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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Mastectomia Segmentar , Humanos , Neoplasias da Mama/cirurgia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/patologia , Feminino , Mastectomia Segmentar/métodos , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/radioterapia , Prognóstico , Tomada de Decisões , Biomarcadores Tumorais/genética , Tomada de Decisão Clínica , Radioterapia AdjuvanteRESUMO
Balamuthia mandrillaris is an amoeba that causes an uncommon but deadly encephalitis, referred to as granulomatous amoebic encephalitis (GAE). The highest incidence reported worldwide has occurred in America, and within the United States, it has been highest in the Southwest affecting predominantly children and young men of Hispanic ethnicity. Clinical presentation of GAE includes fever, headache, nausea, vomiting, lethargy, irritability, stiff neck, hallucinations, photophobia, and seizures. Our patient was a Hispanic male child living in Arizona. The patient presented at 3 years of age for severe encephalitis. Symptoms included difficulty with balance, gait, and sitting up and seizure-like activity. Initial CT showed an area of decreased density consistent with edema in the right frontal and left frontoparietal lobes. Rapid progression was seen on further imaging over the length of the patient's hospital stay revealing diffusion restriction, necrosis/blood products, edema, and hemorrhage. The patient expired three weeks after onset of symptoms and one week after admission to our institution. While there are multiple biochemical techniques that can test for B. mandrillaris, they are rarely employed for multiple reasons stemming from the rare occurrence of this infection. Because of the fatal nature of this infection, we propose (1) testing should be considered if a patient presents with progressing encephalitis on imaging and other pathogenic etiologies are ruled out and (2) the threshold to treat empirically should be low due to the fatal nature of the infection.
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BACKGROUND: Breast-conserving surgery (BCS) followed by adjuvant radiotherapy (RT) is a standard treatment for ductal carcinoma in situ (DCIS). A low-risk patient subset that does not benefit from RT has not yet been clearly identified. The DCISionRT test provides a clinically validated decision score (DS), which is prognostic of 10-year in-breast recurrence rates (invasive and non-invasive) and is also predictive of RT benefit. This analysis presents final outcomes from the PREDICT prospective registry trial aiming to determine how often the DCISionRT test changes radiation treatment recommendations. METHODS: Overall, 2496 patients were enrolled from February 2018 to January 2022 at 63 academic and community practice sites and received DCISionRT as part of their care plan. Treating physicians reported their treatment recommendations pre- and post-test as well as the patient's preference. The primary endpoint was to identify the percentage of patients where testing led to a change in RT recommendation. The impact of the test on RT treatment recommendation was physician specialty, treatment settings, individual clinical/pathological features and RTOG 9804 like criteria. Multivariate logisitc regression analysis was used to estimate the odds ratio (ORs) for factors associated with the post-test RT recommendations. RESULTS: RT recommendation changed 38% of women, resulting in a 20% decrease in the overall recommendation of RT (p < 0.001). Of those women initially recommended no RT (n = 583), 31% were recommended RT post-test. The recommendation for RT post-test increased with increasing DS, from 29% to 66% to 91% for DS <2, DS 2-4, and DS >4, respectively. On multivariable analysis, DS had the strongest influence on final RT recommendation (odds ratio 22.2, 95% confidence interval 16.3-30.7), which was eightfold greater than clinicopathologic features. Furthermore, there was an overall change in the recommendation to receive RT in 42% of those patients meeting RTOG 9804-like low-risk criteria. CONCLUSIONS: The test results provided information that changes treatment recommendations both for and against RT use in large population of women with DCIS treated in a variety of clinical settings. Overall, clinicians changed their recommendations to include or omit RT for 38% of women based on the test results. Based on published clinical validations and the results from current study, DCISionRT may aid in preventing the over- and undertreatment of clinicopathological 'low-risk' and 'high-risk' DCIS patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03448926 ( https://clinicaltrials.gov/study/NCT03448926 ).
