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OBJECTIVE: To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy. METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD). RESULTS: Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups. CONCLUSION: Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age.
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Indazóis , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Intervalo Livre de Progressão , Qualidade de Vida , Humanos , Indazóis/efeitos adversos , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Feminino , Piperidinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Idoso , Neoplasias Ovarianas/tratamento farmacológico , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Idoso de 80 Anos ou mais , Fatores Etários , Adulto , Método Duplo-Cego , Carcinoma Epitelial do Ovário/tratamento farmacológico , Quimioterapia de Manutenção/métodosRESUMO
OBJECTIVE: To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS: PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS: Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS: Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.
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Indazóis , Neoplasias Ovarianas , Piperidinas , Qualidade de Vida , Humanos , Feminino , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Indazóis/uso terapêutico , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/psicologia , Idoso , Adulto , Método Duplo-Cego , Piperazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Quimioterapia de Manutenção/métodos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/psicologia , Idoso de 80 Anos ou maisRESUMO
Climate change has become increasingly intertwined with the occurrence and severity of droughts. As global temperatures rise due to greenhouse gas emissions, weather patterns are altered, leading to shifts in precipitation levels and distribution. These exacerbate the risk of drought in many regions, with potentially devastating consequences. A comprehensive transcriptome analysis was performed on Keteki Joha, an aromatic rice from North East India, with the aim of elucidating molecular responses to drought. Numerous genes linked to drought were activated, with both ABA-dependent and ABA-independent pathways playing crucial roles. Upregulated genes were enriched with gene ontology terms with response to abscisic acid and abscisic acid-activated signalling pathway, suggesting the existence of an ABA-dependent pathway for drought mitigation. The upregulated genes were also enriched with responses to stress, water, heat, jasmonic acid, and hydrogen peroxide, indicating the presence of an ABA-independent pathway alongside the ABA-dependent mechanism. Weighted Correlation Network Analysis (WGCNA) identified 267 genes that specifically govern drought mitigation in Keteki Joha. The late embryogenesis abundant (LEA) gene family emerges as the most overrepresented in both RNA sequencing data and WGCNA analysis, suggesting their dominant role in mitigating drought. Notably, 31 LEA genes were induced in seedlings and 32 in mature stages under drought stress. The LEA3-1, LEA14/WSI18, RAB16A, RAB16B, DHN1, DHN6, LEA1, LEA3, LEA17, and LEA33 exhibited and established co-expression with numerous other drought stress-related genes, indicating their inseparable role in alleviating drought. Consequently, LEA genes have been proposed to be primary and crucial responders to drought in Keteki Joha.
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Ácido Abscísico , Secas , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Oryza , Oryza/genética , Oryza/fisiologia , Ácido Abscísico/metabolismo , Ácido Abscísico/farmacologia , Perfilação da Expressão Gênica , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética , Genes de Plantas , Transcriptoma/genéticaRESUMO
Acrylamide (AA) is a carcinogenic compound that affects people due to its frequent use in laboratories and industry as well as the high-temperature cooking of foods with high hydrocarbon content. AA is known to cause severe reproductive abnormalities. The main aim of this study is to evaluate the protective effect of rutin (RU), a phytoactive compound, against AA-induced reproductive toxicity in female rats. Initially, rats were exposed to AA (40 mg/kg for 10 days). Therapy of RU was given after AA intoxication consecutively for 3 days. After 24 h of the last treatment, all the animals were sacrificed. The study evaluated reproductive hormones, oxidative stress markers, membrane-bound enzymes, DNA damage, histological findings, and an in silico approach to determine the protective efficacy of RU. The results indicated that RU significantly protected against inflammation, oxidative stress, and DNA damage induced by AA, likely due to its antioxidant properties.
