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The Lancet. Oncology Jul 2024The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic... (Randomized Controlled Trial)
Randomized Controlled Trial
Addition of temsirolimus to chemotherapy in children, adolescents, and young adults with intermediate-risk rhabdomyosarcoma (ARST1431): a randomised, open-label, phase 3 trial from the Children's Oncology Group.
BACKGROUND
The Children's Oncology Group defines intermediate-risk rhabdomyosarcoma as unresected FOXO1 fusion-negative disease arising at an unfavourable site or non-metastatic FOXO1 fusion-positive disease. Temsirolimus in combination with chemotherapy has shown promising activity in patients with relapsed or refractory rhabdomyosarcoma. We aimed to compare event-free survival in patients with intermediate-risk rhabdomyosarcoma treated with vincristine, actinomycin, and cyclophosphamide alternating with vincristine and irinotecan (VAC/VI) combined with temsirolimus followed by maintenance therapy versus VAC/VI alone with maintenance therapy.
METHODS
ARST1431 was a randomised, open-label, phase 3 trial conducted across 210 institutions in Australia, Canada, New Zealand, and the USA. Eligible patients were those aged 40 years or younger with non-metastatic FOXO1-positive rhabdomyosarcoma or unresected FOXO1-negative rhabdomyosarcoma disease from unfavourable sites. Two other groups of patients were also eligible: those who had FOXO1-negative disease at a favourable site (excluding orbit) that was unresected; and those who were aged younger than 10 years with stage IV FOXO1-negative disease with distant metastases. Eligible patients had to have a Lansky performance status score of 50 or higher if 16 years or younger and a Karnofsky performance status score of 50 or higher if older than 16 years; all patients were previously untreated. Patients were randomised (1:1) in blocks of four and stratified by histology, stage, and group. Patients received intravenous VAC/VI chemotherapy with a cyclophosphamide dose of 1·2 g/m per dose per cycle with or without a reducing dose of intravenous weekly temsirolimus starting at 15 mg/m or 0·5 mg/kg per dose for those who weighed less than 10 kg. The total duration of therapy was 42 weeks followed by 6 months of maintenance therapy with oral cyclophosphamide plus intravenous vinorelbine for all patients. Temsirolimus was withheld during radiotherapy and for 2 weeks before any major surgical procedure. The primary endpoint was 3-year event-free survival. Data were analysed with a revised intention-to-treat approach. The study is registered with ClinicalTrials.gov (NCT02567435) and is complete.
FINDINGS
Between May 23, 2016, and Jan 1, 2022, 325 patients were enrolled. In 297 evaluable patients (148 assigned to VAC/VI alone and 149 assigned to VAC/VI with temsirolimus), the median age was 6·3 years (IQR 3·0-11·3); 33 (11%) patients were aged 18 years or older; 179 (60%) of 297 were male. 113 (77%) of 148 patients were FOXO1 negative in the VAC/VI group, and 108 (73%) of 149 were FOXO1 negative in the VAC/VI with temsirolimus group. With a median follow-up of 3·6 years (IQR 2·8-4·5), 3-year event-free survival did not differ significantly between the two groups (64·8% [95% CI 55·5-74·1] in the VAC/VI group vs 66·8% [57·5-76·2] in the VAC/VI plus temsirolimus group (hazard ratio 0·86 [95% CI 0·58-1·26]; log-rank p=0·44). The most common grade 3-4 adverse events were anaemia (62 events in 60 [41%] of 148 patients in the VAC/VI group vs 89 events in 87 [58%] of 149 patients in the VAC/VI with temsirolimus group), lymphopenia (83 events in 65 [44%] vs 99 events in 71 [48%]), neutropenia (160 events in 99 [67%] vs 164 events in 105 [70%]), and leukopenia (121 events in 86 [58%] vs 132 events in 93 [62%]). There was one treatment-related death in the VAC/VI with temsirolimus group, categorised as not otherwise specified.
INTERPRETATION
Addition of temsirolimus to VAC/VI did not improve event-free survival in patients with intermediate-risk rhabdomyosarcoma defined by their FOXO1 translocation status and clinical factors. Novel biology-based strategies are needed to improve outcomes in this population.
FUNDING
The Children's Oncology Group (supported by the US National Cancer Institute, US National Institutes of Health).
Topics: Humans; Male; Female; Child; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Sirolimus; Rhabdomyosarcoma; Child, Preschool; Vincristine; Young Adult; Cyclophosphamide; Adult; Dactinomycin; Irinotecan; Infant; Progression-Free Survival; Forkhead Box Protein O1
PubMed: 38936378
DOI: 10.1016/S1470-2045(24)00255-9 -
Jornal Brasileiro de Nefrologia 2024Identifying risk factors for autosomal dominant polycystic kidney disease (ADPKD) progression is important. However, studies that have evaluated this subject using a...