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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Mastectomia Segmentar , Humanos , Feminino , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/radioterapia , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Pessoa de Meia-Idade , Radioterapia Adjuvante , Prognóstico , Estudos Prospectivos , Idoso , Seguimentos , Recidiva Local de Neoplasia/patologia , Tomada de Decisão Clínica , Adulto , Tomada de Decisões , Biomarcadores TumoraisRESUMO
Background: Varicella zoster virus (VZV) has been associated with focal cerebral arteriopathy (FCA) and arterial ischemic stroke (AIS) in childhood. The Vascular effects of Infection in Pediatric Stroke (VIPS) II study aimed to examine this relationship in the modern era when most children in North America and Australia receive VZV vaccination with live, attenuated virus. Methods: This 22-center prospective cohort study enrolled 205 children (28 days-18 years) with AIS (2017-2022), collected baseline [hyperacute (≤72 hours; n=194) and acute (4-6 days; n=181)] and convalescent (1-6 weeks; n=74) serum samples. Sites enrolled 95 stroke-free controls with single serum samples. A virology research laboratory measured VZV IgM and IgG titers by an in-house enzyme-linked immunosorbent assay (ELISA). Baseline IgG seropositivity indicated prior exposure (vaccination/infection) and elevated IgM titers indicated recent reactivation. Results: Median (IQR) age was 11.6 (5.5-15.6) years for cases and 11.8 (6.8-15.3) years for controls. Baseline serologies indicated prior VZV exposure in 198 cases (97%) and all controls. Parents of cases reported VZV vaccination in 160 (78%) and remote chicken pox in three (1.4%). Twenty cases (9.8%) and three controls (3.1%) had serologic evidence of recent VZV reactivation (p=0.06); all had remote VZV exposure (vaccination in 19 cases and all controls) and all were asymptomatic. Recent VZV reactivation was seen in similar proportions in arteriopathic, cardioembolic, and idiopathic stroke. Of 32 cases of FCA, 4 (12.5%) had recent VZV reactivation, versus no cases of arterial dissection (n=10) or moyamoya (n=16). Conclusions: Serologic evidence of recent VZV reactivation (≈1-6 weeks prior to stroke) was present in one in 10 cases of childhood AIS, including those without arteriopathy. Clinically silent VZV reactivation may be a childhood stroke trigger despite widespread vaccination. These cases could represent waning immunity with reactivation of either vaccine virus or wild-type virus after an unrecognized secondary VZV infection.
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OBJECTIVE: This study aims to assess the role of continuous EEG (cEEG) background patterns and duration of cross-clamp time and cardiopulmonary bypass (CPB) in children with congenital heart disease (CHD) undergoing cardiac surgery and its correlation with abnormal neurodevelopmental outcomes at 12-24 months on Bayley Scales of Infant and Toddler Development (BSID-III). METHODS: This retrospective cohort study included infants with CHD and cEEG monitoring, who underwent surgery by 44 weeks gestational age. RESULTS: 34 patients were included, who were operated at median age - 7 days. Longer duration of cross- camp time was associated with poor language composite scores (LCS) (p value = 0.036). A significant association existed between severity of encephalopathy in 24-hour post-operative period and poor LCS (p value = 0.026). CONCLUSION: Majority of neonates with CHD have below average cognitive, language and motor composite scores on BSID-III. Longer duration of cross-clamp time and severity of encephalopathy during 24-hour post-operative EEG monitoring are associated with poor LCS.
