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BACKGROUND & AIMS: Significant geographic variability in gastrointestinal (GI) cancer-related death has been reported in the United States. We aimed to evaluate both modifiable and nonmodifiable factors associated with intercounty differences in mortality due to GI cancer. METHODS: Data from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research platform were used to calculate county-level mortality from esophageal, gastric, pancreatic, and colorectal cancers. Multivariable linear regression models were fit to adjust for county-level covariables, considering both patient (eg, sex, race, obesity, diabetes, alcohol, and smoking) and structural factors (eg, specialist density, poverty, insurance prevalence, and colon cancer screening prevalence). Intercounty variability in GI cancer-related mortality explained by these covariables was expressed as the multivariable model R2. RESULTS: There were significant geographic disparities in GI cancer-related county-level mortality across the US from 2010-2019 with the ratio of mortality between 90th and 10th percentile counties ranging from 1.5 (pancreatic) to 2.1 (gastric cancer). Counties with the highest 5% mortality rates for gastric, pancreatic, and colorectal cancer were primarily in the Southeastern United States. Multivariable models explained 43%, 61%, 14%, and 39% of the intercounty variability in mortality rates for esophageal, gastric, pancreatic, and colorectal cancer, respectively. Cigarette smoking and rural residence (independent of specialist density) were most strongly associated with GI cancer-related mortality. CONCLUSIONS: Both patient and structural factors contribute to significant geographic differences in mortality from GI cancers. Our findings support continued public health efforts to reduce smoking use and improve care for rural patients, which may contribute to a reduction in disparities in GI cancer-related death.
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Neoplasias del Colon , Neoplasias Gastrointestinales , Detección Precoz del Cáncer , Humanos , Modelos Lineales , Población Rural , Estados Unidos/epidemiologíaRESUMEN
A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.
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Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 14/genética , Facies , Femenino , Haploinsuficiencia/genética , Heterocigoto , Humanos , Discapacidad Intelectual/fisiopatología , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatología , Trastornos del Neurodesarrollo/patologíaRESUMEN
BACKGROUND: Goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. We examined prognostic clinical and treatment factors in a population-based cohort. METHODS: Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive. RESULTS: Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25-91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I-III patients, and measuring 16.2 months [95% confidence interval (CI) 9.1-29] for stage IV patients. In 67 stage I-III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis, p = 0.02; 45% Tang B vs. 89% Tang A, p < 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4-20.9; p = 0.015). CONCLUSIONS: In this population-based cohort, we demonstrate excellent survival outcomes in stage I-III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Apéndice/mortalidad , Tumor Carcinoide/mortalidad , Procedimientos Quirúrgicos de Citorreducción/mortalidad , Hipertermia Inducida/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Peritoneales/mortalidad , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/secundario , Adenocarcinoma Mucinoso/terapia , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/terapia , Tumor Carcinoide/secundario , Tumor Carcinoide/terapia , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/secundario , Recurrencia Local de Neoplasia/terapia , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/terapia , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Optimal management of rectal neuroendocrine tumors is not yet well defined. Various pathologic factors, particularly tumor size, have been proposed as prognostic markers. OBJECTIVE: We characterized sequential patients diagnosed with rectal neuroendocrine tumors in a population-based setting to determine whether tumor size and other pathologic markers could be useful in guiding locoregional management. DESIGN: This study is a retrospective analysis of data from the British Columbia provincial cancer registry. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Sequential patients diagnosed with rectal neuroendocrine tumors between 1999 and 2011 were identified. Neuroendocrine tumors were classified as G1 and G2 tumors with a Ki-67 ≤20% and/or mitotic count ≤20 per high-power field. MAIN OUTCOME MEASURES: Baseline clinicopathologic data including TNM staging, depth of invasion, tumor size, treatment modalities, and outcomes including survival data were measured. RESULTS: Of 91 rectal neuroendocrine tumors, the median patient age was 58 years, and 35 were men. Median tumor size was 6 mm. Median length of follow-up was 58.1 months, with 3 patients presenting with stage IV disease. Treatment included local ablation (n = 5), local excision (n = 79), surgical resection (n = 4), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 cases. Local relapse occurred in 8 cases and 1 relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and Ki-67, mitotic count, grade, and lymphovascular invasion (p < 0.01). Larger tumor size was associated with decreased disease-free survival. LIMITATIONS: Sample size was 91 patients in the whole provincial population over a 13-year time period because of the low incidence of rectal neuroendocrine tumors. CONCLUSIONS: In this population-based cohort, rectal neuroendocrine tumors generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. Pathologic markers play a role in risk stratification and prognostication. See Video Abstract at http://links.lww.com/DCR/A514.
