RESUMEN
Concomitant direct oral anticoagulants (DOACs) and tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (anti-VEGF TKI) have been associated with a higher risk of bleeding. Nevertheless, concomitant administration seems frequent in clinical practice in patients with cancer-associated thrombosis and appears to be safe according to the retrospective study by Boileve A. et al. But the risk of an additional pharmacokinetic interaction between anti-VEGF TKI and DOACs must be considered, in case of P-glycoprotein (P-gp) inhibition by the TKI. We describe a case report with a major bleeding event in a renal metastatic cancer patient treated with cabozantinib and rivaroxaban. This case highlights the difficult therapeutic decision in a complex patient with cancer-associated thrombosis, who refused the anticoagulant subcutaneous route. Accumulation of bleeding risk factors (genito-urinary tumor localization) was additive to several pharmacodynamic interactions (acetylsalicylic acid, venlafaxine) and a potential pharmacokinetic interaction between cabozantinib and rivaroxaban. Indeed, cabozantinib-related P-glycoprotein inhibition could have led to a supratherapeutic level of rivaroxaban, contributing partly to the bleeding event. Before combining an anti-VEGF TKI and DOACs, a multidisciplinary pretherapeutic assessment seems crucial to evaluate the patient's bleeding risk factors, pharmacodynamic interactions, and the risk of pharmacokinetic interactions mediated by P-gp.
Asunto(s)
Anticoagulantes , Interacciones Farmacológicas , Piridinas , Rivaroxabán , Humanos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Estudios Retrospectivos , Piridinas/efectos adversos , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/farmacocinética , Rivaroxabán/administración & dosificación , Rivaroxabán/efectos adversos , Rivaroxabán/farmacocinética , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anilidas/administración & dosificación , Anilidas/efectos adversos , Anilidas/farmacocinética , Hemorragia/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Trombosis/inducido químicamente , Trombosis/etiología , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Administración Oral , AncianoRESUMEN
BACKGROUND: Small cell lung carcinoma (SCLC) is characterized by -poor prognosis, -high predilection for -metastasis, -proliferation, and -absence of newer therapeutic options. Elucidation of newer pathways characterizing the disease may allow for development of targeted therapies and consequently favorable outcomes. METHODS: The current study explored the combinatorial action of arsenic trioxide (ATO) and apatinib (APA) in vitro and in vivo. In vitro models were tested using -H446 and -H196 SCLC cell lines. The ability of drugs to reduce -metastasis, -cell proliferation, and -migration were assessed. Using bioinformatic analysis, differentially expressed genes were determined. Gene regulation was assessed using gene knock down models and confirmed using Western blots. The in vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. Growth factor receptor bound protein (GRB) 10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC. RESULTS: In combination, ATO and APA were found to significantly reduce -cell proliferation, -migration, and -metastasis in both the cell lines. Cell proliferation was found to be inhibited by activation of Caspase-3, -7 pathway. In the presence of drugs, it was found that expression of GRB10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3ß/c-Myc signaling pathway. Concurrently, absence of metastasis and reduction of tumor volume were confirmed in vivo. The immunohistochemical results confirmed that the expression level of GRB10 in adjacent tissues was significantly higher than that in human small cell lung cancer tissues. CONCLUSIONS: Synergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA may be mediating its action through the stabilization of GRB10 thus acting as a tumor suppressor. We thus, preliminarily report the impact of GRB10 stability as a target for SCLC treatment.