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OBJECTIVE: PTEN, a known tumor suppressor gene, is a mediator of neurodevelopment. Individuals with germline pathogenic variants in the PTEN gene, molecularly defined as PTEN hamartoma tumor syndrome (PHTS), experience a variety of neurological and neuropsychiatric challenges during childhood, including autism spectrum disorder (ASD). However, the frequency and nature of seizures and the utilization of allied health services have not been described. METHODS: Young patients with PHTS and sibling controls were recruited across five centers in the United States and followed every 6-12 months for a mean of 2.1 years. In addition to the history obtained from caregivers, neurodevelopmental evaluations and structured dysmorphology examinations were conducted, and brain MRI findings, received therapies, and epilepsy characteristics were reported. RESULTS: One hundred and seven patients with PHTS (median age 8.7 years; range 3-21 years) and 38 controls were enrolled. ASD and epilepsy were frequent among patients with PHTS (51% and 15%, respectively), with generalized epilepsy strongly associated with ASD. Patients with epilepsy often required two antiseizure medications. Neuroimaging revealed prominent perivascular spaces and decreased peritrigonal myelination in individuals with PHTS-ASD. Allied therapy use was frequent and involved physical, occupational, speech, and social skills therapies, with 89% of all patients with PHTS, regardless of ASD diagnosis, utilizing at least one service. INTERPRETATION: This prospective, longitudinal study highlights the wide neurological spectrum seen in young individuals with PHTS. ASD is common in PHTS, comorbid with epilepsy, and allied health services are used universally. Our findings inform care discussions with families about neurological outcomes in PHTS.
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Transtorno do Espectro Autista , Epilepsia , Mutação em Linhagem Germinativa , PTEN Fosfo-Hidrolase , Humanos , Masculino , Feminino , Adolescente , Criança , Pré-Escolar , Adulto Jovem , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Epilepsia/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Síndrome do Hamartoma Múltiplo/genéticaRESUMO
We describe prenatal diagnosis of Poland-Möbius syndrome using a combination of ultrasound and MRI. Poland syndrome was diagnosed based on absence of the pectoralis muscles associated with dextroposition of the fetal heart and elevation of the left diaphragm. Associated brain anomalies that led to the diagnosis of Poland-Möbius syndrome, included ventriculomegaly, hypoplastic cerebellum, tectal beaking, and a peculiar flattening of the posterior aspect of the pons and medulla oblongata, which has been reported by postnatal diffusion tensor imaging studies as a reliable neuroimaging marker for Möbius syndrome. Since abnormalities of cranial nerves VI and VII may be difficult to detect prenatally, careful attention to the appearance of the brain stem as illustrated in the current report may aid in the prenatal diagnosis of Möbius syndrome.
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Síndrome de Möbius , Síndrome de Poland , Feminino , Humanos , Gravidez , Imagem de Tensor de Difusão , Síndrome de Möbius/diagnóstico por imagem , Síndrome de Poland/diagnóstico por imagem , Diagnóstico Pré-NatalRESUMO
BACKGROUND: Neonates with congenital heart disease (CHD) undergoing cardiopulmonary bypass (CPB) surgery have increased risk of impaired neurodevelopmental outcomes secondary to brain injury. This study aims to characterize pre- and post-operative continuous EEG (cEEG) patterns to detect abnormal cerebral activity in infants with CHD and investigate whether an association exists between the degree of encephalopathy in pre- and post-operative cEEG. METHODS: This retrospective cohort study conducted between 2010 and 2018 at a tertiary hospital in Cleveland, OH included infants with CHD with cEEG monitoring, who underwent CPB surgery within first 6 months of life. RESULTS: Study included 77 patients, of which 61% were males who were operated at median age 6 days. Pre-operatively, 69% and 87% had normal cEEG and sleep-wake cycles, respectively. Post-operatively, 80% had abnormal cEEG. Longer circulatory arrest time and CPB were associated with lack of continuity (p 0.011), excessive discontinuity (p 0.007) and prolonged inter-burst interval (IBI) duration (p value < 0.001). A significant association existed between severity of encephalopathy in immediate and 24-h post-operative period (p value < 0.001). CONCLUSIONS: More than 80% of neonates with CHD have abnormal post-operative EEG. Longer circulatory arrest time and CPB were associated with lack of continuity, excessive discontinuity, and prolonged IBI duration on post-operative EEG. IMPACT: This study shows that majority of neonates with congenital heart disease (CHD) have normal pre-operative EEG with a continuous background and normal sleep-wake cycles. Also, 80% of neonates had abnormal post-operative EEG. Longer duration of arrest time and bypass time was associated with lack of continuity, excessive discontinuity, and prolonged IBI duration during post-operative EEG monitoring. These findings will help clinicians when counseling parents in the intensive care unit, risk stratification, and long-term neurodevelopmental monitoring in these high-risk patients.