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Acrilamida , Dano ao DNA , Inflamação , Estresse Oxidativo , Rutina , Animais , Rutina/farmacologia , Feminino , Estresse Oxidativo/efeitos dos fármacos , Acrilamida/toxicidade , Dano ao DNA/efeitos dos fármacos , Ratos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Ratos Wistar , Simulação por Computador , Antioxidantes/farmacologia , Antioxidantes/metabolismoRESUMO
Introduction: There is an unmet need for high-quality data for Robot-assisted partial nephrectomy (RAPN) in the Indian population. Indian study group on partial nephrectomy (ISGPN) is a consortium of Indian centers contributing to the partial nephrectomy (PN) database. The current study is a descriptive analysis of perioperative and functional outcomes following RAPN. Methods: For this study, the retrospective ISGPN database was reviewed, which included patients who underwent RAPN for renal masses at 14 centers across India from September 2010 to September 2022. Demographic, clinical, radiological, perioperative, and functional data were collected and analyzed. Ethics approval was obtained from each of the participating centers. Results: In this study, 782 patients were included, and 69.7% were male. The median age was 53 years (interquartile range [IQR 44-62]), median operative time was 180 min (IQR 133-240), median estimated blood loss was 100 mL (IQR 50-200), mean warm ischemia time was 22.7 min and positive surgical margin rates were 2.5%. The complication rate was 16.2%, and most of them were of minor grade. Trifecta and pentafecta outcomes were attained in 61.4% and 60% of patients, respectively. Conclusions: This is the largest Indian multi-centric study using the Indian Robotic PN Collaborative database to evaluate the outcomes of robot-assisted PN, and has proven its safety and efficacy in the management of renal masses.
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Background: Anterior tooth discolorations can be treated conservatively and noninvasively through bleaching to achieve the desired esthetic outcomes. However, bleaching along with composite resin is advisable for certain clinical cases for optimum results. However, shear bond strength (SBS) of composite resin to the bleached tooth gets significantly lowered. Before placing the composite restoration, the bleached enamel needs to be treated with antioxidant agents to increase its SBS. The study aims to evaluate and compare the effect of herbal antioxidants on SBS of composite resin to bleached enamel at different time intervals. Materials and Methods: Sixty extracted single-rooted maxillary incisors postdecoronation, keeping their labial surfaces up were mounted in cold-cure acrylic resin. The samples were randomly divided into: Group I - unbleached; Group II - 10% pine bark extract for 10 min postbleaching; Group III - 10% pine bark extract for 20 min postbleaching; Group IV - application of 10% rosemary extract for 10 min postbleaching, Group V - application of 10% rosemary extract for 20 min postbleaching; Group VI - no application of antioxidant. 35% hydrogen peroxide was used for bleaching all the samples except those which served as negative control. Later composite cylinder 4 mm in diameter and length were built on prepared enamel. The maximum load at failure was recorded using the universal testing machine. Statistical Analysis: Data were analyzed using the analysis of variance and Tukey's t-test with significance level of P < 0.05. Results: Highest load was exhibited by Group I. Group V showed satisfactory shear strength followed by Groups IV, III, II, and VI. Conclusion: Both 10% rosemary and 10% pine bark extracts showed better results when applied for 20 min as compared to 10 min application. Increased duration of antioxidant application increases the SBS.
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OBJECTIVE: Effort has been made to minimize the burden of non-interpretive tasks (NITs), in particular by hiring and training non-radiologist support staff as reading room coordinators (RRCs). Our medical center recruited and trained senior medical students from our affiliated school of medicine to work alongside on-call radiology residents as RRCs. METHODS: A 12-month Malpractice Carrier monetary grant was acquired to fund medical students at with the aim to reduce malpractice risk. After the first year, residents were surveyed regarding the impact of the RRCs on perceived on-call efficiency and morale. Furthermore, report turnaround times (TAT) on call shifts that were and were not accompanied by a RRC were compared. RESULTS: 89 % of residents strongly agreed that the RRC improved workflow efficiency, decreased distractions, and felt less stressed during the call shift when the RRC was on duty. 78 % strongly agreed to be more likely to contact a referring clinician when the RRC was able to help coordinate. The mean TAT in the presence of a RRC was 36.8 min, and the mean TAT in the absence of a RRC was 36.9 min DISCUSSION: After hiring medical students to assist on-call radiology residents with noninterpretive tasks, residents reported subjective indicators of program success, but average report turnaround time was unaffected. Nevertheless, we predict that this type of program will continue to grow among academic radiology departments, though additional research is required to evaluate national trends and impacts on radiologist productivity and well-being.