Asunto(s)
Trióxido de Arsénico , Proliferación Celular , Sinergismo Farmacológico , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-akt , Piridinas , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas , Serina-Treonina Quinasas TOR , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Trióxido de Arsénico/uso terapéutico , Trióxido de Arsénico/farmacología , Humanos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Proliferación Celular/efectos de los fármacos , Animales , Piridinas/farmacología , Piridinas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteína Adaptadora GRB10/genética , Ratones , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Regulación hacia Abajo , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Piridinas/uso terapéutico , Piperazinas , PirimidinasAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Piridinas/uso terapéutico , Piperazinas , PirimidinasRESUMEN
Advancements in human-engineered heart tissue have enhanced the understanding of cardiac cellular alteration. Nevertheless, a human model simulating pathological remodeling following myocardial infarction for therapeutic development remains essential. Here we develop an engineered model of myocardial repair that replicates the phased remodeling process, including hypoxic stress, fibrosis, and electrophysiological dysfunction. Transcriptomic analysis identifies nine critical signaling pathways related to cellular fate transitions, leading to the evaluation of seventeen modulators for their therapeutic potential in a mini-repair model. A scoring system quantitatively evaluates the restoration of abnormal electrophysiology, demonstrating that the phased combination of TGFß inhibitor SB431542, Rho kinase inhibitor Y27632, and WNT activator CHIR99021 yields enhanced functional restoration compared to single factor treatments in both engineered and mouse myocardial infarction model. This engineered heart tissue repair model effectively captures the phased remodeling following myocardial infarction, providing a crucial platform for discovering therapeutic targets for ischemic heart disease.
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Dioxoles , Fibrosis , Infarto del Miocardio , Piridinas , Ingeniería de Tejidos , Animales , Infarto del Miocardio/patología , Infarto del Miocardio/terapia , Infarto del Miocardio/metabolismo , Infarto del Miocardio/genética , Ratones , Humanos , Piridinas/farmacología , Piridinas/uso terapéutico , Ingeniería de Tejidos/métodos , Dioxoles/farmacología , Dioxoles/uso terapéutico , Miocardio/patología , Miocardio/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Benzamidas/farmacología , Benzamidas/uso terapéutico , Modelos Animales de Enfermedad , Transducción de Señal , Masculino , Ratones Endogámicos C57BL , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Remodelación Ventricular/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Corazón/fisiopatología , Corazón/efectos de los fármacos , AmidasRESUMEN
It is highly uncommon for solid tumours to metastasise to the testis. Here, we report a case of metachronous testicular metastasis from clear cell renal cell cancer (RCC) in a male patient 3 years after left radical nephrectomy. Ultrasound of the scrotum showed a 3.5 cm × 4 cm left testicular mass with normal serum tumour markers. The patient underwent left high inguinal orchidectomy, which revealed metastatic renal cell carcinoma. CT of the chest, abdomen and pelvis showed multiple liver secondaries. Cabozantinib was started for metastatic RCC, and the patient showed no evidence of disease progression in a follow-up of 1 year.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Nefrectomía , Orquiectomía , Neoplasias Testiculares , Humanos , Masculino , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Neoplasias Testiculares/secundario , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Persona de Mediana Edad , Neoplasias Primarias Secundarias/patología , Anilidas/uso terapéutico , Piridinas/uso terapéuticoRESUMEN
Chronic pulmonary aspergillosis (CPA) represents a spectrum of lung disorders caused by local proliferation of Aspergillus hyphae in individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. While long-term systemic antifungal treatment is still the mainstay for management, surgery is considered mainly in rarer invasive disease manifestations such as sinusitis and osteomyelitis. Optimal application of existing antifungal agents with suitable pharmacokinetic properties is important for the treatment of diseases such as CPA, which requires long-term use. Appropriate management of side effects by therapeutic drug monitoring, maintenance of adherence, and assessment of drug resistance to Aspergillus can provide safe and effective treatment in the future. Most available antifungal agents for the management of mycoses in humans have disadvantages that can limit their use in clinical practice. By contrast, second generation antifungals such as triazoles have advantages of extended antifungal spectrum and availability in both oral and intravenous formulations. Isavuconazole, a new extended spectrum triazole, has been shown to be effective against Aspergillus. The safety profile and excellent pharmacokinetic characteristics of isavuconazole make it an attractive option for treatment of invasive fungal infections including CPA. With this drug now available in Japan, new evidence is expected to expand treatment options. This review focuses on the selection of antifungal agents based on national and international guidelines and the characteristics of each agent for their appropriate use in CPA.