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Recurrencia Local de Neoplasia/patología , Tumores Neuroendocrinos/patología , Neoplasias del Recto/patología , Recto/patología , Anciano , Colombia Británica/epidemiología , Supervivencia sin Enfermedad , Femenino , Humanos , Antígeno Ki-67/metabolismo , Masculino , Márgenes de Escisión , Persona de Mediana Edad , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Tumores Neuroendocrinos/mortalidad , Tumores Neuroendocrinos/radioterapia , Tumores Neuroendocrinos/cirugía , Pronóstico , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Recto/cirugía , Estudios RetrospectivosRESUMEN
Enzalutamide, an androgen receptor signaling inhibitor, is a standard of care treatment for metastatic castration-resistant prostate cancer. We present the first reported case of enzalutamide in a patient with end-stage renal disease, on dialysis. While there were no significant toxicities, a sustained increase in systolic blood pressure was maintained after starting enzalutamide, suggestive of a degree of drug accumulation. Further evaluation of novel hormonal agents in end-stage renal disease patients should be encouraged as this population is typically excluded from clinical trials.
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Antineoplásicos/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Benzamidas , Presión Sanguínea/efectos de los fármacos , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Masculino , Nitrilos , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/complicaciones , Diálisis RenalRESUMEN
Iron overload (IOL) portends inferior outcome in myelodysplastic syndromes (MDS). Erythropoiesis-stimulating agents (ESA) may reduce red blood cell transfusion requirements. MDS patients receiving ESA were reviewed for characteristics, response to ESA by International Working Group 2006 criteria and ferritin levels. Forty-nine patients received an ESA, had ferritin levels available, and were not receiving iron chelation therapy. Baseline characteristics were not significantly different between ESA responders (ER) and non-responders (ENR; P = NS). The median ESA treatment duration was 6.7 (1.5-85.9) months. Twenty-one (43 %) patients had an ESA response. Median ferritin level in ER was pre-ESA, 473 (range 91-2727) and post-ESA, 801 (130-11,164) ng/mL (P = 0.01), and in ENR pre-ESA, 672 (76-3285) and post-ESA, 1423 (431-6593) ng/mL (P < 0.0001). There was a significant association between ESA response, post-ESA hemoglobin ≥100 g/L, and post-ESA ferritin <1000 ng/mL (P = 0.0003 and 0.03, respectively). At a median follow-up of 28 months, the 2-year overall survival for ER and ENR, respectively, were 80 % and 86 % (P = NS). In lower-risk MDS patients responding to ESA, although an expected decrease in ferritin levels over treatment was not seen, ferritin levels increased less than in non-responders. Whether IOL may be reduced by ESA over a longer treatment duration may require analysis of larger numbers of patients.
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Hematínicos/uso terapéutico , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/tratamiento farmacológico , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Eritropoyesis/efectos de los fármacos , Eritropoyesis/fisiología , Femenino , Estudios de Seguimiento , Hematínicos/farmacología , Humanos , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/epidemiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Interprofessional collaboration is integral to effective patient care in today's healthcare system. Early exposure to other professions in a hands-on manner during education can be helpful for future practice. However, opportunities for interprofessional education are typically faculty driven and remain limited. Thirty-eight students from different health professions at the University of British Columbia worked collaboratively to promote cardiovascular risk reduction in Vancouver's Downtown Eastside. Student attitudes toward interprofessionalism were assessed using the Interdisciplinary Education Perception Scale (IEPS). While 38 participants (55%) completed the survey prior to participation in this initiative, only 21 individuals completed the follow-up survey After participation, there were significant improvements in the competency and autonomy (p = 0.02) and perception of actual cooperation (p = 0.04). Students did not report any difference in their perceived need for cooperation after participation in the initiative. These results suggest that student-led community service initiatives can be an effective method for interprofessional education amongst health professional students.