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Internato e Residência , Radiologia , Estudantes de Medicina , Humanos , Radiologia/educação , Radiografia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Adhesiveness with radicular dentin is absent with gutta-percha, leading to microleakage and hence re-infection. Root canal sealer helps to achieve an adhesive interface between gutta-percha and root dentin thereby resisting the displacement forces during the functioning of teeth which is evaluated by the push-out test. The aim of this study is to compare the push-out bond strength and to assess the relative bond failure between dentin-sealer, sealer-main cone of (1) epoxy resin, (2) silicon, (3) mineral trioxide aggregate (MTA), (4) calcium hydroxide, (5) bioceramic, (6) zinc oxide eugenol containing root canal sealers. METHODOLOGY: Sixty human permanent lower premolars with one root were collected, disinfected, and decoronated at cemento-enamel junction. Instrumentation was done with a K3 40,0.06 Ni-Ti rotary file and obturated using the main cone and sealer. Based on the sealer utilized, six groups were created: Group 1: AH-Plus, Group 2: RoekoSeal, Group 3: MTA Fillapex, Group 4: Apexit, Group 5: Smart Paste Bio, and Group 6: Procosol. One slice each was obtained from the coronal, middle, and apicalsections of all the obturated canals. Push-out bond strength and failure modes were studied. Statistics involved analysis of variance (ANOVA) followed by the post hoc Tukey test. RESULTS: All three sections exhibited the highest strength for Smart Paste Bio sealer and the least was for RoekoSeal. With all the sealers, the apical section had the highest strength followed by the middle and coronal. CONCLUSION: The smart seal system was superior to all other sealers and displayed a good bond to dentin.
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Background: An endodontic treatment is considered a success after thorough chemomechanical debridement coupled with obturating root canals in a concrete way thereby providing hermetic seal. Gutta-percha being nonadherent necessitates use of a sealer to achieve hermetic seal. Adequate adhesion of root canal sealer with gutta-percha core and radicular dentin ensures lack of apical leakage. Materials and Methods: Sixty extracted mandibular premolars with single root canal decoronated at cementoenamel junction were selected and randomly allocated to two groups (n = 30). Samples in Group 1 were prepared with BT Race file, while Group 2 samples were prepared with BT Race alongwith XP Endo file. Absorbent paper points were used for canal drying and samples were randomly divided into six subgroups. In Subgroup I, obturation was done with bio-ceramic (BC) sealer (Endosequence BC) and BC gutta-percha. In Subgroup II, resin-based (AH plus) sealer and gutta-percha were used. In Subgroup III, calcium hydroxide-based (Sealapex) sealer and gutta-percha were used. Sectioning of root samples was done perpendicularly into coronal, middle, and apical segments of 3 mm each. A universal testing machine was used for sample testing, in which push-out bond strength corresponded to the highest value obtained. Stereomicroscopic (×20) study of the samples determined the failure mode at dentin/sealer/main cone interface. Statistical Analysis: Analysis of variance and post hoc Tukey's tests were used for data analysis. Results: Endosequence BC with XP-Endo files showed the highest mean push-out bond strength (16.31 MPa), whereas Sealapex without XP-Endo file had the lowest values (12.76 MPa). Mixed failure of adhesive and cohesive mode was observed for most samples. Conclusion: Adjunctive irrigation agitation technique utilizing XP-Endo Finisher facilitates biofilm eradication from difficult niches in root canals, thereby improving adhesion of sealer and subsequently the sealer bond strength.
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Oxidative injury is concerned with the pathogenesis of several liver injuries, including those from acute liver failure to cirrhosis. This study was designed to explore the antioxidant activity of Bacopa monnieri (BM) on Aflatoxin B1 (AFB1) induced oxidative damage in Wistar albino rats. Aflatoxin B1 treatment (200 µg/kg/day, p.o.) for 28 days induced oxidative injury by a significant alteration in serum liver function test marker enzymes (AST, ALT, ALP, LDH, albumin and bilirubin), inflammatory cytokines (IL-6, IL-10 and TNF-α), thiobarbituric acid reactive substances (TBARS) along with reduction of antioxidant enzymes (GSH, SOD, CAT), GSH cycle enzymes and drug-metabolizing enzymes (AH and AND). Treatment of rats with B. monnieri (20, 30 and 40 mg/kg for 5 days, p.o.) after 28 days of AFB1 intoxication significantly restored these parameters near control in a dose-dependent way. Histopathological examination disclosed extensive hepatic injuries, characterized by cellular necrosis, infiltration, congestion and sinusoidal dilatation in the AFB1-treated group. Treatment with B. monnieri significantly reduced these toxic effects resulting from AFB1. B. monnieriper se group (40 mg/kg) did not show any significant change and proved safe. The cytotoxic activity of B. monnieri was also evaluated on HepG2 cells and showed a good percentage of cytotoxic activity. This finding suggests that B. monnieri protects the liver against oxidative damage caused by AFB1, which aids in the evaluation of the traditional usage of this medicinal plant.
