RESUMEN
The microcephaly-capillary malformation (MIC-CAP) syndrome is a life-threatening disease caused by biallelic mutations of the STAMBP gene, which encodes an endosomal deubiquitinating enzyme. To establish a suitable preclinical animal model for clinical therapeutic practice, we generated a central nervous system (CNS)-specific Stambp knockout mouse model (StambpSox1-cKO), which phenocopies Stambp null mice including progressive microcephaly, postnatal growth retardation and complete penetrance of preweaning death. In this MIC-CAP syndrome mouse model, early-onset neuronal death occurs specifically in the hippocampus and cortex, accompanied by aggregation of ubiquitinated proteins, and massive neuroinflammation. Importantly, neonatal AAV9-mediated gene supplementation of Stambp in the brain could significantly improve neurological defects, sustain growth, and prolong lifespan of StambpSox1-cKO mice. Together, our findings reveal a central role of brain defects in the pathogenesis of STAMBP deficiency and provide preclinical evidence that postnatal gene replacement is an effective approach to cure the disease.
RESUMEN
BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors combined with endocrine therapy (ET) comprise the standard treatment for patients with hormone receptor-positive and human epidermal growth factor 2 (HER2)-negative metastatic breast cancer. The optimal systematic treatment after progression on palbociclib and the role of HER2 expression among these patients remain unclear. METHODS: The authors retrospectively identified 361 patients who received palbociclib combined with ET. Progression-free survival (PFS) and overall survival (OS) were analyzed based on subsequent treatments and HER2 status (PFSsub and OSsub, respectively). PFS1 and OS1 were calculated from palbociclib administration to disease progression/death and death from any cause, respectively. PFSsub and OSsub were calculated from subsequent treatment initiation. RESULTS: The median PFS1 and OS1 were 10.2 and 39.9 months, respectively. The median PFSsub and OSsub of 111 patients (54.7%) who received chemotherapy were 4.9 months and 20.0 months, respectively, whereas those of 89 patients (43.8%) who received endocrine backbone therapy were 5.9 months and 29.3 months, respectively. Among them, 31 patients (15.3%) who received abemaciclib combined with new ET showed better PFSsub and OSsub (12.2 months and not reached, respectively). The median PFS1 was significantly shorter in the HER2-low subgroup than in the HER2-zero subgroup among patients who received second-line or later palbociclib (6.1 vs. 7.8 months; p = .040) but did not differ among patients who received first-line palbociclib. CONCLUSIONS: Various regimens after palbociclib use were received. An improvement was noted in PFS among patients who received endocrine backbone therapy relative to chemotherapy, which may have been secondary to the receipt of chemotherapy by patients with more aggressive disease. HER2 status was not related to the effect of first-line palbociclib, but it may play a role in later lines.
Asunto(s)
Neoplasias de la Mama , Piperazinas , Humanos , Femenino , Neoplasias de la Mama/patología , Estudios Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Piridinas , Receptor ErbB-2/metabolismoRESUMEN
BACKGROUND: The contradictory role of CD8 + CD28- T cells in tumour immunity has been reported, while their biological and clinical significance in HER2-positive metastatic breast cancer (MBC) is still unknown. METHODS: HER2-positive MBC patients with no prior therapy in the metastatic setting were retrospectively recruited at two medical centres. Peripheral CD8 + CD28- T cells (pTCD8+CD28-) were detected at baseline and following therapeutic intervals. Progression-free survival (PFS) was compared according to pTCD8+CD28- levels. The molecular features of pTCD8+CD28- and its correlation with tumour immunity were also investigated. RESULTS: A total of 252 patients were enrolled, and the median follow-up time was 29.6 months. pTCD8+CD28- high at baseline has prolonged PFS compared to pTCD8+CD28- low (P = 0.001). Patients who maintained pTCD8+CD28- high had a longer PFS than those who kept pTCD8+CD28- low (P < 0.001). The enhanced pTCD8+CD28- level also indicates a longer PFS compared to pTCD8+CD28- low (P = 0.025). Here, pTCD8+CD28- was demonstrated as an antigen-experienced effector T cell. Higher IL-2 level (P = 0.034) and lower TGF-ß level (P = 0.016) in the serum and highly infiltrated CD8 + CD28- T cells (P = 0.037) were also connected to pTCD8+CD28- high. CONCLUSIONS: High pTCD8+CD28- level is associated with a favourable tumour immunity and a better PFS of HER2-targeting therapy in MBC patients.