Asunto(s)
Antifúngicos , Aspergilosis Pulmonar , Triazoles , Humanos , Antifúngicos/farmacocinética , Antifúngicos/administración & dosificación , Antifúngicos/uso terapéutico , Aspergilosis Pulmonar/tratamiento farmacológico , Enfermedad Crónica , Triazoles/farmacocinética , Triazoles/administración & dosificación , Triazoles/uso terapéutico , Aspergillus/efectos de los fármacos , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Piridinas/farmacocinética , Nitrilos/uso terapéutico , Nitrilos/administración & dosificación , Nitrilos/farmacocinética , Farmacorresistencia FúngicaRESUMEN
BACKGROUND AND OBJECTIVES: Ubrogepant is a calcitonin gene-related peptide receptor antagonist approved for the acute treatment of migraine. The PRODROME trial previously demonstrated that ubrogepant treatment during prodrome prevents the onset of moderate or severe headache. In this analysis of the PRODROME trial, the benefits of ubrogepant treatment during the prodrome on patient-reported outcomes (PROs) are evaluated. METHODS: PRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial that enrolled adults who experienced 2-8 migraine attacks per month with moderate-severe headache pain. Eligible participants treated 2 qualifying prodrome events, defined as a migraine attack with prodromal symptoms when the participant was confident a headache would follow within 1-6 hours. Participants were randomized to treatment sequence A (placebo then ubrogepant 100 mg) or sequence B (ubrogepant 100 mg then placebo). This analysis evaluated the ability to function normally over 24 hours (secondary end point) and at specific time points after dose (additional end point). Other PRO end points included activity limitation over 24 hours and satisfaction with study medication at 8 and 24 hours. RESULTS: Of 518 randomized participants, 477 comprised the modified intent-to-treat population. After treatment of qualifying prodrome events, a significantly greater ability to function normally over 24 hours was observed for participants after treatment with ubrogepant 100 mg compared with placebo (odds ratio [OR] 1.66, 95% CI 1.40-1.96; p < 0.0001). As early as 2 hours after dose, a greater proportion of ubrogepant-treated participants reported "no disability, able to function normally" compared with placebo (OR 1.76, 95% CI 1.32-2.35; nominal p = 0.0001). Ubrogepant administered during the prodrome was also associated with a greater reduction in activity limitations over 24 hours after dose (OR 2.07, 95% CI 1.61-2.67; nominal p < 0.0001). At 8 and 24 hours after dose, rates of being "satisfied" or "extremely satisfied" were greater for ubrogepant than for placebo (8 hours: OR 2.37, 95% CI 1.78-3.15; nominal p < 0.0001; 24 hours: OR 2.32, 95% CI 1.78-3.02; nominal p < 0.0001). DISCUSSION: Ubrogepant 100 mg administered during the prodrome was associated with significantly greater ability to function normally, greater reduction in activity limitations over 24 hours, and greater satisfaction with study medication, compared with placebo. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; first patient enrolled: August 21, 2020. clinicaltrials.gov/ct2/show/NCT04492020. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that taking ubrogepant 100 mg during a migraine prodrome allows more patients to function normally over the next 24 hours.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Estudios Cruzados , Trastornos Migrañosos , Medición de Resultados Informados por el Paciente , Piridinas , Humanos , Masculino , Femenino , Adulto , Método Doble Ciego , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Trastornos Migrañosos/tratamiento farmacológico , Persona de Mediana Edad , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/uso terapéutico , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Pirroles/administración & dosificación , Pirroles/uso terapéutico , Resultado del TratamientoRESUMEN
Ollier Disease (OD) and Maffucci syndrome (MS) is a rare bone disorder that affects the growth and development of the bones, with an estimated prevalence of 1 in 100,000 people. It is associated with somatic mosaicism of isocitrate dehydrogenase-1 (IDH1) or 2 (IDH2) pathogenic variants. Ivosidenib is indicated for the treatment of acute myeloid leukemia and locally advanced or metastatic cholangiocarcinoma and is currently investigated in low-grade glioma with a susceptible isocitrate dehydrogenase-1 (IDH1) pathogenic variant, but its effects in patients with OD or MS are unknown. We here report the first case of a patient with MS who was treated with Ivosidenib for recurrent IDH-1 mutated glioma. Besides the stabilization of the tumor size, the patient observed significant improvement in his enchondromas that became stiffer, with reduced pain, and significant modification of the mineralization of the enchondromas observed on X-rays. This first case report provides hope for the medical management of patients suffering because of OD or MS. Future clinical research is urgently needed to evaluate long-term benefit risk profile of IDH inhibitors in these rare diseases.
