RESUMO
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1+ ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1+ ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).
Assuntos
Benzamidas , Piridinas , Rabdomiossarcoma , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Piridinas/farmacologia , Piridinas/uso terapêutico , Animais , Benzamidas/uso terapêutico , Benzamidas/farmacologia , Camundongos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma/metabolismo , Linhagem Celular Tumoral , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologiaRESUMO
Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias Encefálicas , Neoplasias da Mama , Glioblastoma , Imunoconjugados , Recidiva Local de Neoplasia , Humanos , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Adulto , Idoso , Imunoconjugados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Estudos Prospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismoRESUMO
In this study we have identified POLθ-S6K-p62 as a novel druggable regulator of radiation response in prostate cancer. Despite significant advances in delivery, radiotherapy continues to negatively affect treatment outcomes and quality of life due to resistance and late toxic effects to the surrounding normal tissues such as bladder and rectum. It is essential to develop new and effective strategies to achieve better control of tumor. We found that ribosomal protein S6K (RPS6KB1) is elevated in human prostate tumors, and contributes to resistance to radiation. As a downstream effector of mTOR signaling, S6K is known to be involved in growth regulation. However, the impact of S6K signaling on radiation response has not been fully explored. Here we show that loss of S6K led to formation of smaller tumors with less metastatic ability in mice. Mechanistically we found that S6K depletion reduced NFκB and SQSTM1 (p62) reporter activity and DNA polymerase θ (POLθ) that is involved in alternate end-joining repair. We further show that the natural compound berberine interacts with S6K in a in a hitherto unreported novel mode and that pharmacological inhibition of S6K with berberine reduces Polθ and downregulates p62 transcriptional activity via NFκB. Loss of S6K or pre-treatment with berberine improved response to radiation in prostate cancer cells and prevented radiation-mediated resurgence of PSA in animals implanted with prostate cancer cells. Notably, silencing POLQ in S6K overexpressing cells enhanced response to radiation suggesting S6K sensitizes prostate cancer cells to radiation via POLQ. Additionally, inhibition of autophagy with CQ potentiated growth inhibition induced by berberine plus radiation. These observations suggest that pharmacological inhibition of S6K with berberine not only downregulates NFκB/p62 signaling to disrupt autophagic flux but also decreases Polθ. Therefore, combination treatment with radiation and berberine inhibits autophagy and alternate end-joining DNA repair, two processes associated with radioresistance leading to increased radiation sensitivity.
Assuntos
NF-kappa B , Neoplasias da Próstata , Tolerância a Radiação , Proteína Sequestossoma-1 , Transdução de Sinais , Masculino , Animais , Humanos , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/genética , Neoplasias da Próstata/tratamento farmacológico , Proteína Sequestossoma-1/metabolismo , Proteína Sequestossoma-1/genética , NF-kappa B/metabolismo , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Camundongos , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/genéticaRESUMO
Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.
Assuntos
Subunidade alfa de Receptor de Interleucina-4 , Animais , Camundongos , Subunidade alfa de Receptor de Interleucina-4/genética , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma/metabolismo , Humanos , Células Satélites de Músculo Esquelético/metabolismo , Rabdomiossarcoma Alveolar/genética , Rabdomiossarcoma Alveolar/patologia , Rabdomiossarcoma Alveolar/metabolismo , Modelos Animais de Doenças , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Rabdomiossarcoma Embrionário/metabolismo , Transdução de Sinais , Receptores de Superfície CelularRESUMO
Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions: Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.