Asunto(s)
Neoplasias de la Mama , Antígenos CD28 , Linfocitos T CD8-positivos , Receptor ErbB-2 , Adulto , Femenino , Humanos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Antígenos CD28/metabolismo , Linfocitos T CD8-positivos/inmunología , Metástasis de la Neoplasia , Supervivencia sin Progresión , Receptor ErbB-2/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND: Pyrotinib is currently approved for the treatment of HER2-positive advanced breast cancer in China. Data on the overall survival (OS) and efficacy in patients with brain metastasis (BM) remain scarce. This study evaluated the effectiveness of pyrotinib in a real-world setting, especially in patients with BM. METHODS: We reviewed patients with metastatic breast cancer treated with pyrotinib-based therapy between June 2018 and June 2022. Progression-free survival (PFS), OS, objective response rate, and safety were analyzed following the administration of pyrotinib. RESULTS: A total of 239 patients were included. The median PFS in patients who received pyrotinib-based therapy as first-line (15/239), second-line (115/239), or third-or-higher-line (109/239) treatment was 14.00, 9.33, and 8.20 months, respectively, and the median OS was not reached, 29.07 and 22.23 months, respectively. The median PFS in patients who pretreated with trastuzumab (214/239), trastuzumab plus pertuzumab (22/239), lapatinib (68/239), or trastuzumab emtansine (14/239) was 9.33, 6.87, 7.20, and 7.20 months, respectively. In 61 patients with BM, the median PFS was 7.50 months, the median central nervous system (CNS)-PFS was 11.17 months, and the median OS was 21.27 months. Furthermore, 19 patients with concomitant brain radiotherapy tended to achieve a longer OS than 42 patients without radiation (34.17 vs. 20.70 months, Pâ =â .112). CONCLUSIONS: Long-term outcomes of pyrotinib-based therapy are promising for patients with HER2-positive metastatic breast cancer in real world and in patients with BM, regardless of the treatment lines and prior anti-HER2 therapies.
Asunto(s)
Acrilamidas , Aminoquinolinas , Neoplasias Encefálicas , Neoplasias de la Mama , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéuticoRESUMEN
PURPOSE: This study evaluated the effectiveness of ovarian function suppression (OFS) of various gonadotropin-releasing hormone agonists (GnRHa) combined with aromatase inhibitors (AI) in premenopausal patients with hormone receptor-positive (HR-positive) breast cancer. Potential risk factors associated with insufficient OFS were analyzed. PATIENTS AND METHODS: Premenopausal HR-positive breast cancer patients who had received AI with GnRHa were studied retrospectively. Patients were divided into different groups according to monthly or trimonthly GnRHa schedules they received, and the effectiveness of OFS was compared between groups. Insufficient OFS was defined as at least one instance of estradiol ≥ 30 pg/ml. Patient data was gathered from medical records for this comparison. RESULTS: Of the 264 patients enrolled in this study, 117 were administered 3.6 mg of goserelin monthly (goserelin 1 M group), 63 received 3.75 mg of leuprorelin monthly (leuprorelin 1 M group) and 84 were given 11.25 mg of leuprorelin every three months (leuprorelin 3 M group). Overall, 7.20% experienced insufficient OFS. The incidence rates in the three GnRHa depot groups were 7.69%, 6.35%, and 7.14%, respectively, without a significant statistical difference (P = 0.900). Notably, younger patients exhibited a higher likelihood of insufficient OFS [OR = 0.900, 95%CI (0.824-0.982), P = 0.018]. CONCLUSION: Insufficient OFS remains a concern during GnRHa and AI treatment. The effectiveness of the three GnRHa depots commonly used in China seems comparable. Younger patients face a heightened risk of insufficient OFS.