Asunto(s)
Encondromatosis , Glicina , Isocitrato Deshidrogenasa , Mutación , Piridinas , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Masculino , Mutación/genética , Piridinas/uso terapéutico , Encondromatosis/diagnóstico por imagen , Encondromatosis/tratamiento farmacológico , Encondromatosis/patología , Encondromatosis/genética , Glicina/análogos & derivados , Glicina/uso terapéutico , Condroma/diagnóstico por imagen , Condroma/tratamiento farmacológico , Condroma/patología , Adulto , RadiografíaRESUMEN
BACKGROUND: Data on long-term cancer survivors treated with apatinib are lacking. This study aimed to describe the characteristics of long-term cancer survivors after apatinib-based therapy, and to know about their satisfaction degree with apatinib and severity of depression and insomnia. METHODS: Patients with solid tumors who had received apatinib-based therapy for at least 5 years were invited to complete an online questionnaire. Characteristics of patients and treatment, knowledge of apatinib, satisfaction degree, and severity of depression and insomnia assessed by Patient Health Questionnaire-9 and Insomnia Severity Index were collected. RESULTS: Between December 8, 2023 and March 1, 2024, a total of 436 patients completed the online questionnaire. Most patients were satisfied with the efficacy (96.6%) and safety (93.1%) of apatinib, were willing to continue apatinib treatment (99.5%), and would recommend apatinib to other patients (93.3%). Continuous apatinib treatment resulted in significant negative impact on daily life, work, or study in only two (0.5%) patients. Almost all patients currently had no or mild depression (97.0%) and insomnia (97.9%) problems. The most common patient-reported adverse events were hand-foot syndrome (21.3%) and hypertension (18.3%). CONCLUSIONS: Our survey showed a high satisfaction degree with apatinib in long-term cancer survivors. Long-term apatinib treatment resulted in almost no negative impact on patient's quality of life.
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Supervivientes de Cáncer , Neoplasias , Medición de Resultados Informados por el Paciente , Piridinas , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Piridinas/uso terapéutico , Piridinas/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Supervivientes de Cáncer/psicología , Neoplasias/tratamiento farmacológico , Anciano , Adulto , Encuestas y Cuestionarios , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Depresión/inducido químicamente , Satisfacción del Paciente , Calidad de VidaRESUMEN
BACKGROUND: Hypertensive crisis is an acute increase in blood pressure >180/120 mm Hg. A titratable antihypertensive agent is preferred to lower blood pressure acutely in a controlled way and prevent an abrupt overcorrection. Nicardipine and clevidipine are both dihydropyridine calcium channel blockers that provide unique benefits for blood pressure control. OBJECTIVE: The purpose of this study was to compare the efficacy and safety of nicardipine or clevidipine for blood pressure control in the setting of hypertensive crisis. METHODS: This was a single-center, retrospective cohort study. Eligible patients received either nicardipine or clevidipine for the treatment of hypertensive crisis. The primary outcome was achievement of 25% reduction in mean arterial pressure at 1 h. The secondary outcome was achievement of a systolic blood pressure (SBP) of <160 mm Hg at 2-6 h from the start of the infusion. RESULTS: This study included a total of 156 patients, 74 in the nicardipine group and 82 in the clevidipine group. The SBP on admission and at the start of the infusion were similar between groups. There was no difference between groups in achieving a 25% reduction in mean arterial pressure at 1 h. Nicardipine achieved an SBP goal of <160 mm Hg at 2-6 h significantly more often than the clevidipine group (89.2% vs. 73.2%; p = 0.011). CONCLUSIONS: There is no difference between agents for initial blood pressure control in the treatment of hypertensive crisis. Nicardipine showed more sustained SBP control, with a lower risk of rebound hypertension and a significant cost savings compared with clevidipine.