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Lesões Encefálicas , Cardiopatias Congênitas , Masculino , Recém-Nascido , Humanos , Lactente , Feminino , Estudos Retrospectivos , Eletroencefalografia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/cirurgia , Monitorização FisiológicaRESUMO
The survival for breast cancer (BC) is improving but remains lower in Black women than White women. A number of factors potentially drive the racial differences in BC outcomes. The aim of our study was to determine if insulin resistance (defined as homeostatic model assessment for insulin resistance (HOMA-IR)), mediated part of the relationship between race and BC prognosis (defined by the improved Nottingham prognostic index (iNPI)). We performed a cross-sectional study, recruiting self-identified Black and White women with newly diagnosed primary invasive BC from 10 US hospitals between March 2013 and February 2020. Survey, anthropometric, laboratory, and tumor pathology data were gathered, and we compared the results between Black and White women. We calculated HOMA-IR as well as iNPI scores and examined the associations between HOMA-IR and iNPI. After exclusions, the final cohort was 1206: 911 (76%) White and 295 (24%) Black women. Metabolic syndrome and insulin resistance were more common in Black than White women. Black women had less lobular BC, three times more triple-negative BC, and BCs with higher stage and iNPI scores than White women (P < 0.001 for all comparisons). Fewer Black women had BC genetic testing performed. HOMA-IR mediated part of the association between race and iNPI, particularly in BCs that carried a good prognosis and were hormone receptor (HR)-positive. Higher HOMA-IR scores were associated with progesterone receptor-negative BC in White women but not Black women. Overall, our results suggest that HOMA-IR contributes to the racial disparities in BC outcomes, particularly for women with HR-positive BCs.
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Neoplasias da Mama , Resistência à Insulina , Feminino , Humanos , Neoplasias da Mama/patologia , População Branca , Negro ou Afro-Americano , Estudos Transversais , Prognóstico , Estudos de CoortesRESUMO
BACKGROUND: Advances in surgical techniques to tackle critical congenital heart diseases (CHD) have enhanced the survival rates and life expectancy of children born with heart disease. Studies to better acknowledge their neurodevelopmental trajectory have paramount implications. OBJECTIVE: The aim of this study is to examine the nature of brain MRI findings in infants born with critical congenital heart diseases needing intervention in the first 6 months of life, with the help of an MRI scoring system and correlation with long term neurodevelopmental outcomes. METHODS: Brain MRI scans of eligible infants were extracted from database, reexamined to categorize, and score them into three main functional areas: cognitive/grey matter, motor/white matter, and visual. The scoring system also included stage of myelination and presence of punctate hemorrhages. The correlation of individual and total MRI scores with neurodevelopmental assessment using Bayley Scales for Infant and Toddler Development- version 3 (BSID III) were examined via logistic regression models while controlling for confounding variables. RESULT: Median (IQR) MRI score was 6 (4-7) with grey matter score of 2 (1-4). Initial BSID III scores were 80 ± 15, 80 ± 18, and 81 ± 19 for cognitive, motor and language components, respectively. The MRI cognitive score had direct correlation with respiratory index prior to surgery (cc = 0.47, p = 0.03) and cross-clamping time (cc = 0.65, p = 0.001). It displayed a significant inverse correlation with language scores for BSID III at 9 months (R = -0.42, p = 0.04) which lost significance in subsequent visits. CONCLUSION: This pilot study proved the feasibility of correlating structural brain abnormalities in MRI with later brain developmental deficits in infants with CHD. We envision establishing a standardized MRI scoring system to be performed on a large multi-center cohort that would help better predict and measure brain injury in infants with CHDs.
