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1.
Cell ; 187(18): 4905-4925.e24, 2024 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-38971151

RESUMO

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD and neoadjuvant therapies, co-occurring with other tumor-reactive T cells, particularly terminally exhausted CD8+ T cells (Tex). TME-wide interferon signaling correlates with cancer cells upregulating MHC class II and co-inhibitory ligands, potentially driving Treg and Tex fates. Depleting eTregs in HRD mouse models, with or without PARP inhibition, significantly suppresses tumor growth without observable toxicities, underscoring the potential of eTreg-focused therapeutics for HGSOC and other HRD-related tumors.


Assuntos
Terapia Neoadjuvante , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Linfócitos T Reguladores , Microambiente Tumoral , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/imunologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Humanos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Camundongos , Terapia Neoadjuvante/métodos , Microambiente Tumoral/efeitos dos fármacos , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Indazóis/uso terapêutico , Indazóis/farmacologia , Recombinação Homóloga , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral
2.
N Engl J Med ; 391(3): 224-234, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39018532

RESUMO

BACKGROUND: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis. METHODS: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline. RESULTS: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group). CONCLUSIONS: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.).


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Profilaxia Pós-Exposição , SARS-CoV-2 , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Administração Oral , Antivirais/uso terapêutico , Antivirais/efeitos adversos , Antivirais/administração & dosagem , COVID-19/prevenção & controle , Método Duplo-Cego , Combinação de Medicamentos , Quimioterapia Combinada , Indazóis/efeitos adversos , Indazóis/uso terapêutico , Indóis/efeitos adversos , Indóis/uso terapêutico , Indóis/administração & dosagem , Lactamas , Leucina , Nitrilas , Prolina , Ritonavir/uso terapêutico , Ritonavir/efeitos adversos , Ritonavir/administração & dosagem
3.
J Pathol ; 264(2): 129-131, 2024 10.
Artigo em Inglês | MEDLINE | ID: mdl-39072755

RESUMO

In a recent issue of The Journal of Pathology, Chen and colleagues established novel patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma to characterize resistance mechanisms against targeted therapy with tyrosine kinase inhibitors. Prolonged exposure to escalating concentrations of the tyrosine kinase inhibitor, entrectinib, ultimately led to the occurrence of resistant clones that harbored an inactivating mutation in the NF2 gene, not previously described in this context, accompanied by increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling. Finally, an inhibitor screen identified, among others, MEK and mTOR inhibitors as potential combination agents. © 2024 The Pathological Society of Great Britain and Ireland.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Neurofibromina 2/genética , Proteínas de Fusão Oncogênica/genética , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Receptor trkA/genética , Receptor trkA/metabolismo , Transdução de Sinais/genética , Indazóis/uso terapêutico , Indazóis/farmacologia , Mutação , Sarcoma/genética , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
4.
Semin Cell Dev Biol ; 121: 53-62, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33867214

RESUMO

In rodents and humans, the major cellular events at spermatogenesis include self-renewal of spermatogonial stem cells and undifferentiated spermatogonia via mitosis, commitment of spermatogonia to differentiation and transformation to spermatocytes, meiosis, spermiogenesis, and the release of spermatozoa at spermiation. While details of the morphological changes during these cellular events have been delineated, knowledge gap exists between the morphological changes in the seminiferous epithelium and the underlying molecular mechanism(s) that regulate these cellular events. Even though many of the regulatory proteins and biomolecules that modulate spermatogenesis are known based on studies using genetic models, the underlying regulatory mechanism(s), in particular signaling pathways/proteins, remain unexplored since much of the information regarding the signaling regulation is unknown. Studies in the past decade, however, have unequivocally demonstrated that the testis is using several signaling proteins and/or pathways to regulate multiple cellular events to modulate spermatogenesis. These include mTORC1/rpS6/Akt1/2 and p-FAK-Y407. While selective inhibitors and/or agonists and antagonists are available to examine some of these signaling proteins, their use have limitations due to their specificities and also potential systemic cytotoxicity. On the other hand, the use of genetic models has had profound implications for our understanding of the molecular regulation of spermatogenesis, and these knockout (null) models have also revealed the factors that are critical for spermatogenesis. Nonetheless, additional studies using in vitro and in vivo models are necessary to unravel the signaling pathways involved in regulating seminiferous epithelial cycle. Emerging data from studies, such as the use of the adjudin pharmaceutical/toxicant model, have illustrated that this non-hormonal male contraceptive drug is utilizing specific signaling pathways/proteins to induce specific defects in spermatogenesis, yielding mechanistic insights on the regulation of spermatogenesis. We sought to review these recent data in this article, highlighting an interesting approach that can be considered for future studies.