Asunto(s)
Inhibidores de la Aromatasa , Neoplasias de la Mama , Hormona Liberadora de Gonadotropina , Premenopausia , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Adulto , Estudios Retrospectivos , Hormona Liberadora de Gonadotropina/agonistas , Persona de Mediana Edad , Inhibidores de la Aromatasa/uso terapéutico , Ovario/efectos de los fármacos , Ovario/metabolismo , Antineoplásicos Hormonales/uso terapéutico , Resultado del Tratamiento , Receptores de Estrógenos/metabolismo , Goserelina/uso terapéutico , Goserelina/administración & dosificación , Leuprolida/uso terapéutico , Leuprolida/administración & dosificación , Receptores de Progesterona/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
PURPOSE: In patients with first-line advanced breast cancer (ABC), the correlation between ctDNA variant allele frequency (VAF) and tumor disease burden, and its prognostic value remains poorly investigated. METHODS: This study included patients with ABC diagnosed at Peking University Cancer Hospital who performed ctDNA test before receiving first-line treatment. Baseline plasma samples were collected for assessing ctDNA alterations and VAF with next-generation sequencing. The sum of tumor target lesion diameters (SLD) was measured with imaging methods according to RECIST 1.1 criteria. RESULTS: The final cohort included 184 patients. The median age of the cohort was 49.4 (IQR: 42.3-56.8) years. The median VAF was 15.6% (IQR: 5.4%-33.7%). VAF showed positive correlation with SLD in patients with relatively large tumor lesions (r = 0.314, p = 0.003), but not in patients with small tumor lesions (p = 0.226). VAF was associated with multiple metastasis sites (p = 0.001). Multivariate Cox regression analysis showed that high VAF was associated with shorter overall survival (OS) (HR: 3.519, 95% confidence interval (CI): 2.149-5.761), and first-line progression-free survival (PFS) (HR: 2.352, 95%CI: 1.462-3.782). Combined VAF and SLD improved prediction performance, both median OS and PFS of patients in VAF(H)/SLD(H) group were significantly longer than VAF(L)/SLD(L) group (mOS: 49.3 vs. 174.1 months; mPFS: 9.6 vs. 25.3 months). CONCLUSION: ctDNA VAF associated with tumor disease burden, and was a prognostic factor for patients with ABC. A combination of ctDNA test and radiographic imaging might enhance tumor burden evaluation, and improve prognosis stratification in patients with ABC.
Asunto(s)
Neoplasias de la Mama , ADN Tumoral Circulante , Neoplasias Pulmonares , Humanos , Adulto , Persona de Mediana Edad , Femenino , ADN Tumoral Circulante/genética , Carga Tumoral , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Biomarcadores de Tumor/genética , Pronóstico , Neoplasias Pulmonares/genética , Frecuencia de los Genes , MutaciónRESUMEN
Emerald ash borer (EAB, Agrilus planipennis) is an invasive killer of ash trees (Fraxinus spp.) in North America and Europe. Ash species co-evolved with EAB in their native range in Asia are mostly resistant, although the precise mechanism(s) remain unclear. Very little is also known about EAB or ash tree microbiomes. We performed the first joint comparison of phloem mycobiome and metabolites between a native and a nonnative ash species, infested and uninfested with EAB, in conjunction with investigation of larval mycobiome. Phloem mycobiome communities differed between the tree species, but both were unaffected by EAB infestation. Several indicator taxa in the larval gut shared a similarly high relative abundance only with the native host trees. Widely targeted metabolomics revealed 24 distinct metabolites in native trees and 53 metabolites in nonnative trees, respectively, that differed in relative content between infested and uninfested trees only in one species. Interestingly, four metabolites shared a strong relationship with the phloem mycobiomes, majority of which affected only the native trees. Collectively, our results demonstrate a complex interplay between host tree chemistry and mycobiome, and suggest the shared relationships between the mycobiomes of the native host tree and EAB may reflect their shared co-evolution.
RESUMEN
Cyclin-dependent kinase 7 (CDK7) serves as a pivotal regulator in orchestrating cellular cycle dynamics and gene transcriptional activity. Elevated expression levels of CDK7 have been ubiquitously documented across a spectrum of malignancies and have been concomitantly correlated with adverse clinical outcomes. This review delineates the biological roles of CDK7 and explicates the molecular pathways through which CDK7 exacerbates the oncogenic progression of breast cancer. Furthermore, we synthesize the extant literature to provide a comprehensive overview of the advancement of CDK7-specific small-molecule inhibitors, encapsulating both preclinical and clinical findings in breast cancer contexts. The accumulated evidence substantiates the conceptualization of CDK7 as a propitious therapeutic target in breast cancer management.