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Cardiopatias Congênitas , Transtornos do Neurodesenvolvimento , Substância Branca , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Imageamento por Ressonância Magnética/métodos , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Projetos PilotoRESUMO
BACKGROUND: Black women with breast cancer have a worse overall survival compared with White women; however, no difference in Oncotype DX™ (ODX) recurrence scores has been observed to explain this health disparity. Black women are also disproportionately affected by insulin resistance. We evaluated whether insulin resistance is associated with a higher ODX recurrence score and whether there is a difference between White and Black women to explain disparate clinical outcomes. METHODS: A subgroup analysis of patients in a multi-institutional cross-sectional study evaluating differences in insulin resistance between White and Black women was performed. Women diagnosed with a new hormone receptor-positive, HER2/neu-negative breast cancer with an ODX recurrence score were identified. Fasting blood glucose and insulin measurements were used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) score, a method for assessing insulin resistance, and compared against ODX scores. RESULTS: Overall, 412 women (358 White women, 54 Black women) were identified. Compared with White women, Black women had a higher body mass index (30 vs. 26 kg/m2, p < 0.0001), higher HOMA-IR score (2.4 vs. 1.4, p = 0.004), and more high-grade tumors (30% vs. 16%, p = 0.01). There was a direct positive association with an increasing ODX score and HOMA-IR (p = 0.014). On subset analysis, this relationship was seen in White women (p = 0.005), but not in Black women (p = 0.55). CONCLUSION: In women with newly diagnosed breast cancer, increasing insulin resistance is associated with a higher recurrence score; however, this association was not present in Black women. This lack of association may be due to the small number of Black women in the cohort, or possibly a reflection of a different biological disease process of the patient's tumor.
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Neoplasias da Mama , Resistência à Insulina , Negro ou Afro-Americano , Estudos Transversais , Feminino , Humanos , Recidiva Local de NeoplasiaRESUMO
BACKGROUND: Benign hereditary chorea (BHC) is an autosomal dominant disorder characterized by early-onset non-progressive involuntary movements. Although NKX2-1 mutations or deletions are the cause of BHC, some BHC families do not have pathogenic alterations in the NKX2-1 gene, indicating that mutations of non-coding regulatory elements of NKX2-1 may also play a role. METHODS AND RESULTS: By using whole-genome microarray analysis, we identified a 117 Kb founder deletion in three apparently unrelated BHC families that were negative for NKX2-1 sequence variants. Targeted next generation sequencing analysis confirmed the deletion and showed that it was part of a complex local genomic rearrangement. In addition, we also detected a 648 Kb de novo deletion in an isolated BHC case. Both deletions are located downstream from NKX2-1 on chromosome 14q13.2-q13.3 and share a 33 Kb smallest region of overlap with six previously reported cases. This region has no gene but contains multiple evolutionarily highly conserved non-coding sequences. CONCLUSION: We propose that the deletion of potential regulatory elements necessary for NKX2-1 expression in this critical region is responsible for BHC phenotype in these patients, and this is a novel disease-causing mechanism for BHC.