Assuntos
Hidrazinas/uso terapêutico , Indazóis/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina/imunologia , Espermatogênese/imunologia , Animais , Humanos , Hidrazinas/farmacologia , Indazóis/farmacologia , Masculino , Transdução de Sinais
5.
Clin Infect Dis ; 79(3): 643-651, 2024 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-38864601

RESUMO

BACKGROUND: Nirmatrelvir-ritonavir is recommended for persons at risk for severe coronavirus disease 2019 (COVID-19) but remains underutilized. Information on which eligible groups are likely to benefit from treatment is needed. METHODS: We conducted a target trial emulation study in the Veterans Health Administration comparing nirmatrelvir-ritonavir treated versus matched untreated veterans at risk for severe COVID-19 who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from April 2022 through March 2023. We measured incidence of any hospitalization or all-cause mortality at 30 days. Outcomes were measured for the entire cohort, as well as among subgroups defined by 30-day risk of death or hospitalization, estimated using an ensemble risk prediction model. RESULTS: Participants were 87% male with median age 66 years and 16% unvaccinated. Compared with matched untreated participants, those treated with nirmatrelvir-ritonavir (n = 24 205) had a lower 30-day risk for hospitalization (1.80% vs 2.30%; risk difference [RD], -0.50% points [95% confidence interval {CI}: -.69 to -.35]) and death (0.11% vs 0.30%; RD, -0.20 [95% CI: -.24 to -.13]). The greatest reductions in combined hospitalization or death were observed in the highest risk quartile (RD -2.85 [95% CI: -3.94 to -1.76]), immunocompromised persons (RD -1.91 [95% CI: -3.09 to -.74]), and persons aged ≥75 years (RD -1.16 [95% CI: -1.73 to -.59]). No reductions were observed in the 2 lowest risk quartiles or persons younger than 65 years. CONCLUSIONS: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death in older veterans, those at highest predicted risk for severe outcomes, and immunocompromised groups. Benefit was not observed in younger veterans or groups at lower predicted risk for hospitalization and death.


Assuntos
Tratamento Farmacológico da COVID-19 , Hospitalização , Ritonavir , Veteranos , Humanos , Masculino , Ritonavir/uso terapêutico , Idoso , Feminino , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , SARS-CoV-2 , Antivirais/uso terapêutico , COVID-19/mortalidade , COVID-19/epidemiologia , Estados Unidos/epidemiologia , Indazóis/uso terapêutico
6.
J Neurochem ; 168(4): 428-440, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36912731

RESUMO

People bitten by Alpine vipers are usually treated with antivenom antisera to prevent the noxious consequences caused by the injected venom. However, this treatment suffers from a number of drawbacks and additional therapies are necessary. The venoms of Vipera ammodytes and of Vipera aspis are neurotoxic and cause muscle paralysis by inducing neurodegeneration of motor axon terminals because they contain a presynaptic acting sPLA2 neurotoxin. We have recently found that any type of damage to motor axons is followed by the expression and activation of the intercellular signaling axis consisting of the CXCR4 receptor present on the membrane of the axon stump and of its ligand, the chemokine CXCL12 released by activated terminal Schwann cells. We show here that also V. ammodytes and V. aspis venoms cause the expression of the CXCL12-CXCR4 axis. We also show that a small molecule agonist of CXCR4, dubbed NUCC-390, induces a rapid regeneration of the motor axon terminal with functional recovery of the neuromuscular junction. These findings qualify NUCC-390 as a promising novel therapeutics capable of improving the recovery from the paralysis caused by the snakebite of the two neurotoxic Alpine vipers.