Asunto(s)
Neoplasias de la Mama , Quinasas Ciclina-Dependientes , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/fisiopatología , Quinasas Ciclina-Dependientes/metabolismoRESUMEN
The purpose of this study is to further investigate the relationship between sweetener exposure and the risk of endometrial cancer (EC). Up until December 2022, a literature search in an electronic database was carried out utilizing PubMed, Web of Science, Ovid, and Scopus. The odds ratio (OR) and 95 % confidence interval (CI) were used to evaluate the results. Sweeteners were divided into nutritional sweeteners (generally refers to sugar, such as sucrose and glucose) and non-nutritional sweeteners (generally refers to artificial sweeteners, such saccharin and aspartame). Ten cohort studies and two case-control studies were eventually included. The study found that in 12 studies, compared with the non-exposed group, the incidence rate of EC in the sweetener exposed group was higher (OR = 1·15, 95 % CI = [1·07, 1·24]). Subgroup analysis showed that in 11 studies, the incidence rate of EC in the nutritional sweetener exposed group was higher than that in the non-exposed group (OR = 1·25, 95 % CI = [1·14, 1·38]). In 4 studies, there was no difference in the incidence rate of EC between individuals exposed to non-nutritional sweeteners and those who were not exposed to non-nutritional sweeteners (OR = 0·90, 95 % CI = [0·81, 1·01]). This study reported that the consumption of nutritional sweeteners may increase the risk of EC, whereas there was no significant relationship between the exposure of non-nutritional sweeteners and the incidence of EC. Based on the results of this study, it is recommended to reduce the intake of nutritional sweeteners, but it is uncertain whether use of on-nutritional sweeteners instead of nutritional sweetener.
Asunto(s)
Neoplasias Endometriales , Edulcorantes no Nutritivos , Femenino , Humanos , Aspartame/efectos adversos , Neoplasias Endometriales/epidemiología , Neoplasias Endometriales/etiología , Edulcorantes no Nutritivos/efectos adversos , Sacarina/efectos adversos , Sacarosa/efectos adversos , Edulcorantes/efectos adversos , Estudios Observacionales como AsuntoRESUMEN
PURPOSE: Current evidence on the association between plant-based diet indices (PDIs) and mortality is inconsistent. We aimed to investigate the association of PDIs with all-cause and cause-specific mortality and to examine whether such associations were modified by socioeconomic deprivation level. METHODS: A total of 189,003 UK Biobank participants with at least one 24-h dietary assessment were included. All food items were categorised into three groups, including healthy plant foods, less healthy plant foods, and animal foods. Three PDIs, including the overall PDI (positive scores for all plant-based food intake and inverse scores for animal-based foods), the healthful PDI (hPDI) (positive scores only for healthy plant food intake and inverse scores for others), and the unhealthful PDI (uPDI) (positive scores only for less healthy plant food intake and inverse scores for others), were calculated according to the quantities of each food subgroup in three categories. The Townsend deprivation index was used as the indicator of socioeconomic deprivation level. Cox proportional hazard models were used to estimate the hazard ratios (HRs) of PDIs for all-cause and cause-specific mortality. The modification effects of socioeconomic deprivation levels on these associations were evaluated. RESULTS: During a median follow-up of 9.6 years, 9335 deaths were documented. Compared with the lowest quintile, the highest quintile of overall PDI was associated with adjusted HRs of 0.87 (95% CI 0.81-0.93) for all-cause mortality and 0.77 (0.66-0.91) for cardiovascular mortality. Compared with the lowest quintile, the highest quintile of hPDI was associated with lower risks of all-cause mortality (0.92, 0.86-0.98), and death caused by respiratory disease (0.63, 0.47-0.86), neurological disease (0.65, 0.48-0.88), and cancer (0.90, 0.82-0.99). Compared with the lowest quintile, the highest quintile of uPDI was associated with an HR of 1.29 (1.20-1.38) for all-cause mortality, 1.95 (1.40-2.73) for neurological mortality, 1.54 (1.13-2.09) for respiratory mortality, and 1.16 (1.06-1.27) for cancer mortality. The magnitudes of associations of hPDI and uPDI with mortality were larger in the most socioeconomically deprived participants (the highest tertile) than in the less deprived ones (p-values for interaction were 0.039 and 0.001, respectively). CONCLUSIONS: This study showed that having a high overall PDI and hPDI were related to a reduced risk of death, while the uPDI was linked to a higher risk of death. Sticking to a healthy plant-based diet may help decrease mortality risks across socioeconomic deprivation levels, especially for those who are the most socioeconomically deprived.