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BACKGROUND: Oral cancer poses a significant threat to public health worldwide. In addition, because many chemotherapy treatments have negative side effects, natural herbs may be beneficial for oral cancer therapy. Achyranthes aspera (AA), a potential medicinal herb, exerts various pharmacological and biochemical activities. OBJECTIVE: The present study aimed to predict the anti-oral cancer potential of AA using in silico tools and cell death by in vitro testing. METHODS: A total of fourteen bioactive constituents from AA herb were selected using phytochemical databases. The toxicity of AA herb extract was analysed through MTT assay against oral carcinoma A253 cell line. The binding activities of the phytocomponents against serine/ threonine-specific protein kinases isoforms, namely Akt1 (PDB ID: 3qkk) and Akt2 (PDB ID: 2jdo) proteins, were analysed using Discovery Studio 2021 and PyRx docking software. RESULTS: Cell viability data revealed that AA extract decreased the viability and reduced the number of live cells of the oral carcinoma A253 cell line in a dose-dependent manner. The halfmaximal concentration (IC50) value of AA was assessed as 204.74 µg/ml. Based on binding affinity, saponin C (-CDOCKER energy = -77.9862), oleanolic acid (-CDOCKER energy = - 49.4349), spinasterol (-CDOCKER energy = -38.1246), 36,47-dihydroxyhenpentacontan-4-one (-CDOCKER energy = -32.4386), and 20-hydroxyecdysone (-CDOCKER energy = -31.9138) were identified as the best compounds against Akt1, while, compounds saponin C (-CDOCKER energy = -134.412), oleanolic acid (-CDOCKER energy = -90.0846), spinasterol (-CDOCKER energy = -78.3213), 20-hydroxyecdysone (-CDOCKER energy = -80.1049), and ecdysone (- CDOCKER energy = -73.3885) were identified as Akt2 inhibitors. These top compounds fulfilled drug score values, pharmacokinetic and physicochemical characteristics, and druglikeness parameters. CONCLUSION: The present findings reveal that the lead phytomolecules of AA could be effective and developed as a prospective drug against oral cancer.
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Viruses utilize cell surface glycans and plasma membrane receptors to attain an adequate attachment strength for initiating cellular entry. We show that SARS-CoV-2 particles bind to endogenous ACE2 receptors and added sialylated gangliosides in near-native membranes. This was explored using supported membrane bilayers (SMBs) that were formed using plasma membrane vesicles having endogenous ACE2 and GD1a gangliosides reconstituted in lipid vesicles. The virus binding rate to the SMBs is influenced by GD1a and inhibition of the ganglioside reduces the extent of virus binding to the membrane receptors. Using combinations of inhibition assays, we confirm that added GD1a in lipid membranes increases the availability of the endogenous ACE2 receptor and results in the synergistic binding of SARS-CoV-2 to the membrane receptors in SMBs.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/metabolismo , Enzima de Conversão de Angiotensina 2 , Gangliosídeos , Membrana Celular/metabolismoRESUMO
Agriculture and changing environmental conditions are closely related, as weather changes could adversely affect living organisms or regions of crop cultivation. Changing environmental conditions trigger different abiotic stresses, which ultimately cause the accumulation of reactive oxygen species (ROS) in plants. Common ROS production sites are the chloroplast, endoplasmic reticulum, plasma membrane, mitochondria, peroxisomes, etc. The imbalance in ROS production and ROS detoxification in plant cells leads to oxidative damage to biomolecules such as lipids, nucleic acids, and proteins. At low concentrations, ROS initiates signaling events related to development and adaptations to abiotic stress in plants by inducing signal transduction pathways. In plants, a stress signal is perceived by various receptors that induce a signal transduction pathway that activates numerous signaling networks, which disrupt gene expression, impair the diversity of kinase/phosphatase signaling cascades that manage the stress response in the plant, and result in changes in physiological responses under various stresses. ROS production also regulates ABA-dependent and ABA-independent pathways to mitigate drought stress. This review focuses on the common subcellular location of manufacturing, complex signaling mechanisms, and networks of ROS, with an emphasis on cellular effects and enzymatic and non-enzymatic antioxidant scavenging mechanisms of ROS in Poaceae crops against drought stress and how the manipulation of ROS regulates stress tolerance in plants. Understanding ROS systems in plants could help to create innovative strategies to evolve paths of cell protection against the negative effects of excessive ROS in attempts to improve crop productivity in adverse environments.