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Actitud del Personal de Salud , Conducta Cooperativa , Personal de Salud/educación , Relaciones Interprofesionales , Estudiantes del Área de la Salud/psicología , Colombia Británica , Curriculum , Femenino , Humanos , Masculino , Rol ProfesionalRESUMEN
BACKGROUND: Fentanyl-detected illicit drug overdose deaths in British Columbia (BC) recently increased dramatically from 13 deaths in 2012 to 90 deaths in 2014, signaling an emerging public health concern. Illicit fentanyl is sold as pills or powders, often mixed with other substances like heroin or oxycodone; reports from coroners suggested that fentanyl was frequently taken unknowingly by people who use drugs. This study aimed to assess the prevalence and characteristics of fentanyl use among clients accessing harm reduction (HR) services in BC. METHODS: Participants attending HR services at 17 sites across BC were invited to complete an anonymous questionnaire describing drugs they have used within the last 3 days and provide a urine sample to test for fentanyl. Data from eligible participants were analyzed using descriptive, bivariate, and multivariate statistical methods. RESULTS: Surveys from 17 HR sites were received, resulting in analysis of responses from 242 eligible participants. Most participants used multiple substances (median = 3), with crystal meth (59%) and heroin (52%) use most frequently reported. Seventy participants (29%) tested positive for fentanyl, 73% of whom did not report using fentanyl. Controlling for age, gender, and health authority, reported use of fentanyl (odds ratio (OR) = 6.13, 95% confidence interval (CI) = [2.52, 15.78], p < 0.001) and crystal methamphetamine (OR = 3.82, 95% CI = [1.79, 8.63], p < 0.001) use were significantly associated with fentanyl detection. CONCLUSIONS: The proportion of those testing positive who did not report knowingly using fentanyl represents a considerable public health concern. The risk of overdose among this vulnerable population highlights the need for targeted HR strategies, such as increased accessibility to naloxone, overdose education, and urine screens.
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Fentanilo/orina , Narcóticos/orina , Detección de Abuso de Sustancias/métodos , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/orina , Adulto , Colombia Británica , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Encuestas y Cuestionarios , Adulto JovenRESUMEN
PURPOSE: Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency. METHODS: This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m2 intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m2 once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m2 once every 3 weeks. RESULTS: Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m2 once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with ATM mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a PALB2 mutation (primary peritoneal cancer). CONCLUSION: Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.
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Indoles , Irinotecán , Neoplasias , Humanos , Persona de Mediana Edad , Femenino , Masculino , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Indoles/uso terapéutico , Indoles/administración & dosificación , Indoles/efectos adversos , Anciano , Adulto , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Mutación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína BRCA2/genética , Proteína BRCA1/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Recombinación Homóloga , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can 'open' chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. METHODS: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). FINDINGS: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR <0.05). Cellular proteomics also identified immune dysregulation and increased abundance of other lysine modification and histone binding proteins, representing a potential compensatory mechanism. A 12-year-old boy with KS, suffering from recurrent episodes of cognitive decline, exhibited improved cognitive function and neuropsychological assessment performance after 12 months on the ketogenic diet, with concomitant improvement in transcriptomic ribosomal protein dysregulation. INTERPRETATION: Our data reveals that lysine methyltransferase deficiency is associated with ribosomal protein dysfunction, with secondary immune dysregulation. Diet and the production of bioactive molecules such as ketone bodies serve as a significant environmental factor that can induce epigenetic changes and improve clinical outcomes. Integrating transcriptomic, proteomic, and clinical data can define mechanisms of disease and treatment effects in individuals with neurodevelopmental disorders. FUNDING: This study was supported by the Dale NHMRC Investigator Grant (APP1193648) (R.D), Petre Foundation (R.D), and The Sydney Children's Hospital Foundation/Kids Research Early and Mid-Career Researcher Grant (E.T).