Asunto(s)
Dieta Vegetariana , Neoplasias , Humanos , Causas de Muerte , Estudios Prospectivos , Dieta a Base de Plantas , Dieta , Factores SocioeconómicosRESUMEN
Dual-source drinking water distribution systems (DWDS) over single-source water supply systems are becoming more practical in providing water for megacities. However, the more complex water supply problems are also generated, especially at the hydraulic junction. Herein, we have sampled for a one-year and analyzed the water quality at the hydraulic junction of a dual-source DWDS. The results show that visible changes in drinking water quality, including turbidity, pH, UV254, DOC, residual chlorine, and trihalomethanes (TMHs), are observed at the sample point between 10 and 12 km to one drinking water plant. The average concentration of residual chlorine decreases from 0.74 ± 0.05 mg/L to 0.31 ± 0.11 mg/L during the water supplied from 0 to 10 km and then increases to 0.75 ± 0.05 mg/L at the end of 22 km. Whereas the THMs shows an opposite trend, the concentration reaches to a peak level at hydraulic junction area (10-12 km). According to parallel factor (PARAFAC) and high-performance size-exclusion chromatography (HPSEC) analysis, organic matters vary significantly during water distribution, and tryptophan-like substances and amino acids are closely related to the level of THMs. The hydraulic junction area is confirmed to be located at 10-12 km based on the water quality variation. Furthermore, data-driven models are established by machine learning (ML) with test R2 higher than 0.8 for THMs prediction. And the SHAP analysis explains the model results and identifies the positive (water temperature and water supply distance) and negative (residual chlorine and pH) key factors influencing the THMs formation. This study conducts a deep understanding of water quality at the hydraulic junction areas and establishes predictive models for THMs formation in dual-sources DWDS.
Asunto(s)
Agua Potable , Aprendizaje Automático , Calidad del Agua , Abastecimiento de Agua , Agua Potable/química , Agua Potable/análisis , Trihalometanos/análisis , Modelos Teóricos , Contaminantes Químicos del Agua/análisis , Cloro/análisisRESUMEN
OBJECTIVES: Patients with severe stroke are at high risk of developing acute respiratory distress syndrome (ARDS), but this severe complication was often under-diagnosed and rarely explored in stroke patients. We aimed to investigate the prevalence, early predictors, and outcomes of ARDS in severe stroke. METHODS: This prospective study included consecutive patients admitted to neurological intensive care unit (neuro-ICU) with severe stroke, including acute ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The incidence of ARDS was examined, and baseline characteristics and severity scores on admission were investigated as potential early predictors for ARDS. The in-hospital mortality, length of neuro-ICU stay, the total cost in neuro-ICU, and neurological functions at 90 days were explored. RESULTS: Of 140 patients included, 35 (25.0%) developed ARDS. Over 90% of ARDS cases occurred within 1 week of admission. Procalcitonin (OR 1.310 95% CI 1.005-1.707, P = 0.046) and PaO2/FiO2 on admission (OR 0.986, 95% CI 0.979-0.993, P < 0.001) were independently associated with ARDS, and high brain natriuretic peptide (OR 0.994, 95% CI 0.989-0.998, P = 0.003) was a red flag biomarker warning that the respiratory symptoms may be caused by cardiac failure rather than ARDS. ARDS patients had longer stays and higher expenses in neuro-ICU. Among patients with ARDS, 25 (62.5%) were moderate or severe ARDS. All the patients with moderate to severe ARDS had an unfavorable outcome at 90 days. CONCLUSIONS: ARDS is common in patients with severe stroke, with most cases occurring in the first week of admission. Procalcitonin and PaO2/FiO2 on admission are early predictors of ARDS. ARDS worsens both short-term and long-term outcomes. The conflict in respiratory support strategies between ARDS and severe stroke needs to be further studied.
Asunto(s)
Síndrome de Dificultad Respiratoria , Accidente Cerebrovascular , Humanos , Síndrome de Dificultad Respiratoria/epidemiología , Síndrome de Dificultad Respiratoria/complicaciones , Masculino , Femenino , Anciano , Estudios Prospectivos , Prevalencia , Persona de Mediana Edad , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/complicaciones , Unidades de Cuidados Intensivos/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Mortalidad Hospitalaria , Anciano de 80 o más Años , Tiempo de Internación/estadística & datos numéricosRESUMEN
Achieving magnetic control of ferroelectricity or electric control of magnetism is usually challenging in material systems as their magnetism and ferroelectricity have distinct fundamental origins and are subject to different symmetry constraints. However, such control has significant promise for a wide range of device applications. In this work, we employ first-principles density functional theory calculations to demonstrate the emergence of spin-driven ferroelectricity in a vertically stacked two-dimensional (2D) van der Waals magnetic heterostructure, formed by two ferromagnetic (FM) CrBr3 layers separated by an antiferromagnetic (AFM) MnPSe3 layer, delicately designed to be structurally inversion symmetric but magnetically asymmetric. The spin-induced out-of-plane electric polarization of the entire heterostructure can be reversibly controlled by an external magnetic field. We further validate the effectiveness of this design strategy in several other lattice-matched FM/AFM/FM heterostructures, thereby providing a novel family of multiferroic systems based on 2D materials.