INTRODUCTION
Identifying risk factors for autosomal dominant polycystic kidney disease (ADPKD) progression is important. However, studies that have evaluated this subject using a Brazilian sample is sparce. Therefore, the aim of this study was to identify risk factors for renal outcomes and death in a Brazilian cohort of ADPKD patients.
METHODS
Patients had the first medical appointment between January 2002 and December 2014, and were followed up until December 2019. Associations between clinical and laboratory variables with the primary outcome (sustained decrease of at least 57% in the eGFR from baseline, need for dialysis or renal transplantation) and the secondary outcome (death from any cause) were analyzed using a multiple Cox regression model. Among 80 ADPKD patients, those under 18 years, with glomerular filtration rate <30 mL/min/1.73 m2, and/or those with missing data were excluded. There were 70 patients followed.
RESULTS
The factors independently associated with the renal outcomes were total kidney length - adjusted Hazard Ratio (HR) with a 95% confidence interval (95% CI): 1.137 (1.057-1.224), glomerular filtration rate - HR (95% CI): 0.970 (0.949-0.992), and serum uric acid level - HR (95% CI): 1.643 (1.118-2.415). Diabetes mellitus - HR (95% CI): 8.115 (1.985-33.180) and glomerular filtration rate - HR (95% CI): 0.957 (0.919-0.997) were associated with the secondary outcome.
CONCLUSIONS
These findings corroborate the hypothesis that total kidney length, glomerular filtration rate and serum uric acid level may be important prognostic predictors of ADPKD in a Brazilian cohort, which could help to select patients who require closer follow up.
Topics: Humans; Polycystic Kidney, Autosomal Dominant; Male; Female; Disease Progression; Brazil; Glomerular Filtration Rate; Adult; Middle Aged; Risk Factors; Cohort Studies; Uric Acid; Retrospective Studies
PubMed: 38935976
DOI: 10.1590/2175-8239-JBN-2023-0040en -
MMWR. Morbidity and Mortality Weekly... Jun 2024In 2022, 81,806 opioid-involved overdose deaths were reported in the United States, more than in any previous year. Medications for opioid use disorder (OUD),...
In 2022, 81,806 opioid-involved overdose deaths were reported in the United States, more than in any previous year. Medications for opioid use disorder (OUD), particularly buprenorphine and methadone, substantially reduce overdose-related and overall mortality. However, only a small proportion of persons with OUD receive these medications. Data from the 2022 National Survey on Drug Use and Health were applied to a cascade of care framework to estimate and characterize U.S. adult populations who need OUD treatment, receive any OUD treatment, and receive medications for OUD. In 2022, 3.7% of U.S. adults aged ≥18 years needed OUD treatment. Among these, only 25.1% received medications for OUD. Most adults who needed OUD treatment either did not perceive that they needed it (42.7%) or received OUD treatment without medications for OUD (30.0%). Compared with non-Hispanic Black or African American and Hispanic or Latino adults, higher percentages of non-Hispanic White adults received any OUD treatment. Higher percentages of men and adults aged 35-49 years received medications for OUD than did women and younger or older adults. Expanded communication about the effectiveness of medications for OUD is needed. Increased efforts to engage persons with OUD in treatment that includes medications are essential. Clinicians and other treatment providers should offer or arrange evidence-based treatment, including medications, for patients with OUD. Pharmacists and payors can work to make these medications available without delays.
Topics: Humans; United States; Adult; Middle Aged; Male; Female; Opioid-Related Disorders; Young Adult; Adolescent; Buprenorphine; Aged; Opiate Substitution Treatment; Methadone
PubMed: 38935567
DOI: 10.15585/mmwr.mm7325a1 -
Organic Letters Jun 2024Pyrrole alkaloids (PAs) are a diverse class of natural products with complex carbon frameworks and broad bioactivities that are usually derived from marine sponges. and...
Pyrrole alkaloids (PAs) are a diverse class of natural products with complex carbon frameworks and broad bioactivities that are usually derived from marine sponges. and are two independent sponges collected from the South China Sea in 2013 and 2018, respectively. We discovered PAs are common constituents in both two sponges; more specifically, produces pyrrole-imidazole alkaloids, and contains pyrrolidone alkaloids. In this study, three pyrrole steroid metabolites were obtained. Compounds and are a pair of epimers sharing a new 5/7/5/6/6 pentacyclic structural configuration, and compound has a new rigid 5/6/6 tricyclic structure. Interestingly, their scaffolds all possess a 6/6 bicyclic system on the featured classic pyrrole/pyrrolidone skeletons, so-dubbed tagpyrrollins A and B ( and , respectively) and tagpyrrollidone A (). From a biosynthetic viewpoint, 4,5-dihydroxypent-2-enal probably plays a crucial role in constructing these pyrrole steroid analogues. Based on our previous study on the inhibitory activity of spongiacidin targeting AKR1B1, a drug target for the treatment of chronic diabetic complications, in this study we found that tagpyrrolin A () also exhibits an inhibitory effect against AKR1B1.