Assuntos
Indazóis , Receptores CXCR4 , Venenos de Víboras , Viperidae , Animais , Paralisia/induzido quimicamente , Receptores CXCR4/agonistas , Venenos de Víboras/antagonistas & inibidores , Venenos de Víboras/toxicidade , Vipera/metabolismo , Viperidae/metabolismo , Camundongos , Indazóis/farmacologia , Indazóis/uso terapêutico , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Mordeduras de Serpentes/tratamento farmacológico
7.
Cancer ; 130(11): 1940-1951, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38288862

RESUMO

BACKGROUND: This phase 1b study (ClinicalTrials.gov identifier NCT03695380) evaluated regimens combining PARP and MEK inhibition, with or without PD-L1 inhibition, for BRCA wild-type, platinum-sensitive, recurrent ovarian cancer (PSROC). METHODS: Patients with PSROC who had received one or two prior treatment lines were treated with 28-day cycles of cobimetinib 60 mg daily (days 1-21) plus niraparib 200 mg daily (days 1-28) with or without atezolizumab 840 mg (days 1 and 15). Stage 1 assessed safety before expansion to stage 2, which randomized patients who had BRCA wild-type PSROC to receive either doublet or triplet therapy, stratified by genome-wide loss of heterozygosity status (<16% vs. ≥16%; FoundationOne CDx assay) and platinum-free interval (≥6 to <12 vs. ≥12 months). Coprimary end points were safety and the investigator-determined objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Potential associations between genetic parameters and efficacy were explored, and biomarker profiles of super-responders (complete response or those with progression-free survival [PFS] >15 months) and progressors (disease progression as the best response) were characterized. RESULTS: The ORR in patients who had BRCA wild-type PSROC was 35% (95% confidence interval, 20%-53%) with the doublet regimen (n = 37) and 27% (95% confidence interval, 14%-44%) with the triplet regimen (n = 37), and the median PFS was 6.0 and 7.4 months, respectively. Post-hoc analyses indicated more favorable ORR and PFS in the homologous recombination-deficiency-signature (HRDsig)-positive subgroup than in the HRDsig-negative subgroup. Tolerability was consistent with the known profiles of individual agents. NF1 and MKNK1 mutations were associated with sustained benefit from the doublet and triplet regimens, respectively. CONCLUSIONS: Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.


Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno B7-H1 , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Ftalazinas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Idoso , Adulto , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Ftalazinas/uso terapêutico , Ftalazinas/administração & dosagem , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Proteína BRCA1/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Idoso de 80 Anos ou mais , Platina/uso terapêutico , Platina/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Proteína BRCA2/genética , Intervalo Livre de Progressão , Azetidinas
8.
Mol Med ; 30(1): 163, 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39333897

RESUMO

BACKGROUND: Fibrosis cataract occurs in patients receiving cataract extraction. Still, no medication that can cure the disease exists in clinical. This study aims to investigate the effects and mechanisms of Entrectinib on fibrotic cataract in vitro and in vivo. METHODS: The human lens cells line SRA 01/04 and C57BL/6J mice were applied in the study. Entrectinib was used in animals and cells. Cataract severity was assessed by slit lamp and Hematoxylin and Eosin staining. Expression of alpha-smooth muscle actin, fibronectin, and collagen I were examined by real-time quantitative PCR, western blotting, and immunofluorescence. Cell proliferation was evaluated by Cell Counting Kit-8. Cell migration was measured by wound healing and transwell assays. Molecular docking, Drug Affinity Responsive Target Stability, and Cellular Thermal Shift Assay were applied to seek and certify the target of Entrectinib treating fibrosis cataract. RESULTS: Entrectinib can ameliorate fibrotic cataract in vitro and in vivo. At the RNA and the protein levels, the expression of alpha-smooth muscle actin, collagen I, and fibronectin can be downgraded by Entrectinib, while E-cadherin can be upregulated. The migration and proliferation of cells were inhibited by Entrectinib. Mechanistically, Entrectinib obstructs TGFß2/Smad and TGFß2/non-Smad signaling pathways to hinder the fibrosis cataract by targeting PYK2 protein. CONCLUSIONS: Targeting with PYK2, Entrectinib can block TGF-ß2/Smad and TGF-ß2/non-Smad signaling pathways, lessen the activation of EMT, and alleviate fibrosis cataract. Entrectinib may be a potential treatment for fibrosis cataract in clinic.