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Antihipertensivos , Presión Sanguínea , Hipertensión , Nicardipino , Piridinas , Humanos , Nicardipino/uso terapéutico , Nicardipino/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Piridinas/uso terapéutico , Piridinas/farmacología , Piridinas/efectos adversos , Presión Sanguínea/efectos de los fármacos , Anciano , Bloqueadores de los Canales de Calcio/uso terapéutico , Bloqueadores de los Canales de Calcio/farmacología , Resultado del Tratamiento , Estudios de Cohortes , Crisis HipertensivaRESUMEN
BACKGROUND: The combination of anti-programmed death 1 (PD-1) inhibitors and tyrosine kinase inhibitors is an effective treatment strategy in endometrial cancer. We aimed to explore the efficacy and safety of camrelizumab plus apatinib as an alternative therapeutic option in patients with previously treated endometrial cancer. METHODS: This single-arm Simon's two-stage phase II trial was conducted at the Fudan University Shanghai Cancer Center. Patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy were screened for potential participation. Eligible patients were treated with intravenous camrelizumab (200 mg d1 q2w) and oral apatinib (250 mg qd) every 4 weeks. The primary end point was the objective response rate (ORR) per RECIST v1.1 in the intention-to-treat principle. RESULTS: Between January 20, 2020, and October 14, 2022, 36 patients (29 with microsatellite stability/mismatch repair proficient [MSS/pMMR] tumors; two with microsatellite instability-high/mismatch repair deficient [MSI-H/dMMR] tumors) were enrolled and treated. The confirmed ORR was 44.4% (95% CI: 27.9, 61.9) and the disease control rate was 91.7% (95% CI: 77.5, 98.2). The median duration of response was 9.3 (95% CI: 4.3, not reached) months, the median progression-free survival was 6.2 (95% CI: 5.3, 11.1) months, and the median overall survival was 21.0 (95% CI: 13.4, not reached) months during a median follow-up of 14.2 (interquartile range: 10.3, 27.6) months. Treatment-related adverse events of grade 3 or 4 occurred in 20 (55.6%) patients, with the most common being increased γ-glutamyl transferase (27.8%), alanine aminotransferase (16.7%) and aspartate aminotransferase (13.9%), and hypertension (11.1%). No treatment-related death occurred. CONCLUSIONS: Camrelizumab plus apatinib showed promising antitumor activity with manageable toxicity in patients with advanced or recurrent endometrial cancer who had failed at least one prior systemic therapy. The findings of this study support further investigation of camrelizumab plus apatinib as an alternative therapeutic option, especially for patients with MSS/pMMR tumors. TRIAL REGISTRATION: This trial was retrospectively registered with ChiCTR.org.cn, number ChiCTR2000031932.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Endometriales , Piridinas , Humanos , Femenino , Persona de Mediana Edad , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Neoplasias Endometriales/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificaciónRESUMEN
This retrospective cohort study analyzed data from a Japanese health insurance database to assess the effectiveness of baloxavir (n = 4822) for preventing severe events compared with oseltamivir (n = 10,523) in patients with influenza B. The primary endpoint was hospitalization incidence (Days 2-14). The secondary endpoints included intravenous antibacterial drug use, pneumonia hospitalization, heart failure hospitalization, inhalational oxygen requirement, and use of other anti-influenza drugs. The hospitalization incidence was significantly lower with baloxavir (0.15% vs. 0.37%; risk ratio: 2.48, 95% confidence interval: 1.13-5.43). Pneumonia and additional anti-influenza therapy were also less frequent with baloxavir, thus supporting its use. Trial Registration: UMIN Clinical Trials Registry Study ID: UMIN000051382.
Asunto(s)
Antivirales , Dibenzotiepinas , Virus de la Influenza B , Gripe Humana , Morfolinas , Oseltamivir , Pacientes Ambulatorios , Piridonas , Triazinas , Humanos , Gripe Humana/tratamiento farmacológico , Dibenzotiepinas/uso terapéutico , Oseltamivir/uso terapéutico , Antivirales/uso terapéutico , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Adulto , Piridonas/uso terapéutico , Morfolinas/uso terapéutico , Triazinas/uso terapéutico , Anciano , Virus de la Influenza B/efectos de los fármacos , Adulto Joven , Adolescente , Hospitalización/estadística & datos numéricos , Niño , Piridinas/uso terapéutico , Japón/epidemiología , Preescolar , Resultado del Tratamiento , Lactante , Anciano de 80 o más AñosRESUMEN
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.