PubMed: 38935544
DOI: 10.1021/acs.orglett.4c01976 -
Expert Opinion on Pharmacotherapy Jun 2024The treatment landscape of non-small cell lung cancer (NSCLC) has seen significant advancements in recent years, marked by a shift toward target agents and immune... (Review)
Review
INTRODUCTION
The treatment landscape of non-small cell lung cancer (NSCLC) has seen significant advancements in recent years, marked by a shift toward target agents and immune checkpoint inhibitors (ICIs). However, chemotherapy remains a cornerstone of treatment, alone or in combination. Microtubule-targeting agents, such as taxanes and vinca alkaloids, play a crucial role in clinical practice in both early and advanced settings in NSCLC.
AREA COVERED
This review outlines the mechanisms of action, present significance, and prospective advancements of microtubule-targeting agents (MTAs), with a special highlight on new combinations in phase 3 trials. The online databases PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms 'Microtubule-targeting agents' and 'non-small cell lung cancer' or synonyms, with a special focus over the last 5 years of publications.
EXPERT OPINION
Despite the emergence of immunotherapy, MTA remains crucial, often used alongside or after immunotherapy, especially in squamous cell lung cancer. Next-generation sequencing expands treatment options, but reliable biomarkers for immunotherapy are lacking. While antibody-drug conjugates (ADCs) show promise, managing toxicities remain vital. In the early stages, MTAs, possibly with ICIs, are standard, while ADCs may replace traditional chemotherapy in the advanced stages. Nevertheless, MTAs remain essential in subsequent lines or for patients with contraindications.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Tubulin Modulators; Antineoplastic Agents; Immune Checkpoint Inhibitors; Immunotherapy; Animals; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38935538
DOI: 10.1080/14656566.2024.2369196 -
Molecular Diversity Jun 2024As mimetic compounds of the natural alkaloid mackinazolinone, forty pyrido[1,2-a]thiazolo[5,4-d] pyrimidinone were designed and synthesized from a bioisosterism...
As mimetic compounds of the natural alkaloid mackinazolinone, forty pyrido[1,2-a]thiazolo[5,4-d] pyrimidinone were designed and synthesized from a bioisosterism approach. The structure of these compounds was confirmed through analysis using H NMR, C NMR, and HRMS techniques. All the compounds were evaluated for their anticholinesterase activities and cytotoxicity on normal cells (293 T) by the Ellman method and methyl thiazolyl tetrazolium (MTT) method in vitro. and the structure-activity relationships (SARs) were summarized. The results showed that most of the compounds effectively inhibited acetylcholinesterase (AChE) in the micromolar range with weak cytotoxicity. Compound 7o exhibited the best inhibitory activity against AChE, displaying an IC values of 1.67 ± 0.09 µM and an inhibitory constant K of 11.31 µM as a competitive inhibitor to AChE. Molecular docking indicated that compound 7o may bind to AChE via hydrogen bond and π-π stacking. Further molecular dynamics (MD) simulations indicated a relatively low binding free energy (- 27.91 kJ·mol) of compound 7o with AChE. In summary, the collective findings suggested that 7o was promising as a potential novel drug candidate worthy of further investigation for the treatment of Alzheimer's disease.
PubMed: 38935303
DOI: 10.1007/s11030-024-10920-x -
Natural Product Research Jun 2024One previously undescribed abietane diterpene alkaloid containing an oxazole ring (), one unreported abietane diterpene (), and nine known abietane diterpenes () were...
One previously undescribed abietane diterpene alkaloid containing an oxazole ring (), one unreported abietane diterpene (), and nine known abietane diterpenes () were isolated from the roots and rhizomes of Diels. Their structures and absolute configurations were elucidated by a combination of HRESIMS, 1D and 2D NMR, and ECD. All compounds were evaluated for their cytotoxic activity against several human cancer cell lines (HepG2, A549, H460, MCF7, PC3, and Hela). The results showed that exhibited a moderate cytotoxic effect on HepG2 cells (IC: 14.22 ± 1.05 μM) and was able to inhibit the cell growth of MCF7 and Hela cells by 35.08% and 47.26% respectively, at a concentration of 20 μM, while other compounds showed low cytotoxic activity.