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Aborto Induzido , Atitude do Pessoal de Saúde , Bolsas de Estudo , Obstetrícia , Humanos , Bolsas de Estudo/métodos , Feminino , Aborto Induzido/psicologia , Aborto Induzido/educação , Gravidez , Obstetrícia/educação , Estados Unidos , Masculino , Inquéritos e Questionários , Adulto , Internato e Residência/métodos , Ginecologia/educaçãoRESUMO
BACKGROUND: Previous studies have compared Impella use to intra-aortic balloon pump (IABP) use in patients with acute myocardial infarction and cardiogenic shock (AMI-CS) undergoing percutaneous coronary intervention (PCI). Our objective was to compare clinical outcomes in patients with AMI-CS undergoing PCI who received Impella (percutaneous left ventricular assist device) without vasopressors, IABP without vasopressors, and vasopressors without mechanical circulatory support (MCS). METHODS: We queried the National Inpatient Sample (NIS) using ICD-10 codes (2015-2018) to identify patients with AMI-CS undergoing PCI. We created three propensity-matched cohorts to examine clinical outcomes in patients receiving Impella versus IABP, Impella versus vasopressors without MCS, and IABP versus vasopressors without MCS. RESULTS: Among 17,762 patients, Impella use was associated with significantly higher in-hospital major bleeding (31.4% vs. 13.6%; p < 0.001) and hospital charges (p < 0.001) compared to IABP use, with no benefit in mortality (34.1% vs. 26.9%; p = 0.06). Impella use was associated with significantly higher mortality (42.3% vs. 35.7%; p = 0.02), major bleeding (33.9% vs. 22.7%; p = 0.001), and hospital charges (p < 0.001), when compared to the use of vasopressors without MCS. There were no significant differences in clinical outcomes between IABP use and the use of vasopressor without MCS. CONCLUSIONS: In this analysis of retrospective data of patients with AMI-CS undergoing PCI, Impella use was associated with higher mortality, major bleeding, and in-hospital charges when compared to vasopressor therapy without MCS. When compared to IABP use, Impella was associated with no mortality benefit, along with higher major bleeding events and in-hospital charges. A vasopressor-only strategy suggested no difference in clinical outcomes when compared to IABP. This study uses the NIS for the first time to highlight outcomes in AMI-CS patients undergoing PCI when treated with vasopressor support without MCS, compared to Impella and IABP use.
Assuntos
Coração Auxiliar , Infarto do Miocárdio , Intervenção Coronária Percutânea , Humanos , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/terapia , Intervenção Coronária Percutânea/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/terapia , Infarto do Miocárdio/complicações , Balão Intra-Aórtico/efeitos adversos , Coração Auxiliar/efeitos adversos , Hemorragia/etiologiaRESUMO
OBJECTIVE: To assess the rate of gastric emptying in spontaneously hypertensive rats (SHR) and to evaluate rapid gastric emptying as a possible predisposing factor for hypertension. Rapid gastric emptying of carbohydrates, known to elevate postprandial serum glucose, has been reported to occur in many insulin-resistant states, including hypertension. SHR exhibit insulin resistance similar to human hypertensive patients. No prior studies have assessed gastric emptying of an oral glucose solution in SHR as compared with control Wistar Kyoto rats (WKY). METHODS: Using scintigraphic imaging, gastric emptying of a physiologic, orally consumed glucose solution was assessed in 12 SHR and 12 control WKY at 5âweeks of age, prior to the development of hypertension, and at 12âweeks of age after hypertension was fully established. RESULTS: At 5âweeks, the gastric half-emptying time (GHET) was 67.8â±â9.8âmin for the SHR vs. 109.3â±â18 ( P â=â0.042)âminutes for the WKY controls. At 12âweeks, the GHET was 37.29â±â10.3âmin for the SHR vs. 138.53â±â37.6 ( P â=â0.016)âmin for the WKY controls. CONCLUSION: Gastric emptying was significantly more rapid in the SHR before and after the development of hypertension. Even though SHR are known to have increased sympathetic activity associated with their development of hypertension, this increased sympathetic activity does not inhibit gastric emptying. SHR are a promising animal model for investigating therapeutic agents for treating hypertension aimed at slowing the rate of gastric emptying.
Assuntos
Esvaziamento Gástrico , Hipertensão , Ratos , Animais , Humanos , Lactente , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Glucose , Pressão Sanguínea/fisiologiaRESUMO
Tumor-associated macrophages (TAMs) are integral to the development of complex tumor microenvironments (TMEs) and can execute disparate cellular programs in response to extracellular cues. However, upstream signaling processes underpinning this phenotypic plasticity remain to be elucidated. Here, we report that concordant AXL-STAT3 signaling in TAMs is triggered by lung cancer cells or cancer-associated fibroblasts in the cytokine milieu. This paracrine action drives TAM differentiation toward a tumor-promoting "M2-like" phenotype with upregulation of CD163 and putative mesenchymal markers, contributing to TAM heterogeneity and diverse cellular functions. One of the upregulated markers, CD44, mediated by AXL-IL-11-pSTAT3 signaling cascade, enhances macrophage ability to interact with endothelial cells and facilitate formation of primitive vascular networks. We also found that AXL-STAT3 inhibition can impede the recruitment of TAMs in a xenograft mouse model, thereby suppressing tumor growth. These findings suggest the potential application of AXL-STAT3-related markers to quantitatively assess metastatic potential and inform therapeutic strategies in lung cancer.
