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Journal of Clinical Oncology : Official... Jan 2024Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient... (Randomized Controlled Trial)
Randomized Controlled Trial
Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial.
PURPOSE
Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease.
METHODS
This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control.
RESULTS
Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab control: HR, 0.77 [95% CI, 0.56 to 1.07]; = .120; durvalumab + olaparib control: HR, 0.59 [95% CI, 0.42 to 0.83]; = .003). The safety profiles of the experimental arms were generally consistent with individual agents.
CONCLUSION
Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.
Topics: Female; Humans; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Endometrial Neoplasms; Neoplasm Recurrence, Local; Paclitaxel; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Double-Blind Method
PubMed: 37864337
DOI: 10.1200/JCO.23.02132 -
Cell Death & Disease Dec 2023Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and...
Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and approximately half of patients develop acquired drug resistance within 2 years of treatment, necessitating exploration of new treatment strategies. Targeting ferroptosis as a novel approach to tumor treatment has gained attention. Yet, there is limited research on ferroptosis in GIST, and the underlying mechanism remains unclear. In this study, we revealed that IM increased lipid reactive oxygen species and intracellular Fe levels, and decreased glutathione levels in GIST. This effect could be partially inhibited by Ferrostatin-1. Additionally, knocking down STUB1 and overexpressing GPX4 reversed the IM-induced ferroptosis effect. Moreover, STUB1 was identified as a novel E3 ubiquitin ligase of GPX4, promoting the ubiquitination at site K191 of GPX4. The combination of the GPX4 inhibitor RSL3 and IM synergistically induces ferroptosis, inhibiting GIST proliferation both in vivo and in vitro. Furthermore, STUB1 and GPX4 expression serve as independent prognostic factors for GIST. In conclusion, This study is the first to demonstrate that IM induces ferroptosis by promoting STUB1-mediated GPX4 ubiquitination in GIST, and the combination of RSL3 and IM emerges as a promising therapeutic strategy for GIST.
Topics: Humans; Imatinib Mesylate; Gastrointestinal Stromal Tumors; Ferroptosis; Ubiquitination; Ubiquitin-Protein Ligases
PubMed: 38110356
DOI: 10.1038/s41419-023-06300-2 -
Cancer Cell Mar 2024KRAS inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS-mutated lung cancers; however, most patients eventually develop resistance. In...
KRAS inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRAS and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRAS and Kras lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
Topics: Animals; Mice; Humans; Proto-Oncogene Proteins p21(ras); Lung Neoplasms; Genes, ras; Carcinoma, Squamous Cell; Mutation; Acetonitriles; Piperazines; Pyrimidines
PubMed: 38402609
DOI: 10.1016/j.ccell.2024.01.012 -
Gastroenterology Mar 2024Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to...
BACKGROUND & AIMS
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, and it has high metastatic and recurrence rates. We aimed to characterize the proteomic features of GIST to understand biological processes and treatment vulnerabilities.
METHODS
Quantitative proteomics and phosphoproteomics analyses were performed on 193 patients with GIST to reveal the biological characteristics of GIST. Data-driven hypotheses were tested by performing functional experiments using both GIST cell lines and xenograft mouse models.
RESULTS
Proteomic analysis revealed differences in the molecular features of GISTs from different locations or with different histological grades. MAPK7 was identified and functionally proved to be associated with tumor cell proliferation in GIST. Integrative analysis revealed that increased SQSTM1 expression inhibited the patient response to imatinib mesylate. Proteomics subtyping identified 4 clusters of tumors with different clinical and molecular attributes. Functional experiments confirmed the role of SRSF3 in promoting tumor cell proliferation and leading to poor prognosis.
CONCLUSIONS
Our study provides a valuable data resource and highlights potential therapeutic approaches for GIST.