RESUMEN
BACKGROUND: This head-to-head study compared a 3-week versus 4-week schedule of nab-paclitaxel in patients with metastatic breast cancer (mBC). METHODS: Patients with HER2-negative mBC were enrolled and randomly assigned (1:1) to receive nab-paclitaxel for a 3-week schedule (125 mg/m2 on days 1 and 8) or a 4-week schedule (same dose on days 1, 8, and 15) until disease progression or treatment intolerance. Patients with intolerable toxicities were allowed to receive a maintenance regimen after benefiting from nab-paclitaxel. The primary endpoint was progression-free survival (PFS). RESULTS: Ninety-four patients were included in the analysis (nâ =â 47 in each arm). A longer median PFS (mPFS) was observed in the 3-week versus the 4-week schedule in the overall population (not reached vs. 6.8 months; hazard ratio [HR]â =â 0.44; Pâ =â .029). Patients in the 2 arms had a similar overall survival (28.0 vs. 25.8 months), objective response rate (51.1% vs. 48.9%), and disease control rate (93.6% vs. 80.9%). The 3-week schedule was associated with a lower rate of toxicity-related treatment discontinuation (8.5% vs. 29.8%) and dose delays (6.4% vs. 23.4%). CONCLUSION: This study demonstrated the better antitumor activity and safety profile of a 3-week over 4-week nab-paclitaxel schedule in HER2-negative mBC, suggesting that a 3-week schedule may be a better treatment regimen in clinical practice (ClinicalTrials.gov Identifier: NCT04192331).
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Resultado del Tratamiento , Paclitaxel/efectos adversos , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE: PUFFIN (NCT02896855), a Chinese bridging study in patients with previously untreated HER2-positive locally recurrent or metastatic breast cancer, assessed consistency of efficacy and safety of pertuzumab plus trastuzumab and docetaxel versus placebo, trastuzumab, and docetaxel, with CLEOPATRA (NCT00567190). METHODS: Eligible patients, n = 243, were randomized 1:1, stratified by visceral disease and hormone receptor status, to pertuzumab, trastuzumab, and docetaxel or placebo, trastuzumab, and docetaxel. PRIMARY ENDPOINT: investigator-assessed progression-free survival (PFS). Secondary endpoints: safety and overall survival (OS). After primary analysis, patients could cross over to the pertuzumab arm. RESULTS: Updated median PFS: 16.5 months (pertuzumab arm) and 12.5 months (placebo arm), with a hazard ratio (HR) of 0.60 [95% confidence interval (CI) 0.45, 0.81; p = 0.0008]. Median OS was not reached in either arm; the OS HR was 0.68 (95% CI 0.45, 1.03; p = 0.0658). Safety was similar in both arms with no new safety signals: 73.8% (pertuzumab arm) and 69.2% (placebo arm) experienced grade ≥ 3 adverse events. No heart failure, symptomatic left ventricular systolic dysfunction, or left ventricular ejection fraction decline of < 40% were reported. CONCLUSIONS: The PUFFIN final analysis showed, per the primary analysis, that overall efficacy of pertuzumab plus trastuzumab and docetaxel was consistent with CLEOPATRA. Safety remained consistent with the known pertuzumab profile. Overall, PUFFIN contributes to the totality of data with pertuzumab in previously untreated HER2-positive locally recurrent or metastatic breast cancer and supports the favorable benefit-risk profile of pertuzumab in Chinese patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02896855, registered 7 September 2016.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Trastuzumab/efectos adversos , Neoplasias de la Mama/patología , Docetaxel/uso terapéutico , Volumen Sistólico , Pueblos del Este de Asia , Receptor ErbB-2 , Taxoides/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Función Ventricular IzquierdaRESUMEN