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Coreia/genética , Sequências Reguladoras de Ácido Nucleico , Fator Nuclear 1 de Tireoide/genética , Adolescente , Criança , Coreia/patologia , Cromossomos Humanos Par 14/genética , Sequência Conservada , Feminino , Humanos , Masculino , Linhagem , Deleção de SequênciaRESUMO
Purpose: To evaluate the efficacy and safety of iTEAR, a novel, portable, sonic external neuromodulation device, for the treatment of dry eye disease (DED). Methods: This was a multicenter, open-label, single-arm clinical trial that included adult patients with DED with a Schirmer score of ≤10 mm in at least one eye. Enrolled subjects were instructed to apply the study device at least twice per day for 30 seconds bilaterally to the external nasal nerve. After the initial baseline visit, patients were followed up at days 3, 14, 30, 90, and 180. The primary efficacy endpoint was the Schirmer index (change from unstimulated to stimulated tear production as measured by the Schirmer test) at day 30. The major secondary endpoint was the change in symptoms of DED at day 30 evaluated using the Ocular Surface Disease Index (OSDI). Results: A total of 101 subjects evaluated at day 30 had a mean Schirmer index of 9.4 mm (95% confidence interval [CI], 7.4-11.3), and the baseline OSDI improved by an average of 14.4 (95% CI, 11.1-17.7). Both endpoints were highly statistically and clinically significant at all time points. There were two mild unanticipated adverse events definitely related to the device. Conclusions: The safety and efficacy of the iTEAR device observed in this study support its indication for treating DED. Translational Relevance: Neurostimulation has the potential to improve signs and symptoms of DED.
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Síndromes do Olho Seco , Adulto , Método Duplo-Cego , Síndromes do Olho Seco/terapia , Humanos , LágrimasRESUMO
BACKGROUND: Racial disparities in breast cancer survival between Black and White women persist across all stages of breast cancer. The metabolic syndrome (MetS) of insulin resistance disproportionately affects more Black than White women. It has not been discerned if insulin resistance mediates the link between race and poor prognosis in breast cancer. We aimed to determine whether insulin resistance mediates in part the association between race and breast cancer prognosis, and if insulin receptor (IR) and insulin-like growth factor receptor (IGF-1R) expression differs between tumors from Black and White women. METHODS: We conducted a cross-sectional, multi-center study across ten hospitals. Self-identified Black women and White women with newly diagnosed invasive breast cancer were recruited. The primary outcome was to determine if insulin resistance, which was calculated using the homeostatic model assessment of insulin resistance (HOMA-IR), mediated the effect of race on prognosis using the multivariate linear mediation model. Demographic data, anthropometric measurements, and fasting blood were collected. Poor prognosis was defined as a Nottingham Prognostic Index (NPI) > 4.4. Breast cancer pathology specimens were evaluated for IR and IGF-1R expression by immunohistochemistry (IHC). RESULTS: Five hundred fifteen women were recruited (83% White, 17% Black). The MetS was more prevalent in Black women than in White women (40% vs 20%, p < 0.0001). HOMA-IR was higher in Black women than in White women (1.9 ± 1.2 vs 1.3 ± 1.4, p = 0.0005). Poor breast cancer prognosis was more prevalent in Black women than in White women (28% vs 15%. p = 0.004). HOMA-IR was positively associated with NPI score (r = 0.1, p = 0.02). The mediation model, adjusted for age, revealed that HOMA-IR significantly mediated the association between Black race and poor prognosis (ß = 0.04, 95% CI 0.005-0.009, p = 0.002). IR expression was higher in tumors from Black women than in those from White women (79% vs 52%, p = 0.004), and greater IR/IGF-1R ratio was also associated with higher NPI score (IR/IGF-1R > 1: 4.2 ± 0.8 vs IR/IGF-1R = 1: 3.9 ± 0.8 vs IR/IGF-1R < 1: 3.5 ± 1.0, p < 0.0001). CONCLUSIONS: In this multi-center, cross-sectional study of US women with newly diagnosed invasive breast cancer, insulin resistance is one factor mediating part of the association between race and poor prognosis in breast cancer.