Topics: Humans; Animals; Mice; Gastrointestinal Stromal Tumors; Antineoplastic Agents; Proteomics; Imatinib Mesylate; Cell Line, Tumor; Disease Models, Animal; Gastrointestinal Neoplasms; Serine-Arginine Splicing Factors
PubMed: 37995868
DOI: 10.1053/j.gastro.2023.11.284 -
International Journal of Gynecological... Apr 2024In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly... (Randomized Controlled Trial)
Randomized Controlled Trial
Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial.
OBJECTIVE
In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status.
METHODS
Patients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status.
RESULTS
Of 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk.
CONCLUSION
This analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.
Topics: Female; Humans; Bevacizumab; Carcinoma, Ovarian Epithelial; Ovarian Neoplasms; Phthalazines; Piperazines; Progression-Free Survival
PubMed: 38129136
DOI: 10.1136/ijgc-2023-004995 -
Nature Metabolism Sep 2023Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged...
Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFR neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma.
Topics: United States; Animals; Mice; Ranolazine; Melanoma; Immunotherapy; Protein Kinase Inhibitors; Methionine
PubMed: 37563469
DOI: 10.1038/s42255-023-00861-4 -
Journal of Affective Disorders Oct 2023Depression and dementia are highly prevalent in older adults and often co-occur. This Phase IV study investigated the effectiveness and tolerability of vortioxetine in...
BACKGROUND
Depression and dementia are highly prevalent in older adults and often co-occur. This Phase IV study investigated the effectiveness and tolerability of vortioxetine in improving depressive symptoms, cognitive performance, daily and global functioning and health-related quality of life (HRQoL) in patients with major depressive disorder (MDD) and comorbid early-stage dementia.
METHODS
Patients (n = 82) aged 55-85 years with a primary diagnosis of MDD (onset before age 55 years) and comorbid early-stage dementia (diagnosed ≥6 months before screening and after onset of MDD; Mini-Mental State Examination-2 total score, 20-24) received vortioxetine for 12 weeks (initiated at 5 mg/day and up-titrated to 10 mg/day at day 8, with flexible dosing thereafter [5-20 mg/day]). The primary endpoint was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 12.
RESULTS
Significant improvement in depressive symptom severity was seen from week 1 onwards (P < 0.0001). At week 12, the least-square mean (standard error) change in MADRS total score from baseline was -12.4 (0.78). Significant improvements in cognitive performance were observed (from week 1 for the Digit Symbol Substitution Test and week 4 for the Rey Auditory Verbal Learning Test). Patients also experienced significant improvements in daily and global functioning, and HRQoL. Vortioxetine was well tolerated. From week 4 onwards, more than 50 % of patients were receiving 20 mg/day.
LIMITATIONS
Open-label study.
CONCLUSIONS
Vortioxetine demonstrated effectiveness in clinically significantly improving depressive symptoms, cognitive performance, daily and global functioning, and HRQoL in patients with MDD and comorbid early-stage dementia treated for 12 weeks.
TRIAL REGISTRATION
ClinicalTrials.gov/ct2/show/NCT04294654.
Topics: Humans; Aged; Vortioxetine; Depressive Disorder, Major; Quality of Life; Piperazines; Double-Blind Method; Dementia; Treatment Outcome; Sulfides
PubMed: 37315590
DOI: 10.1016/j.jad.2023.06.024 -
Ugeskrift For Laeger Dec 2023Introduction Acetylsalicylic acid (ASA) has commonly been touted for its potential to extend the aesthetic lifespan (EL) of Christmas trees when added to the water in... (Comparative Study)
Comparative Study
Introduction Acetylsalicylic acid (ASA) has commonly been touted for its potential to extend the aesthetic lifespan (EL) of Christmas trees when added to the water in the tree stand. This study examined the efficacy of ASA in prolonging the aesthetic longevity of spruce branches, in comparison to placebo and sildenafil. Intervention We conducted a triple-blinded, randomised clinical trial, wherein 60 spruce branches were allocated to one of three treatment arms in a 1:1:1 ratio. The primary intervention was ASA, compared against both placebo and sildenafil treatments. The study's primary endpoint was the EL of the spruce branches. Results All participating branches completed the study. No statistically significant differences were observed in the survival times across the three groups: ASA 17 days (standard deviation (SD): 6), placebo 20 days (SD: 8), and sildenafil 21 days (SD: 7); p = 0.30. Both the log-rank test and adjusted Cox proportional-hazards analyses failed to show any significant variations in aesthetic survival time among the treatment arms (p > 0.05). Conclusion Given our findings, there is no empirical support for the widely held recommendation of adding ASA to the water at the base of a Christmas tree to extend its aesthetic lifespan. Funding none. Trial registration none.