Assuntos
Neoplasias Pulmonares , Macrófagos Associados a Tumor , Humanos , Animais , Camundongos , Células Endoteliais , Transdução de Sinais , Diferenciação Celular , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.
Assuntos
Tumores Neuroectodérmicos Primitivos Periféricos , Sarcoma de Ewing , Humanos , Animais , Camundongos , Sarcoma de Ewing/tratamento farmacológico , Enoxacino , Benzamidas , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Modelos Animais de Doenças , Proteína Supressora de Tumor p53RESUMO
Purpose: The purpose of this study was to assess the knowledge, attitude, and training of pediatric dental residents and faculty on the management of patients who belong to the LGBTQ (lesbian, gay, bisexual, transgender, and queer) community. Methods: This cross-sectional survey included a 16-item questionnaire to assess the attitudes and training regarding the LGBTQ population, separately for pediatric dental residents and faculty across the United States. Statistical significance was set at the level of five percent, and data were analyzed using descriptive statistics, Wilcoxon rank-sum, and Fisher's exact tests. Results: In total, 132 residents and 40 faculty members completed the survey (response rates equal 14.4 percent and 16.9 percent, respectively). Residents were significantly more likely to respond that requiring LGBTQ training should be in the curriculum and that they have acquired skills to provide equal service to both LGBTQ and non-LGBTQ patients and families (faculty equals 35 percent, residents equals 57.6 percent; P<0.001). Residents were significantly more likely than faculty to respond that the American Academy of Pediatric Dentistry should publish an exclusive policy statement regarding LGBTQ oral health disparities (faculty equals 40 percent, residents equal 62.1 percent; P=0.01). Conclusions: The resident and faculty of pediatric dentistry programs in the United States have adequate awareness of managing lesbian, gay, bisexual, transgender, and queer (LGBTQ) patients in the dental office and are willing to treat these patients, and most respondents have an interest in further education.
Assuntos
Docentes , Odontopediatria , Feminino , Humanos , Estados Unidos , Criança , Estudos Transversais , Atitude , Inquéritos e QuestionáriosRESUMO
BACKGROUND/AIMS: The effect of pregnancy on gastric emptying has not been established, although the predominant clinical assumption is that gastric emptying is delayed during pregnancy. We hypothesized that the rate of emptying of nutrients during pregnancy is not delayed, but is actually more rapid when compared to the non-pregnant state. The rate of gastric emptying is a major determinant of postprandial glucose elevations. MATERIALS AND METHODS: 24 female and 4 male Spague-Dawley rats were used. Female rats were randomly divided into two groups: eight rats for the control group and sixteen rats for the pregnant group. Using physiologic, non-traumatic nuclear medicine scintigraphy imaging methodology, the authors studied gastric emptying of a liquid mixed meal in pregnant rats and non-pregnant controls. Body weights, daily food ingestion, and the rate of nutrient gastric emptying were recorded in both groups at pre-pregnancy, early pregnancy, and late pregnancy. RESULTS: The authors found that pregnancy in this rat model is associated with a 37-43% increased rate of nutrient gastric emptying from the stomach in late pregnancy as compared to non-pregnant control rats and pre-pregnancy rats. CONCLUSION: These findings contradict the current clinical assumption that gastric emptying is delayed in pregnancy. If further studies confirm a more rapid gastric emptying rate during human pregnancy, new therapies aimed at slowing the rate of nutrient absorption should be considered for the prevention and treatment of pregnancy-associated nausea, gestational diabetes, and other insulin-resistant pregnancy-associated states such as pre-eclampsia.
