarcoma Group, French Sarcoma Group, GlaxoSmithKline, and Novartis.
Background:
Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene ...encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined.
Methods:
Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated.
Results:
A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression.
Conclusions:
IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.
PDF