PubMed: 38934460
DOI: 10.1080/14786419.2024.2372829 -
Current Topics in Medicinal Chemistry Jun 2024Upon the release of the selection results of "Qin Medicine," numerous Chinese herbal medicines and proprietary Chinese medicines have regained attention. Physochlainae...
BACKGROUND
Upon the release of the selection results of "Qin Medicine," numerous Chinese herbal medicines and proprietary Chinese medicines have regained attention. Physochlainae Radix (Huashanshen), a herbal medicine named after Mount Hua, the prominent peak in the Qinling Mountains, has garnered particular interest. Despite this, the impact of Physochlainae Radix and Qin medicines as a whole remains significantly overshadowed by the renown of Mount Hua.
METHODS
Search on Using "Physochlainae Radix" as the keyword; searches were conducted across China National Knowledge Infrastructure (CNKI), Wanfang Data, WIP Database, PubMed, Web of Science, and the National Library of China databases.
RESULTS
This study presents an overview of Physochlainae Radix by reviewing its history, chemical composition, preparation methods, planting and cultivation practices, concoctions, alkaloid detection, contraindications for use, resource recycling, and predicting quality markers.
CONCLUSION
To facilitate the further application and development of Physochlainae Radix, this study also addresses the challenges in the development of Qin medicines and proposes potential solutions.
.PubMed: 38934285
DOI: 10.2174/0115680266287982240517050139 -
Frontiers in Endocrinology 2024To examine the potential association between polycystic ovary syndrome (PCOS) and hyperuricemia and to elucidate the underlying contributory factors.
PURPOSE
To examine the potential association between polycystic ovary syndrome (PCOS) and hyperuricemia and to elucidate the underlying contributory factors.
METHODS
Retrospective study on 603 women with PCOS and 604 women without PCOS. Anthropometric features, reproductive hormone profiles, and metabolic parameters were measured and compared between two groups of patients. Examinations of correlations between SUA levels and other parameters were conducted to discern potential correlations.
RESULTS
Both serum uric acid levels and the incidence of hyperuricemia exhibited statistically significant elevations in women with PCOS when compared to their counterparts without PCOS. Nonetheless, this statistical difference was not found between the obese subgroup after stratifying study subjects by body mass index (BMI). Pearson's correlation analysis underscored the prominence of BMI as a robust factor influencing SUA levels in women, regardless of their PCOS status. Furthermore, multivariable linear regression model demonstrated significant positive associations between SUA levels and several variables, namely dehydroepiandrosterone sulfate (DHEA-S), free androgen index (FAI), total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), fasting insulin (FINS), homeostatic model assessment of insulin resistance (HOMA-IR), area under the curve for insulin (AUC-I), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Additionally, it is noteworthy that the prevalence of hyperuricemia exhibited a positive association with fasting plasma glucose (FPG) levels, while conversely, it displayed a negative association with estradiol (E2) levels.
CONCLUSIONS
PCOS is associated with a significant elevation of SUA level and hyperuricemia prevalence. HA, IR, and dyslipidemia may be the mediators in the pathogenesis of hyperuricemia in women with PCOS.
Topics: Humans; Polycystic Ovary Syndrome; Female; Hyperuricemia; Retrospective Studies; Adult; Uric Acid; Insulin Resistance; Body Mass Index; Young Adult
PubMed: 38933825
DOI: 10.3389/fendo.2024.1356859 -
Frontiers in Microbiology 2024Tibetan tea changes during microorganism fermentation. Research on microorganisms in Tibetan tea has focused on their identification, while studies on the influence of...
Tibetan tea changes during microorganism fermentation. Research on microorganisms in Tibetan tea has focused on their identification, while studies on the influence of specific microorganisms on the components and health functions of Tibetan tea are lacking. was inoculated into Tibetan tea for intensive fermentation, and the components of -fermented tea (BLT) were detected by liquid chromatography with tandem mass spectrometry (UHPLC-TOF-MS), and then the effects of BLT on intestinal probiotic functions were investigated by experiments on mice. The results revealed the metabolites of BLT include polyphenols, alkaloids, terpenoids, amino acids, and lipids. Intensified fermentation also improved the antioxidant capacity and the protective effect on the intestinal barrier of Tibetan tea. In addition, the enhanced fermentation of Tibetan tea exerted intestinal probiotic effects by modulating the relative abundance of short-chain fatty acid-producing bacteria in the intestinal flora. Therefore, intensive fermentation with can improve the health benefits of Tibetan tea.
PubMed: 38933031
DOI: 10.3389/fmicb.2024.1376757