Assuntos
Diabetes Gestacional , Êmese Gravídica , Humanos , Animais , Ratos , Feminino , Masculino , Gravidez , Esvaziamento Gástrico , Peso Corporal , Cistografia , GlucoseRESUMO
OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) is an increasingly utilized procedure in pediatric populations. A lack of dedicated pediatric research has led endoscopists to extrapolate adult risk factors and preventative strategies to children. The aim of this multisite, retrospective study was to identify risks for adverse events, procedure failure, and prolonged courses in pediatric patients undergoing ERCP. METHODS: Pediatric patients who had an ERCP at one of our academic centers were identified by query of their electronic medical records. Pre-procedure and post-procedure data were collected with ERCP-related adverse events defined according to the consensus criteria developed by Cotton et al 2010. RESULTS: Between January 2004 and January 2021, 287 children had a total of 716 ERCPs. The procedure success rate was 95.5% with no mortality and an adverse event rate of 12.7%. Younger age was associated with increased case complexity, increased adverse events, and an increased rate of repeat ERCP. Case complexity score correlated with increased procedure time ( P < 0.001) and increased adverse events (tau 0.24, P < 0.01); stent removal and pancreatic stenting were more likely to precede an adverse event. Pancreatitis, pancreatic divisum, and pancreatic stricture/stenosis were associated with increased adverse events and rates of repeat ERCP. CONCLUSIONS: Pediatric ERCP adverse event rates are higher than adults. The complexity grading system proposed by the Cotton et al appears to have applicability to pediatric patients. Young age and interventions affecting the pancreatic duct are associated with adverse ERCP outcomes in pediatrics.
Assuntos
Pancreatite , Pediatria , Adulto , Humanos , Criança , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Colangiopancreatografia Retrógrada Endoscópica/métodos , Estudos Retrospectivos , Pancreatite/epidemiologia , Pancreatite/etiologia , PâncreasRESUMO
BACKGROUND: Androgen deprivation therapy (ADT) can lead to metabolic syndrome (MS) and is implicated in ADT-resistance. Metformin showed antineoplastic activity through mTOR inhibition secondary AMPK-activation. MATERIALS AND METHODS: To investigate whether metformin mitigated ADT-related MS, we conducted a randomized double-blind phase II trial of metformin 500 mg TID or placebo in non-diabetic patients with biochemically-relapsed or advanced PC due for ADT. Fasting serum glucose, insulin, PSA, metformin, weight and waist circumference (WC) were measured at baseline, week 12 and 28. The primary endpoint was a group of MS metrics. Secondary endpoints include PSA response, safety, serum metformin concentrations and analysis of downstream an mTOR target, phospho-S6-kinase. RESULTS: 36 men were randomized to either metformin or placebo. Mean age was 68.4. Mean weight, WC and insulin levels increased in both arms. At week 12 and 28, no statistical differences in weight, WC or insulin were observed in either arm. No significant difference in percentage of patients with PSA <0.2 at week 28 between metformin (45.5%) vs. placebo (46.7%). Analysis in the metformin-arm showed variable down-regulation of phospho-S6 kinase. CONCLUSIONS: In our small study, metformin added to ADT did not show a reduced risk of ADT-related MS or differences in PSA response.
Assuntos
Insulinas , Síndrome Metabólica , Metformina , Neoplasias da Próstata , Masculino , Humanos , Idoso , Neoplasias da Próstata/terapia , Antagonistas de Androgênios/efeitos adversos , Metformina/efeitos adversos , Androgênios , Antígeno Prostático Específico , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/prevenção & controle , Síndrome Metabólica/tratamento farmacológico , Insulinas/uso terapêuticoRESUMO
PURPOSE: Glioblastoma represents the most common primary brain tumor. Although antiangiogenics are used in the recurrent setting, they do not prolong survival. Glioblastoma is known to upregulate fatty acid synthase (FASN) to facilitate lipid biosynthesis. TVB-2640, a FASN inhibitor, impairs this activity. PATIENTS AND METHODS: We conducted a prospective, single-center, open-label, unblinded, phase II study of TVB-2640 plus bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomly assigned to TVB-2640 (100 mg/m2 oral daily) plus bevacizumab (10 mg/kg i.v., D1 and D15) or bevacizumab monotherapy for cycle 1 only (28 days) for biomarker analysis. Thereafter, all patients received TVB-2640 plus bevacizumab until treatment-related toxicity or progressive disease (PD). The primary endpoint was progression-free survival (PFS). RESULTS: A total of 25 patients were enrolled. The most frequently reported adverse events (AE) were palmar-plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue, and skin infection. Most were grade 1 or 2 in intensity. The overall response rate (ORR) for TVB-2640 plus bevacizumab was 56% (complete response, 17%; partial response, 39%). PFS6 for TVB-2640 plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB 16%; P = 0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log-rank test (P = 0.56). CONCLUSIONS: In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was found to be a well-tolerated oral drug that could be safely combined with bevacizumab. The favorable safety profile and response signals support the initiation of a larger multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.