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Aminopiridinas , Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Piperazinas , Inhibidores de Proteínas Quinasas , Purinas , Piridinas , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Persona de Mediana Edad , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Piridinas/uso terapéutico , Estudios Retrospectivos , Anciano , Piperazinas/uso terapéutico , Aminopiridinas/uso terapéutico , Purinas/uso terapéutico , Taiwán , Inhibidores de Proteínas Quinasas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Resultado del Tratamiento , Metástasis de la Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Pueblo AsiaticoRESUMEN
BACKGROUND: Filgotinib, an oral, once-daily, Janus kinase 1 preferential inhibitor, is an approved treatment for moderately to severely active ulcerative colitis. AIMS: The aim of this study is to assess the safety and efficacy of continued filgotinib therapy over ~4 years in the long-term extension of the phase 2b/3 SELECTION trial (SELECTIONLTE; NCT02914535). METHODS: In this interim analysis of SELECTIONLTE, SELECTION completers (week 10 responders to filgotinib who completed the maintenance study) continued their assigned treatment (double-blind filgotinib 200 mg [FIL200] or filgotinib 100 mg) and SELECTION week 10 non-responders received open-label FIL200. We assessed safety by adverse events (AEs), and efficacy by partial Mayo Clinic Score (pMCS), inflammatory biomarkers and health-related quality of life (HRQoL). We compared safety and efficacy between achievers and non-achievers of a multi-component endpoint, comprehensive disease control (CDC), comprising symptomatic, endoscopic, inflammatory biomarker and HRQoL improvements. RESULTS: Data for completers (n = 250) and non-responders (n = 372) were reported for ≤202 weeks. AE occurrences were low and consistent with previous analyses. The as-observed proportion of FIL200-treated patients in pMCS, biomarker and HRQoL remission during SELECTIONLTE remained high among completers (week 144: 80.0%, 86.4% and 86.0%, respectively) and increased among non-responders (week 192: 62.1%, 76.7% and 59.3%, respectively). Significantly higher proportions of CDC achievers at SELECTION week 58 achieved pMCS, IBDQ and corticosteroid-free pMCS remission than non-achievers, up to LTE week 96. CONCLUSIONS: Filgotinib induced and maintained symptomatic remission and improved HRQoL over 4 years. Safety results showed a proven long-term benefit-risk profile. FIL200-treated CDC achievers had better long-term outcomes than non-achievers.
Asunto(s)
Colitis Ulcerosa , Calidad de Vida , Índice de Severidad de la Enfermedad , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Masculino , Femenino , Adulto , Persona de Mediana Edad , Método Doble Ciego , Resultado del Tratamiento , Estudios de Seguimiento , Triazoles/uso terapéutico , Triazoles/efectos adversos , Triazoles/administración & dosificación , Piridinas/uso terapéutico , Piridinas/efectos adversos , Piridinas/administración & dosificación , Adulto JovenAsunto(s)
Glicina , Síndromes Mielodisplásicos , Piridinas , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Piridinas/uso terapéutico , Piridinas/farmacología , Glicina/análogos & derivados , Glicina/uso terapéutico , Glicina/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacosRESUMEN
AIMS: Fruquintinib is a selective small molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 recently approved in the United States (US) for the treatment of adult patients with metastatic colorectal cancer (CRC) who have previously been treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type and medically appropriate, anti-epidermal growth factor receptor therapy. This study aimed to estimate the 5-year budget impact of fruquintinib from a US payer perspective (commercial and Medicare). MATERIALS AND METHODS: A budget impact model was developed to compare two scenarios: a reference scenario in which patients received regorafenib, trifluridine/tipiracil, or trifluridine/tipiracil with bevacizumab and an alternative scenario in which patients received reference scenario treatments or fruquintinib. Market shares were evenly divided across available options. A 5-year time horizon and a hypothetical health plan of 1 million members was assumed. The model included epidemiological inputs to estimate the eligible population; clinical inputs for treatment duration, progression-free survival, overall survival, and adverse event (AE) frequency; and cost inputs for treatment, AEs, disease management, subsequent therapy, and terminal care costs. Budget impact was reported as total, per member per year (PMPY), and per member per month (PMPM). RESULTS: The model estimated an eligible population of 194 patients (39 per year) over 5 years. In the base case, the estimated 5-year budget impact of fruquintinib was $4,077,073 ($0.82 PMPY and 0.07 PMPM) for a commercial health plan. During the first year, the estimated budget impact was $627,570 ($0.63 PMPY and 0.05 PMPM). Results were robust across sensitivity analyses. PMPM costs from the Medicare perspective were greater than the base-case (commercial) ($0.17 vs. $0.07) due to higher incidence of CRC in that population. CONCLUSIONS: Fruquintinib is associated with a low budget impact for payers based on proposed thresholds in the US.