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Negro ou Afro-Americano/estatística & dados numéricos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Resistência à Insulina , População Branca/estatística & dados numéricos , Neoplasias da Mama/metabolismo , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Women who present with locally advanced breast cancer that would require a mastectomy are often recommended to undergo chemotherapy prior to surgery in hopes of down-staging the tumor and allowing for breast-conserving surgery. This approach is very effective in women with triple negative and Her2neu positive locally advanced breast cancer, yet the results in ER/PR positive (luminal) breast cancers have been less effective. In post-menopausal women, neoadjuvant hormonal treatment in such cases can cause tumor regression and allow for breast-conserving therapy, in some patients. In premenopausal women with locally advanced luminal type breast cancer, neoadjuvant hormonal therapy can also be effective and is a valid option according to the NCCN guidelines. Yet, there remains a sense that perhaps treatment of this group of patients with chemotherapy results in better outcomes. For the past fifteen years various molecular profiles of luminal breast cancers have been studied and have been used to help guide decisions as to the benefit of adjuvant treatment - whether chemotherapy is necessary or hormonal therapy alone would be adequate. In the neo-adjuvant setting, these profiles can also help predict which tumors are likely to respond to chemotherapy and which are less likely to respond. The only hormonal drugs available until very recently for use in the neoadjuvant setting were either Tamoxifen or an aromatase inhibitor. In the past few years a new class of drugs, CDK4/6 inhibitors have been developed and approved and have significantly improved response rates and time to progression in patients with metastatic hormone responsive breast cancer, and they have also been studied in small trials in the neoadjuvant setting. In this article we will review the data that is available to help guide the optimal choice of treatment in women who present with locally advanced luminal breast cancers including the use of molecular profiles and the potential role of anti-CDK 4/6 drugs.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Estrogênios , Feminino , Humanos , Mastectomia , ProgesteronaRESUMO
OBJECTIVE: Pathogenic variants in KCNB1, encoding the voltage-gated potassium channel KV 2.1, are associated with developmental and epileptic encephalopathy (DEE). Previous functional studies on a limited number of KCNB1 variants indicated a range of molecular mechanisms by which variants affect channel function, including loss of voltage sensitivity, loss of ion selectivity, and reduced cell-surface expression. METHODS: We evaluated a series of 17 KCNB1 variants associated with DEE or other neurodevelopmental disorders (NDDs) to rapidly ascertain channel dysfunction using high-throughput functional assays. Specifically, we investigated the biophysical properties and cell-surface expression of variant KV 2.1 channels expressed in heterologous cells using high-throughput automated electrophysiology and immunocytochemistry-flow cytometry. RESULTS: Pathogenic variants exhibited diverse functional defects, including altered current density and shifts in the voltage dependence of activation and/or inactivation, as homotetramers or when coexpressed with wild-type KV 2.1. Quantification of protein expression also identified variants with reduced total KV 2.1 expression or deficient cell-surface expression. INTERPRETATION: Our study establishes a platform for rapid screening of KV 2.1 functional defects caused by KCNB1 variants associated with DEE and other NDDs. This will aid in establishing KCNB1 variant pathogenicity and the mechanism of dysfunction, which will enable targeted strategies for therapeutic intervention based on molecular phenotype. ANN NEUROL 2019;86:899-912.
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Variação Genética/genética , Ensaios de Triagem em Larga Escala/métodos , Transtornos do Neurodesenvolvimento/genética , Canais de Potássio Shab/genética , Sequência de Aminoácidos , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Transtornos do Neurodesenvolvimento/diagnóstico , Estrutura Secundária de Proteína , Canais de Potássio Shab/químicaRESUMO
OBJECTIVE: We describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease. METHODS: We identified children with cardiac causes of AIS enrolled in the International Pediatric Stroke Study registry from January 2003 to July 2014. Isolated patent foramen ovale was excluded. Peri-procedural AIS (those occurring during or within 72 hours of cardiac surgery, cardiac catheterization, or mechanical circulatory support) and spontaneous AIS that occurred outside of these time periods were compared. RESULTS: We identified 672 patients with congenital or acquired cardiac disease as the primary risk factor for AIS. Among these, 177 patients (26%) had peri-procedural AIS and 495 patients (74%) had spontaneous AIS. Among non-neonates, spontaneous AIS occurred at older ages (median 4.2 years, interquartile range 0.97 to 12.4) compared with peri-procedural AIS (median 2.4 years, interquartile range 0.35 to 6.1, P < 0.001). About a third of patients in both groups had a systemic illness at the time of AIS. Patients who had spontaneous AIS were more likely to have a preceding thrombotic event (16 % versus 9 %, P = 0.02) and to have a moderate or severe neurological deficit at discharge (67% versus 33%, P = 0.01) compared to those with peri-procedural AIS. CONCLUSIONS: Children with cardiac disease are at risk for AIS at the time of cardiac procedures but also outside of the immediate 72 hours after procedures. Many have acute systemic illness or thrombotic event preceding AIS, suggesting that inflammatory or prothrombotic conditions could act as a stroke trigger in this susceptible population.