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Importance: Advance care planning (ACP) remains low among patients with advanced cancer. Multilevel interventions compared with clinician-level interventions may be more effective in improving ACP. Objective: To evaluate whether a multilevel intervention could improve clinician-documented ACP compared with a clinician-level intervention alone. Design, Setting, and Participants: This randomized clinical trial, performed from September 12, 2019, through May 12, 2021, included adults with advanced genitourinary cancers at an academic, tertiary hospital. Data analysis was performed by intention to treat from May 1 to August 10, 2023. Intervention: Participants were randomized 1:1 to a 6-month patient-level lay health worker structured ACP education along with a clinician-level intervention composed of 3-hour ACP training and integration of a structured electronic health record documentation template (intervention group) or to the clinician-level intervention alone (control group). Main Outcome and Measures: The primary outcome was ACP documentation in the electronic health record by the oncology clinician within 12 months after randomization. Secondary, exploratory outcomes included shared decision-making, palliative care use, hospice use, emergency department visits, and hospitalizations within 12 months after randomization. Results: Among 402 participants enrolled in the study, median age was 71 years (range, 21-102 years); 361 (89.8%) identified as male. More intervention group participants had oncology clinician-documented ACP than control group participants (82 [37.8%] vs 40 [21.6%]; odds ratio [OR], 2.29; 95% CI, 1.44-3.64). At 12-month follow-up, more intervention than control group participants had palliative care (72 [33.2%] vs 25 [13.5%]; OR, 3.18; 95% CI, 1.91-5.28) and hospice use (49 [22.6%] vs 19 [10.3%]; OR, 2.54; 95% CI, 1.44-4.51). There were no differences in the proportion of participants between groups with an emergency department visit (65 [30.0%] vs 61 [33.0%]; OR, 0.87; 95% CI, 0.57-1.33) or hospitalization (89 [41.0%] vs 85 [46.0%]; OR, 0.82; 95% CI, 0.55-1.22). Intervention group participants had fewer hospitalizations than control group participants (mean [SD] number of hospitalizations per year, 0.87 [1.60] vs 1.04 [1.77]) and a lower risk of hospitalization (incidence rate ratio, 0.80; 95% CI, 0.65-0.98). Conclusions and Relevance: In this randomized clinical trial, a multilevel intervention improved oncology clinician-documented ACP compared with a clinician-level intervention alone for patients with genitourinary cancer. The intervention is one approach to effectively increase ACP among patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03856463.
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Planejamento Antecipado de Cuidados , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Participação do Paciente , Registros Eletrônicos de Saúde , Idoso de 80 Anos ou mais , Tutoria/métodos , Cuidados Paliativos , AdultoRESUMO
BACKGROUND: Gender and racial disparities exist after left ventricular assist device (LVAD) implantation. Compared with older devices, the HeartMate 3 (HM3) (Abbott Cardiovascular) has demonstrated improved survival. Whether HM3 differentially improves outcomes by gender or race and ethnic groups is unknown. OBJECTIVES: The purpose of this study is to examine differences by gender and race in the use of HM3 among patients listed for heart transplantation (HT) and associated waitlist and post-transplant outcomes. METHODS: The authors examined all patients (20% women, 33% Black) who received LVADs as bridge to transplantation (BTT) between January 2018 and June 2020, in the OPTN (Organ Procurement and Transplantation Network) database. Trends in use of HM3 were evaluated by gender and race. Competing events of death/delisting and transplantation were evaluated using subdistribution hazard models. Post-transplant outcomes were evaluated using multivariate logistic regression adjusted for demographic, clinical, and donor characteristics. RESULTS: Of 11,524 patients listed for HT during the study period, 955 (8.3%) had HM3 implanted as BTT. Use of HM3 increased for all patients, with no difference in use by gender (P = 0.4) or by race (P = 0.2). Competing risk analysis did not demonstrate differences in transplantation or death/delisting in men compared with women (HT: adjusted HR [aHR]: 0.92 [95% CI: 0.70-1.21]; death/delisting: aHR: 0.91 [95% CI: 0.59-1.42]), although Black patients were transplanted fewer times than White patients (HT: aHR: 0.72 [95% CI: 0.57-0.91], death/delisting: aHR: 1.36 [95% CI: 0.98-1.89]). One-year post-transplant survival was comparable by gender (aHR: 0.52 [95% CI: 0.21-1.70]) and race (aHR: 0.76 [95% CI: 0.34-1.70]), with no differences in rates of stroke, acute rejection, or graft failure. CONCLUSIONS: Use of HM3 among patients listed for HT has increased over time and by gender and race. Black patients with HM3 were less likely to be transplanted compared with White patients, but there were no differences in post-transplant outcomes between these groups or between men and women.