Assuntos
Glioblastoma , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/efeitos adversos , Doença Crônica , Intervalo Livre de Doença , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estudos Prospectivos , RecidivaRESUMO
We reviewed published manuscripts from toxicology and epidemiology reporting harmful health effects and doses of persistent organic pollutants (POPs), published between 2000 and 2021. We found 42 in vitro, 32 in vivo, and 74 epidemiological studies and abstracted the dose associated with harm in a common Molar unit. We hypothesized that the dose associated with harm would vary between animal and human studies. To test this hypothesis, for each of several POPs, we assessed the significance of variation in the dose associated with a harmful effect [categorized as non-thyroid endocrine (NTE), developmental neurotoxicity (DNT), and Thyroid] with study type (in vitro, in vivo, and Epidemiology) using a linear model after adjustment for basis (lipid weight, wet weight). We created a Calculated Safety Factor (CSF) defined as the toxicology dose divided by epidemiology dose needed to exhibit significant harm. Significant differences were found between study types ranging from <1 to 5.0 orders of magnitude in the dose associated with harm. Our CSFs in lipid weight varied from 12.4 (95% confidence interval (CI) 3.3, 47) for NTE effects in Epidemiology relative to in vivo studies to 6,244 (95% CI 2510, 15530) for DNT effects in Epidemiology relative to in vitro in wet weight representing 12.4 to 6.2 thousand-fold more sensitivity in people relative to animals, and mechanistic models, respectively. In lipid weight, all CSF 95% CI lower bounds across effect categories were less than 6.5. CIs for CSFs ranged from less than one to four orders of magnitude for in vivo, and two to five orders of magnitude for in vitro vs. Epidemiology. A global CSF for all Epidemiology vs. all Toxicology was 104.6 (95% CI 72 to 152), significant at p<0.001.
Assuntos
Poluentes Ambientais , Poluentes Orgânicos Persistentes , Animais , Humanos , Poluentes Ambientais/toxicidade , Glândula Tireoide , LipídeosRESUMO
Objectives: The purpose of this study was to determine the impact of progressively increasing continuous positive airway pressure (CPAP) on measurements of the caval index (CI) using bedside ultrasound at the 3 common inferior vena cava (IVC) evaluation sites. Methods: This was a prospective, observational trial that included 165 healthy adults over 18 years old enrolled between February 2015 and May 2018. Measurements of the IVC were obtained during normal tidal respirations from the subxiphoid area in the long and short axis and from the right mid-axillary line in the long axis. Measurements were obtained in each of these locations at atmospheric pressure and with CPAP at 5, 10, and 15 cmH2O. The CI was then calculated for each of the 3 selected locations at each level of pressure. Results: As CPAP pressures increased from 0 to 15 cmH2O the CI measurements obtained at the lateral mid-axillary line did not show any statistically significant variation. There was a statistically significant difference (P < 0.001) when comparing measurements of the CI from the lateral mid-axillary line location to both anterior locations. As CPAP pressures increased, the CI calculated from the subxiphoid area in both the anterior short and anterior long axis orientations initially trended upwards at 5 cmH2O, then began to downtrend as the pressures increased to 10 and 15 cmH2O. Comparing the CI measurements from the anterior long and anterior short axis at 0, 5, 10, and 15 cmH2O, there was no statistically significant difference at any pressure (P > 0.05). Conclusion: When evaluating the IVC in a spontaneously breathing patient, measurements from an anterior orientation are preferred as the lateral mid-axillary view can underestimate CI calculations.