Assuntos
Catarata , Quinase 2 de Adesão Focal , Transdução de Sinais , Fator de Crescimento Transformador beta2 , Animais , Camundongos , Transdução de Sinais/efeitos dos fármacos , Catarata/etiologia , Catarata/tratamento farmacológico , Catarata/metabolismo , Catarata/patologia , Humanos , Fator de Crescimento Transformador beta2/metabolismo , Quinase 2 de Adesão Focal/metabolismo , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Movimento Celular/efeitos dos fármacos , Linhagem Celular , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Indazóis/farmacologia , Indazóis/uso terapêutico , Masculino , Quinase 1 de Adesão Focal
9.
Ann Oncol ; 35(11): 981-992, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39284381

RESUMO

BACKGROUND: The phase III PRIMA/ENGOT-OV26/GOG-3012 trial met its primary endpoint. Niraparib first-line maintenance significantly prolonged progression-free survival (PFS) among patients with newly diagnosed advanced ovarian cancer that responded to first-line platinum-based chemotherapy, regardless of homologous recombination deficiency (HRD) status. Final overall survival (OS) results are reported. PATIENTS AND METHODS: Patients were randomized 2:1 to niraparib or placebo, stratified by response to first-line treatment, receipt of neoadjuvant chemotherapy, and tumor HRD status. After reaching 60% target maturity, OS was evaluated via a stratified log-rank test using randomization stratification factors and summarized using Kaplan-Meier methodology. OS testing was hierarchical [overall population first, then the homologous recombination-deficient (HRd) population]. Other secondary outcomes and long-term safety were assessed; an updated, ad hoc analysis of investigator-assessed PFS was also conducted (cut-off date, 8 April 2024). RESULTS: The median follow-up was 73.9 months. In the overall population, the OS hazard ratio was 1.01 [95% confidence interval (CI) 0.84-1.23; P = 0.8834] for niraparib (n = 487) versus placebo (n = 246). In the HRd (n = 373) and homologous recombination-proficient (n = 249) populations, the OS hazard ratios were 0.95 (95% CI 0.70-1.29) and 0.93 (95% CI 0.69-1.26), respectively. Subsequent poly(ADP-ribose) polymerase inhibitor therapy was received by 11.7% and 15.8% of niraparib patients and 37.8% and 48.4% of placebo patients in the overall and HRd populations, respectively. The 5-year PFS rate numerically favored niraparib in the overall (niraparib, 22%; placebo, 12%) and HRd populations (niraparib, 35%; placebo, 16%). Myelodysplastic syndromes/acute myeloid leukemia incidence was <2.5% (niraparib, 2.3%; placebo, 1.6%). No new safety signals were observed. CONCLUSIONS: In patients with newly diagnosed advanced ovarian cancer at high risk of recurrence, there was no difference in OS between treatment arms. In the HRd population, patients alive at 5 years were two times as likely to be progression free with niraparib treatment than placebo. Long-term safety remained consistent with the established niraparib safety profile.


Assuntos
Indazóis , Quimioterapia de Manutenção , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Indazóis/efeitos adversos , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Pessoa de Meia-Idade , Quimioterapia de Manutenção/métodos , Idoso , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Ftalazinas/uso terapêutico , Ftalazinas/efeitos adversos , Ftalazinas/administração & dosagem , Intervalo Livre de Progressão , Método Duplo-Cego , Taxa de Sobrevida
10.
Radiology ; 312(2): e232149, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-39189900