Fruquintinib is a treatment for metastatic colorectal cancer that has progressed after or not responded to multiple guideline-recommended therapies. This budget impact analysis was conducted to estimate the added costs a health plan would incur over a 5-year period if it chose to cover this therapy. The analysis found that the per plan member per month cost of covering fruquintinib was $0.07 for a United States commercial health plan and $0.17 for Medicare.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzofuranos , Bevacizumab , Neoplasias Colorrectales , Piridinas , Timina , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Benzofuranos/uso terapéutico , Benzofuranos/economía , Estados Unidos , Bevacizumab/uso terapéutico , Bevacizumab/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Piridinas/uso terapéutico , Piridinas/economía , Trifluridina/uso terapéutico , Trifluridina/economía , Presupuestos , Quinazolinas/uso terapéutico , Quinazolinas/economía , Compuestos de Fenilurea/uso terapéutico , Compuestos de Fenilurea/economía , Uracilo/análogos & derivados , Uracilo/uso terapéutico , Uracilo/economía , Compuestos Organoplatinos/uso terapéutico , Compuestos Organoplatinos/economía , Análisis Costo-Beneficio , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Camptotecina/economía , Antineoplásicos/economía , Antineoplásicos/uso terapéutico , Irinotecán/uso terapéutico , Irinotecán/economía , Medicare , Fluorouracilo/uso terapéutico , Fluorouracilo/economía , Oxaliplatino/uso terapéutico , Oxaliplatino/economía , Receptores de Factores de Crecimiento Endotelial Vascular , Modelos Económicos , Combinación de Medicamentos , PirrolidinasRESUMEN
BACKGROUND: The current standard first-line treatment for hormone receptor-positive/human epidermal growth factor receptor 2 negative (HR + /HER2 -) advanced breast cancer (ABC) is a combination of aromatase inhibitor (AI) plus CDK4/6 inhibitors (CDK4/6i). Direct comparison trials of different CDK4/6i are scarce. This real-world study compared the effectiveness of first-line AI plus ribociclib versus palbociclib. METHODS: This multicenter retrospective cohort study, conducted in six cancer centers in Thailand, enrolled patients with HR + /HER2 - ABC treated with first-line AI, and either ribociclib or palbociclib. Propensity score matching (PSM) was performed. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), time to chemotherapy (TTC), and adverse events. RESULTS: Of the 250 patients enrolled, 134 patients with ribociclib and 49 patients with palbociclib were captured after PSM. Baseline characteristics were well-balanced between groups. Median PFS in patients receiving ribociclib and palbociclib were 27.9 and 31.8 months, respectively (hazard ratio: 0.87; 0.55-1.37). The median OS in the AI + ribociclib arm was 48.7 months compared to 59.1 months in the AI + palbociclib arm (hazard ratio: 0.55; 0.29-1.05). The median TTC in the AI + palbociclib group was 56 months, but not reached in the AI + ribociclib group (p = 0.42). The ORR of AI + ribociclib and AI + palbociclib were comparable (40.5% vs. 53.6%, p = 0.29). Patients receiving palbociclib demonstrated a higher proportion of neutropenia compared to those receiving ribociclib, despite a similar dose reduction rate (p = 0.28). Hepatitis rate was similar between the ribociclib (21%) and palbociclib groups (22%). Additionally, a low incidence of QT prolongation was observed in both the ribociclib (5%) and palbociclib groups (4%). CONCLUSION: This preliminary analysis of a real-world study demonstrated the comparable effectiveness of ribociclib and palbociclib with AI as an initial therapy for HR + /HER2 - ABC. No statistically significant difference in PFS, OS, and TTC was found in patients treated with AI combined with palbociclib or ribociclib. Longer follow-up and further prospective randomized head-to-head studies are warranted.