PURPOSE: To evaluate the efficacy and safety of pegylated liposomal doxorubicin (PLD) in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) heavily pretreated with anthracycline and taxanes. METHODS: In this single-arm, phase II study, patients with HER2-negative MBC previously treated with anthracycline and taxanes as second- to fifth chemotherapy received PLD (Duomeisu®, generic doxorubicin hydrochloride liposome) 40 mg/m2 every 4 weeks until disease progression, unacceptable toxicity, or completion of six cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR), and safety. RESULTS: Of 44 enrolled patients (median age, 53.5 years; range, 34-69), 41 and 36 were evaluable for safety and efficacy, respectively. In total, 59.1% (26/44) of patients had ≥ 3 metastatic sites, 86.4% (38/44) had visceral disease, and 63.6% (28/44) had liver metastases. Median PFS was 3.7 months (95% confidence interval [CI] 3.3-4.1) and median OS was 15.0 months (95% CI 12.1-17.9). ORR, DCR, and CBR were 16.7%, 63.9%, and 36.1%, respectively. The most common adverse events (AEs) were leukopenia (53.7%), fatigue (46.3%), and neutropenia (41.5%), with no grade 4/5 AEs. The most common grade 3 AEs were neutropenia (7.3%) and fatigue (4.9%). Patients experienced palmar-plantar-erythrodysesthesia (24.4%, 2.4% grade 3), stomatitis (19.5%, 7.3% grade 2), and alopecia (7.3%). One patient displayed a left ventricular ejection fraction decline of 11.4% from baseline after five cycles of PLD therapy. CONCLUSION: PLD (Duomeisu®) 40 mg/m2 every 4 weeks was effective and well-tolerated in patients with HER2-negative MBC heavily pretreated with anthracycline and taxanes, revealing a potentially viable treatment option for this population. Trial registration Chinese Clinical Trial Registry: ChiCTR1900022568.
Asunto(s)
Neoplasias de la Mama , Neutropenia , Humanos , Persona de Mediana Edad , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Antraciclinas/uso terapéutico , Antraciclinas/farmacología , Volumen Sistólico , Taxoides/uso terapéutico , Función Ventricular Izquierda , Doxorrubicina/efectos adversos , Antibióticos Antineoplásicos/farmacología , Polietilenglicoles/efectos adversos , Neutropenia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento , Metástasis de la Neoplasia/tratamiento farmacológicoRESUMEN
BACKGROUND: Salivary amylase, encoded by the AMY1 gene, initiate the digestion of starch. Whether starch intake or AMY1 copy number is related to disease risk is currently rather unknown. The aim was to investigate the association between starch intake and AMY1 copy number and risk of cardiovascular disease (CVD) and mortality and whether there is an interaction. In addition, we aim to identify CVD-related plasma proteins associated with starch intake and AMY1 copy number. METHODS: This prospective cohort study used data from 21,268 participants from the Malmö Diet and Cancer Study. Dietary data were collected through a modified diet history method and incident CVD and mortality were ascertained through registers. AMY1 gene copy number was determined by droplet digital polymerase chain reaction, a risk score of 10 genetic variants in AMY1 was measured, and a total of 88 selected CVD-related proteins were measured. Cox proportional hazards regression was used to analyze the associations of starch intake and AMY1 copy number with disease risk. Linear regression was used to identify plasma proteins associated with starch intake and AMY1 copy number. RESULTS: Over a median of 23 years' follow-up, 4443 individuals developed CVD event and 8125 died. After adjusting for potential confounders, a U-shape association between starch intake and risk of CVD (P-nonlinearity = 0.001) and all-cause mortality (P-nonlinearity = 0.03) was observed. No significant association was found between AMY1 copy number and risk of CVD and mortality, and there were no interactions between starch intake and AMY1 copy number (P interaction > 0.23). Among the 88 plasma proteins, adrenomedullin, interleukin-1 receptor antagonist protein, fatty acid-binding protein, leptin, and C-C motif chemokine 20 were associated with starch intake after adjusting for multiple testing. CONCLUSIONS: In this large prospective study among Swedish adults, a U-shaped association between starch intake and risk of CVD and all-cause mortality was found. Several plasma proteins were identified which might provide information on potential pathways for such association. AMY1 copy number was not associated with CVD risk or any of the plasma proteins, and there was no interaction between starch intake and AMY1 copy number on disease risk.