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Isquemia Encefálica/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardiopatias/complicações , Doenças Arteriais Intracranianas/etiologia , Sistema de Registros , Acidente Vascular Cerebral/etiologia , Tromboembolia/complicações , Criança , Pré-Escolar , Feminino , Cardiopatias/congênito , Cardiopatias/cirurgia , Humanos , Lactente , Recém-Nascido , Doenças do Recém-Nascido , Complicações Intraoperatórias , Masculino , Complicações Pós-OperatóriasRESUMO
Background and Purpose- Focal cerebral arteriopathy (FCA)-a common cause of arterial ischemic stroke in previously healthy children-often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes. Methods- The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010-2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability. Results- The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2-6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5-9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5-35.5) days poststroke; their median FCASS increase was 4 (2.5-6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures ( P=0.037). Conclusions- Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.
Assuntos
Infarto Encefálico/diagnóstico por imagem , Doenças Arteriais Cerebrais/diagnóstico por imagem , Adolescente , Artéria Cerebral Anterior/diagnóstico por imagem , Infarto Encefálico/etiologia , Infarto Encefálico/fisiopatologia , Artéria Carótida Interna/diagnóstico por imagem , Estenose das Carótidas/complicações , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/fisiopatologia , Angiografia Cerebral , Doenças Arteriais Cerebrais/complicações , Doenças Arteriais Cerebrais/fisiopatologia , Criança , Pré-Escolar , Angiografia por Tomografia Computadorizada , Progressão da Doença , Feminino , Humanos , Lactente , Angiografia por Ressonância Magnética , Masculino , Artéria Cerebral Média/diagnóstico por imagem , Artéria Cerebral Posterior/diagnóstico por imagem , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologiaRESUMO
Studies show decreased risk of breast cancer recurrence and improved survival with statin use, but data on racial disparities regarding breast cancer prognosis and statin use are lacking. Our objective was to investigate if racial disparities in breast cancer prognosis can be partially explained by differences in pre-diagnosis statin use. Patients were identified from a prospective, multicenter study examining the effects of metabolic factors on breast cancer prognosis in Black and White women. Statin use, prognosis (as measured by Nottingham Prognostic Index), anthropometric, tumor, and socio-demographic characteristics were examined. Five hundred eighty-seven women (487 White, 100 Black) with newly diagnosed primary invasive breast cancer were recruited. Obesity was more prevalent in Black women than White women (47 vs 19%, p < 0.01); both groups had similar low-density lipoprotein (LDL) cholesterol levels (113 ± 41 vs 113 ± 36 mg/dl, p = 0.90). More Black women used statins than White women (18 vs 11%, p = 0.06). Black women had a worse prognosis in an adjusted model than White women (OR 2.13 95% CI 1.23-3.67). Statin use was not associated with prognosis in unadjusted (OR 1.03, 95% CI 0.53-2.0) and adjusted models (OR 1.14, 95% CI 0.56-2.31). In women with newly diagnosed breast cancer, Black women were more likely to be treated with statins than White women, contrary to previous studies. Black women had worse prognosis than White women, but this difference was not explained by differences in pre-diagnosis statin use. Our study suggests that differences in pre-diagnosis statin use do not contribute to racial disparities in breast cancer prognosis.