RESUMO

HISTORY: A 65-year-old male patient with a history of sarcomatoid renal cell carcinoma and prior right nephrectomy developed recurrent disease adjacent to the inferior vena cava. The patient underwent surveillance imaging 7 months after initiation of treatment with maximum-dose pazopanib and less than 1 month after completing a 2-month regimen of palliative stereotactic body radiation therapy to the right nephrectomy bed and site of recurrence. (Stereotactic body radiation therapy was initiated 5 months after pazopanib treatment was initiated.) One month after initiating treatment with pazopanib and 6 months before the surveillance imaging, the patient developed diarrhea and required ongoing treatment with loperamide to control symptoms. He denied any fatigue, mouth sores, or extremity pain, but described some abdominal pain and discomfort associated with the diarrhea. He was not experiencing any fevers, and vital signs were normal. White blood cell count was normal at 5100/µL (5.1 ×109/L) (normal range, 4200-10 200/µL [4.2-10.2 ×109/L]), with all components of the differential count also being normal. A normal serum albumin level of 3.9 g/dL (39 g/L) (normal range, 3.5-5.0 g/dL [35-50 g/L]) and low serum total protein level of 6.1 g/dL (61 g/L) (normal range, 6.3-7.9 g/dL [63-79 g/L]) were noted. A comprehensive metabolic panel was performed, indicating a serum chloride level of 98 mmol/L (normal, 100-108 mmol/L) and alkaline phosphatase level of 121 U/L (2.02 µkat/L) (normal, 45-115 U/L [0.75-1.92 µkat/L]). The patient underwent surveillance imaging with contrast-enhanced CT of the abdomen and pelvis in the venous phase (Figure).


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Masculino , Idoso , Neoplasias Renais/diagnóstico por imagem , Carcinoma de Células Renais/diagnóstico por imagem , Indazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Pirimidinas/uso terapêutico , Nefrectomia , Recidiva Local de Neoplasia/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Radiocirurgia/métodos
11.
BMC Cancer ; 23(Suppl 1): 1253, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39054430

RESUMO

BACKGROUND: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. METHODS: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. RESULTS: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. CONCLUSIONS: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03260894 .


Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renais , Indazóis , Neoplasias Renais , Pirimidinas , Sulfonamidas , Sunitinibe , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Sunitinibe/uso terapêutico , Sunitinibe/administração & dosagem , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Idoso , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Adulto , Idoso de 80 Anos ou mais , Oximas
12.
Diabet Med ; 41(9): e15388, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38934613

RESUMO

AIM: The objective was to investigate the specific role and the regulatory mechanism of vascular endothelial growth factor (VEGF) during wound healing in diabetic foot ulcer (DFU). METHODS: Streptozotocin-induced diabetic rats were used to establish a DFU animal model. VEGF and Axitinib (a specific inhibitor of VEGFR) were used for treatment in vivo. The wounds at different time points were imaged and histological analysis of the wounds were performed by haematoxylin and eosin (H&E) staining and Masson's trichrome staining. Immunohistochemical staining was conducted to examine CD31 and eNOS expression in the wounds. Immunofluorescence assay and quantitative real-time PCR were performed to examine macrophage markers. In addition, THP-1 was differentiated to macrophages, and then treated with interleukin (IL)-4 to induce M2 macrophages, followed by VEGF treatment. The conditional medium (CM) from VEGF-mediated macrophages were collected to culture human dermal fibroblasts (HDFs). Cell viability and migration were measured by Cell Counting Kit (CCK)-8, wound-healing and Transwell assays, respectively. RESULTS: VEGF treatment remarkably accelerated wound healing of DFU rats. VEGF promoted collagen deposition and elevated CD31 and eNOS expression, confirming the pro-angiogenesis of VEGF around diabetic wound in rats. Meanwhile, VEGF restricted pro-inflammatory cytokines and increased F4/80 and CD206 expression, highlighting the activated macrophages and enhanced M2 macrophages following VEGF treatment in diabetic wounds of DFU rats. However, Axitinib exerted an opposite function to VEGF in DFU rats. Moreover, VEGF directly promoted macrophage polarization toward M2 phenotype in vitro, and the CM from VEGF-mediated M2 macrophages markedly promoted HDFs proliferation, migration and collagen deposition. CONCLUSION: VEGF might accelerate the wound healing of DFU through promoting M2 macrophage polarization and fibroblast migration.


Assuntos
Axitinibe , Diabetes Mellitus Experimental , Pé Diabético , Macrófagos , Fator A de Crescimento do Endotélio Vascular , Cicatrização , Animais , Pé Diabético/metabolismo , Pé Diabético/patologia , Cicatrização/efeitos dos fármacos , Cicatrização/fisiologia , Ratos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/complicações , Fator A de Crescimento do Endotélio Vascular/metabolismo , Macrófagos/metabolismo , Masculino , Axitinibe/farmacologia , Axitinibe/uso terapêutico , Humanos , Ratos Sprague-Dawley , Ativação de Macrófagos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Indazóis/farmacologia , Indazóis/uso terapêutico
13.
Gynecol Oncol ; 184: 24-30, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38277918