Topics: Humans; Aspirin; Sildenafil Citrate; Water; Picea
PubMed: 38084621
DOI: No ID Found -
Archives of Dermatological Research Jul 2023Androgenetic alopecia (AGA) is the most common cause of hair loss in both genders with a higher psychological impact on females. Currently, topical minoxidil is the only... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison between topical cetirizine with minoxidil versus topical placebo with minoxidil in female androgenetic alopecia: a randomized, double-blind, placebo-controlled study.
Androgenetic alopecia (AGA) is the most common cause of hair loss in both genders with a higher psychological impact on females. Currently, topical minoxidil is the only FDA-approved treatment for female AGA and it needs life-long application and causes side effects. Cetirizine is an antihistamine that may be effective in hair loss treatment. This study aimed to compare the efficacy and safety of topical cetirizine with minoxidil (group 1) versus topical minoxidil with placebo (group 2) in female patients with AGA. This was a double-blind, randomized, controlled, parallel study conducted at Dermatology Clinic, Cairo University Teaching Hospital (Kasr- Al- Ainy), Egypt. Sixty-six patients with female AGA, aged 20-50 years, Sinclair (II-IV), were randomly assigned to one of the 2 groups for 24 weeks. The trichoscopic parameters, patients' self-assessment, side effects and global photographic assessment were evaluated. There was a statistically significant change from baseline in frontal and vertex terminal and vellus hair density (P < 0.0005) with a significant increase in vertex hair shaft thickness and average number of hairs per follicular unit in group 1 (P < 0.05). Patients reported significantly better scores in patient self-assessment in group 1 (P < 0.05). Side effects were not significantly different between groups (P > 0.05). Topical cetirizine increases hair shaft thickness and results in a higher clinical improvement from patients' perspective with a good safety profile (NCT04481412, study start date: July 2020).
Topics: Female; Humans; Male; Minoxidil; Cetirizine; Administration, Topical; Alopecia; Hair; Drug-Related Side Effects and Adverse Reactions
PubMed: 36571611
DOI: 10.1007/s00403-022-02512-2 -
International Journal of Molecular... Dec 2023The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play... (Review)
Review
The pathogenesis of complex diseases such as pulmonary arterial hypertension (PAH) is entirely rooted in changes in the expression of some vasoactive factors. These play a significant role in the onset and progression of the disease. Indeed, PAH has been associated with pathophysiologic alterations in vascular function. These are often dictated by increased oxidative stress and impaired modulation of the nitric oxide (NO) pathway. NO reduces the uncontrolled proliferation of vascular smooth muscle cells that leads to occlusion of vessels and an increase in pulmonary vascular resistances, which is the mainstay of PAH development. To date, two classes of NO-pathway modulating drugs are approved for the treatment of PAH: the phosphodiesterase-5 inhibitors (PD5i), sildenafil and tadalafil, and the soluble guanylate cyclase activator (sGC), riociguat. Both drugs provide considerable improvement in exercise capacity and pulmonary hemodynamics. PD5i are the recommended drugs for first-line PAH treatment, whereas sGCs are also the only drug approved for the treatment of resistant or inoperable chronic thromboembolic pulmonary hypertension. In this review, we will focus on the current information regarding the nitric oxide pathway and its modulation in PAH.
Topics: Humans; Pulmonary Arterial Hypertension; Nitric Oxide; Familial Primary Pulmonary Hypertension; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Soluble Guanylyl Cyclase
PubMed: 38203205
DOI: 10.3390/ijms25010036