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Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Piperazinas , Purinas , Piridinas , Receptor ErbB-2 , Receptores de Estrógenos , Humanos , Piperazinas/administración & dosificación , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Femenino , Piridinas/administración & dosificación , Piridinas/uso terapéutico , Piridinas/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Aminopiridinas/administración & dosificación , Aminopiridinas/uso terapéutico , Aminopiridinas/efectos adversos , Purinas/administración & dosificación , Purinas/efectos adversos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios Retrospectivos , Tailandia/epidemiología , Anciano , Receptor ErbB-2/metabolismo , Adulto , Receptores de Estrógenos/metabolismo , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/uso terapéutico , Receptores de Progesterona/metabolismo , Supervivencia sin ProgresiónRESUMEN
Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.
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Cardiotónicos , Histona Desacetilasa 6 , Inhibidores de Histona Desacetilasas , Piridinas , Humanos , Animales , Piridinas/farmacología , Piridinas/química , Piridinas/síntesis química , Piridinas/uso terapéutico , Inhibidores de Histona Desacetilasas/farmacología , Inhibidores de Histona Desacetilasas/química , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/uso terapéutico , Histona Desacetilasa 6/antagonistas & inhibidores , Histona Desacetilasa 6/metabolismo , Relación Estructura-Actividad , Cardiotónicos/farmacología , Cardiotónicos/química , Cardiotónicos/síntesis química , Cardiotónicos/uso terapéutico , Ratones , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Masculino , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Ratones Desnudos , Descubrimiento de DrogasRESUMEN
IMPORTANCE: Recurrent/metastatic adenoid cystic carcinoma (R/M AdCC) presents a clinical challenge with limited treatment options, particularly in the face of unsatisfactory efficacy from current therapeutic approaches. This review underscores the unmet clinical needs in managing R/M AdCC, emphasising the imperative for novel therapeutic strategies to address this critical gap. OBJECTIVE: The primary objective of this review is to comprehensively analyse and assess trials investigating therapeutic approaches for R/M AdCC. Emphasis is placed on endpoints such as tumour response rates and progression-free survival. The specific interventions, populations, and outcomes examined in these trials will be detailed to provide a focused and informative systematic review. EVIDENCE REVIEW: The systematic search spanned databases, including PubMed, EMBASE, and the Cochrane database of systematic reviews. Employing terms like "Carcinoma, Adenoid Cystic" and "trial," the search focused on English full-text articles from April 1, 2010, to August 9, 2023. Inclusion criteria encompassed studies with patients having R/M AdCC, involving drug interventions. Study quality was assessed using the Newcastle-Ottawa Scale for retrospective studies, Cochrane ROBINS-I tool for non-randomised trials, and the ROB-2 tool for randomised controlled trials. FINDINGS: A total of 46 trials involving 1244 patients are included in this review, encompassing a variety of therapeutic approaches for R/M AdCC. Targeted therapies, particularly Apatinib at 500 mg, exhibit efficacy with a 47.1% objective response rate (ORR). Conversely, immunotherapeutic agents demonstrate suboptimal performance, with an overall ORR ranging from 0 to 18%. While Apatinib shows promise, the review underscores the imperative for a thorough exploration of drugs targeting unique mechanisms in the immunologically cold nature of R/M AdCC. CONCLUSIONS AND RELEVANCE: Substantial progress in systemic therapy for R/M AdCC is evident, driven by early-phase clinical trials, particularly with promising outcomes in VEGF-2 inhibitors. However, challenges persist, notably in immunotherapy due to the cancer's immunologically cold nature. Ongoing research, prioritising early-stage trials, is crucial, emphasising exploration of emerging therapies like cell therapy and antibody-drug conjugates. Transitioning to Phase III trials is essential for more precise therapeutic insights. Collaborative efforts and a focus on personalised precision medicine are vital for overcoming challenges and advancing our understanding of treatment efficacy in this rare cancer.