RESUMO

OBJECTIVE: PARP (poly adenosine diphosphate [ADP]-ribose polymerase) inhibitors are approved as maintenance therapy in platinum sensitive ovarian cancer (OC), in first line and in the recurrent setting, regardless of BRCA mutational status. Real-world data after the introduction of these agents are needed to evaluate whether the benefit observed in phase III randomized clinical trials can be translated into clinical practice. The aim of our study was to provide real-life data on efficacy and safety of niraparib administered as maintenance in platinum sensitive relapsed OC patients (PSROC). METHODS: This retrospective/prospective observational study included relapsed OC patients that received niraparib as maintenance, at the time of platinum sensitive recurrence within the Italian expanded-access program. Clinical data at the time of diagnosis and at the time of recurrence were collected and analyzed. Median progression free survival (PFS) and overall survival (OS) were calculated as the time from start of niraparib treatment to subsequent radiologically confirmed relapse and death or last contact, respectively. RESULTS: Among 304 eligible patients, 260 (85%) had BRCA wild-type tumor and 36. (11.9%) were BRCA mutated. Median PFS was 9.1 months (95% CI: 6.9-11.2) and 10.3 months (95% CI: 7.0-13.5) in the BRCAwt and BRCAmut cohorts, respectively. Furthermore, median OS was 41.7 months (95% CI: 31.6-41.9) and 34.6 months (95% CI: N.E.) in the BRCAwt and BRCAmut cohorts, respectively. CONCLUSION: Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated.


Assuntos
Indazóis , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Indazóis/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Idoso , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Adulto , Estudos Prospectivos , Idoso de 80 Anos ou mais , Quimioterapia de Manutenção/métodos , Intervalo Livre de Progressão
14.
Gynecol Oncol ; 187: 204-211, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38795509

RESUMO

OBJECTIVE: To estimate the annual percentage of patients with epithelial ovarian cancer (EOC) who could be eligible for and benefit from PARP inhibitor therapy amidst changing US Food and Drug Administration (FDA)-approved indications. METHODS: This is a simulated retrospective observational study using publicly available data on patients with advanced-stage EOC. PARPi eligibility is based on FDA approvals and withdrawals from 2014 through 2023, along with published demographic and genomic data. Clinical trial data is used to estimate treatment benefit. PARPi including olaparib, niraparib, and rucaparib are analyzed in aggregate with sub-analyses by molecular classification and treatment timing. Results are reported as the percentage of EOC patients appropriate for any cancer-directed therapy. RESULTS: PARPi were approved for 9 different indications in EOC between 2014 and 2021; reduced to 6 indications by 2023. Eligibility increased from 2.0% (95% CI,1.3%-1.6%) in 2014 to a maximum of 93.4% (95% CI,90.1%-94.6%) in 2021. The maximum percentage of patients with 2-year PFS benefit was 22.0% (95% CI, 17.2%-26.8%) in 2021, projected to decrease to 13.0% (95% CI, 9.9%-15.9%) in 2024. Most of this decrease was seen in the homologous recombination deficient, BRCA wild-type population (8.4% to 4.0%). CONCLUSIONS: PARPi eligibility increased at a greater rate than benefit resulting in a low population-level benefit-to-eligibility ratio until 2021. Recent FDA withdrawals improved this ratio with an accompanied decrease in the absolute number of patients benefiting. To further optimize population-level benefit-to-eligibility ratio of targeted therapies in ovarian cancer, we need to identify better biomarkers, treatment combinations, and novel therapeutic targets.


Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Feminino , Carcinoma Epitelial do Ovário/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Estados Unidos , Indazóis/uso terapêutico , United States Food and Drug Administration , Aprovação de Drogas , Pessoa de Meia-Idade , Ftalazinas/uso terapêutico , Ftalazinas/administração & dosagem , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Definição da Elegibilidade , Seleção de Pacientes , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Indóis
15.
Gynecol Oncol ; 187: 128-138, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38833992

RESUMO

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.