Asunto(s)
Enfermedades Cardiovasculares , alfa-Amilasas Salivales , Humanos , Variaciones en el Número de Copia de ADN , Almidón/metabolismo , Estudios Prospectivos , Amilasas/genética , alfa-Amilasas Salivales/genética , alfa-Amilasas Salivales/metabolismo , Dosificación de Gen , Proteínas Sanguíneas/genéticaRESUMEN
BACKGROUND: We aim to examine the association between ultra-processed foods (UPF) consumption and cardiovascular disease (CVD) risk and to identify plasma proteins associated with UPF. METHODS: This prospective cohort study included 26,369 participants from the Swedish Malmö Diet and Cancer Study, established in 1991-1996. Dietary intake was assessed using a modified diet history method, and UPF consumption was estimated using the NOVA classification system. A total of 88 selected CVD-related proteins were measured among 4475 subjects. Incident CVD (coronary heart disease and ischemic stroke) was defined as a hospital admission or death through registers. Cox proportional hazards regression models were performed to analyze the associations of UPF intake with risks of CVD. Linear regression models were used to identify the plasma proteins associated with UPF intake. RESULTS: During 24.6 years of median follow-up, 6236 participants developed CVD, of whom 3566 developed coronary heart disease and 3272 developed ischemic stroke. The adjusted hazard ratio (95% confidence interval) in the 4th versus 1st quartile of UPF was 1.18 (1.08, 1.29) for CVD, 1.20 (1.07, 1.35) for coronary heart disease, and 1.17 (1.03, 1.32) for ischemic stroke. Plasma proteins interleukin 18, tumor necrosis factor receptor 2, macrophage colony-stimulating factor 1, thrombomodulin, tumor necrosis factor receptor 1, hepatocyte growth factor, stem cell factor, resistin, C-C motif chemokine 3, and endothelial cell-specific molecule 1 were positively associated with UPF after correcting for multiple testing. CONCLUSIONS: Our study showed that high UPF intake increased the risk of CVD and was associated with several protein biomarkers. Future studies are warranted to validate these findings and assess the potential pathways between UPF intake and CVD.
Asunto(s)
Enfermedades Cardiovasculares , Enfermedad Coronaria , Accidente Cerebrovascular Isquémico , Humanos , Alimentos Procesados , Enfermedades Cardiovasculares/epidemiología , Estudios Prospectivos , Biomarcadores , Proteínas Sanguíneas , Enfermedad Coronaria/epidemiología , Comida Rápida/efectos adversos , DietaRESUMEN
BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer and primary resistance to trastuzumab have a poor clinical outcome and lack good evidence to inform clinical decision. This study investigated the efficacy and safety of pyrotinib plus capecitabine in this population. METHODS: This phase 2 trial was conducted at 16 sites in China. Patients received oral pyrotinib 400 mg once daily and capecitabine 1000 mg/m2 twice a day on days 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: Between June 2019 and September 2021, 100 patients were enrolled with a median age of 51 years (range, 24-69). All patients had been treated with trastuzumab and 21 (21.0%) patients had prior use of pertuzumab. As of August 31, 2022, the median follow-up duration was 20.1 months (range, 1.3-38.2). The median PFS was 11.8 months (95% confidence interval [CI], 8.4-15.1), which crossed the pre-specified efficacy boundary of 8.0 months. The objective response rate was 70.0% (70/100), with a median duration of response of 13.8 months (95% CI, 10.2-19.3). The disease control rate was 87.0% (87/100). The median overall survival was not reached. The most common grade ≥ 3 treatment-emergent adverse event was diarrhea (24 [24.0%]). No treatment-related deaths occurred. CONCLUSIONS: Pyrotinib plus capecitabine can be considered to be a treatment option in HER2-positive advanced breast cancer patients who have shown primary resistance to trastuzumab. Even in the era of modern anti-HER2 treatments, this clinical setting warrants more investigations to meet unmet needs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04001621. Retrospectively registered on June 28, 2019.
Asunto(s)
Neoplasias de la Mama , Capecitabina , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Adulto Joven , Acrilamidas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/etiología , Capecitabina/uso terapéutico , Receptor ErbB-2/genética , TrastuzumabRESUMEN
BACKGROUND: The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). METHODS: This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCAmut). RESULTS: Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6-51.0) and 65.4% (95% CI 50.9-78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7-84.3); this dose was determined to be the RP2D. Patients with gBRCAmut had higher ORR and longer median progression-free survival (PFS) than those with gBRCAwt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg. CONCLUSIONS: Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).