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Proteínas de Unión al ADN , Dieta Cetogénica , Cara , Enfermedades Hematológicas , Proteómica , Proteínas Ribosómicas , Enfermedades Vestibulares , Enfermedades Vestibulares/genética , Enfermedades Vestibulares/metabolismo , Enfermedades Vestibulares/dietoterapia , Humanos , Cara/anomalías , Masculino , Enfermedades Hematológicas/metabolismo , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/etiología , Enfermedades Hematológicas/dietoterapia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Niño , Proteómica/métodos , Femenino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regulación de la Expresión Génica , Mutación , Transcriptoma , Anomalías MúltiplesRESUMEN
People with neurofibromatosis 1 (NF1) have low bone mineralization, but the natural history and pathogenesis are poorly understood. We performed a sibling-matched case-control study of bone mineral status, morphology, and metabolism. Eighteen children with NF1 without focal bony lesions were compared to unaffected siblings and local population controls. Bone mineral content at the lumbar spine and proximal femur (dual energy X-ray absorptiometry (DXA)) was lower in children with NF1; this difference persisted after adjusting for height and weight. Peripheral quantitative computed tomography (pQCT) of the distal tibia showed that trabecular density was more severely compromised than cortical. Peripheral QCT-derived estimates of bone strength and resistance to bending and stress were poorer among children with NF1 although there was no difference in fracture frequencies. There were no differences in the size or shape of bones after adjusting for height. Differences in markers of bone turnover between cases and controls were in the directions predicted by animal studies, but did not reach statistical significance. Average serum calcium concentration was higher (although within the normal range) in children with NF1; serum 25-OH vitamin D, and PTH levels did not differ significantly between cases and controls. Children with NF1 were less mature (assessed by pubertal stage) than unaffected siblings or population controls. Children with NF1 have a generalized difference of bone metabolism that predominantly affects trabecular bone. Effects of decreased neurofibromin on bone turnover, calcium homeostasis, and pubertal development may contribute to the differences in bone mineral content observed among people with NF1.
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Huesos/fisiopatología , Neurofibromatosis 1/fisiopatología , Absorciometría de Fotón , Adolescente , Biomarcadores/sangre , Biomarcadores/orina , Densidad Ósea , Calcio/sangre , Estudios de Casos y Controles , Niño , Femenino , Fémur/diagnóstico por imagen , Humanos , Vértebras Lumbares/diagnóstico por imagen , Masculino , Neurofibromatosis 1/diagnóstico por imagen , Neurofibromatosis 1/metabolismo , Fenotipo , Valores de Referencia , Análisis de Regresión , Hermanos , Tomografía Computarizada por Rayos X , Vitamina D/análogos & derivados , Vitamina D/sangre , Adulto JovenRESUMEN
In this issue of Cancer Cell, Topp et al. analyze data from 799 patients treated with pembrolizumab beyond progression by RECIST 1.1 across six trials. Although 8.9%-24.4% of patients demonstrate a ≥30% reduction in target lesions, conversely 11%-18% of patients had a ≥20% increase. The benefits of treatment beyond progression must be carefully weighed against physical and financial toxicities.
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Progresión de la Enfermedad , Neoplasias , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
A recent article analyzed paired cell-free DNA among patients with platinum-sensitive BRCA- or PALB2-mutated pancreatic cancer who received maintenance olaparib. Reversion mutations were linked with worse outcomes. These types of paired correlative studies are needed to improve our understanding of drug resistance and guide future clinical trials. See related article by Brown et al., p. 5207.
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Antineoplásicos , Neoplasias Ováricas , Neoplasias Pancreáticas , Femenino , Humanos , Antineoplásicos/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias Ováricas/genética , Proteína BRCA2/genética , Ftalazinas/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genéticaRESUMEN
There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI (n = 154) or thoracic (n = 69) malignancies. TTPp was associated with SBS3 (p < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with gBRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1, was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression (p ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy.
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[Bonnet et al. (2010); J Med Genet 47: 377-384] recently suggested a 4q21 microdeletion syndrome with several common features, including severe intellectual disability, lack of speech, hypotonia, significant growth restriction, and distinctive facial features. Overlap of the deleted regions of 13 patients, including a patient we previously reported, delineates a critical region, with PRKG2 and RASGEF1B emerging as candidate genes. Here we provide a detailed clinical report and photographic life history of our previously reported patient. Previous case reports of this new syndrome have not described the prognosis or natural history of these patients.
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Deleción Cromosómica , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 4/genética , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Adulto , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Resultado Fatal , Femenino , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Fenotipo , Síndrome , Adulto JovenRESUMEN
RAD51 is integral in homologous recombination DNA damage repair and has garnered much interest as both a biomarker and potential therapeutic target in oncology. Multiple in vitro and in vivo studies have demonstrated its role as a predictive marker, particularly in the context of platinum-based therapies and poly ADP-ribose polymerase (PARP) inhibitors. In this review, we highlight the development of RAD51 inhibitors, with a focus on novel molecules and ongoing clinical trials. Despite many efforts to develop effective and tolerable direct RAD51 inhibitors, identification of these agents remains challenging. Clinically, however, there may be a role of pharmacological indirect RAD51 inhibition.