Assuntos
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/métodos
16.
Gynecol Oncol ; 189: 68-74, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39032397

RESUMO

OBJECTIVES: Patterns of disease recurrence on poly(ADP-ribose) polymerase inhibitor maintenance therapy are unclear and may affect subsequent treatment. This ad hoc subgroup analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study evaluated patterns of initial recurrence in patients with advanced ovarian cancer (AOC). METHODS: PRIMA included participants at high risk for disease progression. This ad hoc analysis only evaluated participants randomized to niraparib maintenance without evidence of disease at baseline. The number and site(s) of initial recurrent lesions at investigator-assessed progressive disease (PD) were evaluated. RESULTS: Of the 314 niraparib-treated patients analyzed, 190 developed ≥1 new lesion (median number of new lesions, 1.0; interquartile range, 1-2). In total, 93.2% (177/190) of patients developed 1-3 lesions at first disease progression. The most common sites of recurrence were the peritoneum (30.0% [57/190]), lymph nodes (26.3% [50/190]), and liver (20.5% [39/190]). Similar results were observed when patients with PD were stratified by biomarker status, disease stage at diagnosis, and type of debulking surgery. Patients with homologous recombination-proficient tumors, stage III disease, or a history of primary debulking developed a median of 2.0 new lesions at first progression; patients with homologous recombination-deficient tumors, stage IV disease, or a history of interval debulking developed a median of 1.0 new lesion. CONCLUSIONS: Many patients with AOC without lesions at first-line maintenance treatment initiation develop oligometastatic disease at first recurrence. Prospective evaluation is required to determine whether these patients have improved outcomes when local therapies are combined with continuous, systemic, targeted maintenance therapy.


Assuntos
Indazóis , Quimioterapia de Manutenção , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Indazóis/administração & dosagem , Indazóis/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Pessoa de Meia-Idade , Idoso , Quimioterapia de Manutenção/métodos , Adulto , Ftalazinas/administração & dosagem , Ftalazinas/efeitos adversos , Ftalazinas/uso terapêutico , Progressão da Doença
17.
Gynecol Oncol ; 184: 168-177, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38325276

RESUMO

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.


Assuntos
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 mais
18.
Value Health ; 27(9): 1175-1178, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38871026

RESUMO

OBJECTIVES: We sought to quantify exposure to and financial impacts of poly (adenosine diphosphate ribose) polymerase inhibitor (PARPi) treatments for eventually withdrawn ovarian cancer indications. METHODS: We identified in Optum's deidentified Clinformatics® Data Mart database 1695 patients with ovarian cancer diagnoses who received olaparib, rucaparib, or niraparib between January 2015 and September 2021. We describe PARPi use and out-of-pocket, total healthcare, and PARPi spending among patients with ovarian cancer with 3 or more previous lines of therapy. RESULTS: Of the 1695 patients who received PARPi, 254 were estimated to have been heavily pretreated and exposed to eventually withdrawn indications. Cumulative total medical and pharmacy costs for these patients were $53 392 184; PARPi costs accounted for 34%. Median PARPi cost per patient was $43 347. Cumulative out-of-pocket costs totaled $533 281. CONCLUSIONS: Potential patient harm, including financial toxicity, might have been mitigated through more stringent drug approval requirements.


Assuntos
Gastos em Saúde , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/economia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/economia , Pessoa de Meia-Idade , Idoso , Piperidinas/economia , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Indazóis/economia , Indazóis/uso terapêutico , Indazóis/efeitos adversos , Ftalazinas/economia , Ftalazinas/uso terapêutico , Ftalazinas/efeitos adversos , Indóis/economia , Indóis/uso terapêutico , Indóis/efeitos adversos , Piperazinas
19.
Ann Fam Med ; 22(4): 336-346, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39038972