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Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Listas de Espera , Humanos , Feminino , Transplante de Coração/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Insuficiência Cardíaca/etnologia , Insuficiência Cardíaca/cirurgia , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/mortalidade , Fatores Sexuais , Estados Unidos/epidemiologia , Estudos Retrospectivos , Adulto , Grupos Raciais , Idoso , População Branca/estatística & dados numéricosRESUMO
Myocardial infarctions locally deprive myocardium of oxygenated blood and cause immediate cardiac myocyte necrosis. Irreparable myocardium is then replaced with a scar through a dynamic repair process that is an interplay between hypoxic cells of the infarct zone and normoxic cells of adjacent healthy myocardium. In many cases, unresolved inflammation or fibrosis occurs for reasons that are incompletely understood, increasing the risk of heart failure. Crosstalk between hypoxic and normoxic cardiac cells is hypothesized to regulate mechanisms of repair after a myocardial infarction. To test this hypothesis, microfluidic devices are fabricated on 3D printed templates for co-culturing hypoxic and normoxic cardiac cells. This system demonstrates that hypoxia drives human cardiac fibroblasts toward glycolysis and a pro-fibrotic phenotype, similar to the anti-inflammatory phase of wound healing. Co-culture with normoxic fibroblasts uniquely upregulates pro-inflammatory signaling in hypoxic fibroblasts, including increased secretion of tumor necrosis factor alpha (TNF-α). In co-culture with hypoxic fibroblasts, normoxic human induced pluripotent stem cell (hiPSC)-derived cardiac myocytes also increase pro-inflammatory signaling, including upregulation of interleukin 6 (IL-6) family signaling pathway and increased expression of IL-6 receptor. Together, these data suggest that crosstalk between hypoxic fibroblasts and normoxic cardiac cells uniquely activates phenotypes that resemble the initial pro-inflammatory phase of post-infarct wound healing.
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BACKGROUND: Cardiac allograft vasculopathy (CAV) is associated with increased mortality in patients with orthotopic heart transplantation (OHT). In addition to immunosuppression, CAV can be treated with percutaneous coronary intervention (PCI) with drug eluting stents (DES) for focal lesions. There is a paucity of data on the rate of DES restenosis in patients with small vessel CAV. METHODS: This was a retrospective observational study of 101 coronary vessels treated with a DES diameter of 2.5 mm or less (small vessels) in 61 OHT patients compared to 72 coronary vessels treated with a DES diameter of >2.5 mm (large vessels) in 44 OHT patients at a single center between 2004 and 2022. Baseline demographic data, angiographic characteristics, and clinical outcomes were analyzed. RESULTS: At an average of 1.6 years after DES placement, follow-up angiography revealed in-stent restenosis in 36 (39 %) small vessel interventions and 11 (17 %) large vessel interventions (p = 0.003). Long term mortality did not differ between the groups (59 % vs 59 % at a median of 4.7 [IQR 2.4-7.8] years follow up). CONCLUSION: DES restenosis rates are high in small vessel CAV. Additional studies specifically examining PCI in small vessel CAV as well as the potential role for newer treatment strategies for CAV are warranted.
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PURPOSE: To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). METHODS: Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. RESULTS: Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)-deficient, and 17.1% were HR repair (HRR)-mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. CONCLUSION: Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab , Resistencia a Medicamentos Antineoplásicos , Indazóis , Neoplasias Ovarianas , Piperidinas , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Idoso , Bevacizumab/uso terapêutico , Adulto , Indazóis/uso terapêutico , Idoso de 80 Anos ou mais , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos de CoortesRESUMO
PURPOSE: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile. METHODS: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed. FINDINGS: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia. IMPLICATIONS: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www. CLINICALTRIALS: gov.
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In recent years, there has been continuous improvement in the treatment and diagnosis of cancer, which has led to a significant improvement in the survival rate of cancer patients. Treatments that include chemotherapy, radiotherapy, surgery, or combined therapy have several side effects that may lead to premature ovarian insufficiency in females or substantial male germ cell loss. Reproductive biologists recommend that all patients who are diagnosed with a malignant tumor must undergo a consultation for fertility protection and preservation. In this review, we discuss the background knowledge, methods, and options for fertility preservation and how these new strategies help oncologists, surgeons, pediatricians, and hematologists, conserve fertility and be aware of the concepts, methods, and importance of fertility guards. This review may aid in the advancement of novel personalized methods for fertility preservation according to patients' conditions.