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The 2017 National Inpatient Sample database was utilized to investigate the association between cannabis legalization in the United States and hospitalizations for psychosis associated with cannabis use. We compared the odds of hospital discharges for psychosis associated with cannabis use in adults between the Pacific census division (where most states legalized recreational cannabis use) and other divisions using multivariable logistic regression, adjusting for confounders. We calculated a score for each census division representing cannabis legality as the population-weighted sum of state scores: 1=illegal or cannabidiol/low potency cannabis; 2= medical marijuana; and 3=recreational and medical marijuana legalized. Pearson's correlation coefficients (r) quantified the relationship between scores and the proportion of hospitalizations with psychosis associated with cannabis. In 2017, there were an estimated 129,070 hospital discharges for psychosis associated with cannabis use. The Pacific census division had significantly higher odds of discharges than other divisions (adjusted odds ratio 1.55; 95% confidence interval 1.25 - 1.93). There was a significant correlation between the cannabis legality score and proportion of hospital discharges for psychosis associated with cannabis use (r = 0.67, p<0.05). In conclusion, we observed a higher proportion of hospital discharges for psychosis associated with cannabis use in areas with more liberal cannabis legalization laws.
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Cannabis , Alucinógenos , Marihuana Medicinal , Psiquiatría , Trastornos Psicóticos , Adulto , Agonistas de Receptores de Cannabinoides , Cannabis/efectos adversos , Hospitalización , Humanos , Trastornos Psicóticos/epidemiología , Estados Unidos/epidemiologíaRESUMEN
The PI3K pathway may be a potential mechanism to overcome cisplatin resistance. We conducted a phase Ib trial of alpelisib and cisplatin for patients with solid tumor malignancies with planned dose expansion in HPV-associated tumors. The primary objective was to determine the MTD and recommended phase II dose. Two different weekly doses of cisplatin (30 and 35 mg/m2) were evaluated with escalating doses of alpelisib, administered daily during a 21-day treatment cycle. Twenty-three patients were enrolled: 91% received >3 prior regimens with median of 4 (range 1-10), and 78% progressed on prior platinum. The MTD was alpelisib 250 mg daily with weekly cisplatin 30 mg/m2. There were 3 DLTs: all grade 4 hyperglycemia. Frequent treatment-related adverse events of any grade included fatigue (52%), diarrhea (39%), nausea (38%), hyperglycemia (30%), anemia (22%), and nephropathy (17%). Hyperglycemia was linked to baseline hemoglobin A1C, but not body mass index. Twelve patients discontinued treatment for toxicity (n = 9 during cycle 1) and 11 discontinued for progression. Of 14 evaluable patients who received at least one treatment cycle, 4 (29%) patients demonstrated partial response, and 7 had stable disease for a disease control rate of 79%. The median PFS measured 4.3 months (95% CI, 1.6-4.5). No difference in PFS was observed between PIK3CA-mutated and wild-type tumors. While the combination of alpelisib and cisplatin demonstrated preliminary evidence of activity despite platinum resistance, toxicities hindered prolonged treatment. Prospective studies are planned using carboplatin and alpelisib to improve toxicity and tolerability. Significance: The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.
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Cisplatino , Neoplasias , Humanos , Cisplatino/efectos adversos , Fosfatidilinositol 3-Quinasas/metabolismo , Estudios Prospectivos , Neoplasias/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3RESUMEN
BACKGROUND: Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations. METHODS: A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3-3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3-3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1-2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8-2.5 yrs). FINDINGS: There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p<0.0001). In addition, the kynurenic acid/kynurenine (KYNA/KYN) ratio was lower in the epileptic spasms subgroup compared to OND (p<0.0001). Epileptic spasms patients who were steroid responders or partial steroid responders had lower KYNA/KYN ratio compared to patients who were refractory to steroids (p<0.005, p<0.05 respectively). INTERPRETATION: This study demonstrates decreased CSF kynurenic acid and KYNA/KYN in epileptic spasms, which may also represent a biomarker for steroid responsiveness. Given the anti-inflammatory and neuroprotective properties of kynurenic acid, further therapeutics able to increase kynurenic acid should be explored. FUNDING: Financial support for the study was granted by Dale NHMRC Investigator grant APP1193648, Petre Foundation, Cerebral Palsy Alliance and Department of Biochemistry at the Children's Hospital at Westmead. Prof Guillemin is funded by NHMRC Investigator grant APP1176660 and Macquarie University.