RESUMO

BACKGROUND: The efficacy, effectiveness, and safety of the approved nirmatrelvir/ritonavir regimen for treatment of laboratory-confirmed mild/moderately severe COVID-19 remains unclear. METHODS: We systematically identified randomized controlled trials (RCTs) and real-world studies (RWS; observational studies) of the efficacy/effectiveness and/or safety of the approved nirmatrelvir/ritonavir regimen for COVID-19. We pooled appropriate data (adjusted estimates for RWS) using an inverse variance, random-effects model. We calculated statistical heterogeneity using the I 2 statistic. Results are presented as relative risk (RR) with associated 95% CI. We further assessed risk of bias/study quality and conducted trial sequential analysis of the evidence from RCTs. RESULTS: We included 4 RCTs (4,070 persons) and 16 RWS (1,925,047 persons) of adults (aged ≥18 years). One and 3 RCTs were of low and unclear risk of bias, respectively. The RWS were of good quality. Nirmatrelvir/ritonavir significantly decreased COVID-19 hospitalization compared with placebo/no treatment (RR = 0.17; 95% CI, 0.10-0.31; I 2 = 77.2%; 2 RCTs, 3,542 persons), but there was no significant difference for decrease of worsening severity (RR = 0.82; 95% CI, 0.66-1.01; I 2 = 47.5%; 3 RCTs, 1,824 persons), viral clearance (RR = 1.19; 95% CI, 0.93-1.51; I 2 = 82%; 2 RCTs, 528 persons), adverse events (RR = 1.41; 95% CI, 0.92-2.14; I 2 = 70.6%; 4 RCTs, 4,070 persons), serious adverse events (RR = 0.82; 95% CI, 0.41-1.62; I 2 = 0%; 3 RCTs, 3,806 persons), and all-cause mortality (RR = 0.27; 95% CI, 0.04-1.70; I 2 = 49.9%; 3 RCTs, 3,806 persons), although trial sequential analysis suggested that the current total sample sizes for these outcomes were not large enough for conclusions to be drawn. Real-world studies also showed significantly decreased COVID-19 hospitalization (RR = 0.48; 95% CI, 0.37-0.60; I 2 = 95.0%; 11 RWS, 1,421,398 persons) and all-cause mortality (RR = 0.24; 95% CI, 0.14-0.34; I 2 = 65%; 7 RWS, 286,131 persons) for nirmatrelvir/ritonavir compared with no treatment. CONCLUSIONS: Nirmatrelvir/ritonavir appears to be promising for preventing hospitalization and potentially decreasing all-cause mortality for persons with mild/moderately severe COVID-19, but the evidence is weak. More studies are needed.


Assuntos
Tratamento Farmacológico da COVID-19 , Ritonavir , SARS-CoV-2 , Humanos , Ritonavir/uso terapêutico , Antivirais/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Quimioterapia Combinada , COVID-19/mortalidade , Indazóis/uso terapêutico
20.
Ther Drug Monit ; 46(3): 321-331, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38723115

RESUMO

BACKGROUND: Pazopanib, an anti-angiogenic multitarget tyrosine kinase inhibitor, has been approved for the treatment of metastatic renal cell carcinoma and soft tissue sarcoma. However, its recommended dose does not always produce consistent outcomes, with some patients experiencing adverse effects or toxicity. This variability is due to differences in the systemic exposure to pazopanib. This review aimed to establish whether sufficient evidence exists for the routine or selective therapeutic drug monitoring of pazopanib in adult patients with approved indications. METHODS: A systematic search of the PubMed and Web of Science databases using search terms related to pazopanib and therapeutic drug monitoring yielded 186 and 275 articles, respectively. Ten articles associated with treatment outcomes or toxicity due to drug exposure were selected for review. RESULTS: The included studies were evaluated to determine the significance of the relationship between drug exposure/Ctrough and treatment outcomes and between drug exposure and toxicity. A relationship between exposure and treatment outcomes was observed in 5 studies, whereas the trend was nonsignificant in 4 studies. A relationship between exposure and toxicity was observed in 6 studies, whereas 2 studies did not find a significant relationship; significance was not reported in 3 studies. CONCLUSIONS: Sufficient evidence supports the therapeutic drug monitoring of pazopanib in adult patients to improve its efficacy and/or safety in the approved indications.


Assuntos
Inibidores da Angiogênese , Carcinoma de Células Renais , Monitoramento de Medicamentos , Indazóis , Neoplasias Renais , Pirimidinas , Sarcoma , Sulfonamidas , Indazóis/uso terapêutico , Humanos , Sulfonamidas/uso terapêutico , Sulfonamidas/farmacocinética , Pirimidinas/uso terapêutico , Pirimidinas/farmacocinética , Monitoramento de Medicamentos/métodos , Carcinoma de Células Renais/tratamento farmacológico , Sarcoma/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/farmacocinética
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