RESUMO
INTRODUCTION: Following ileocolic resection (ICR), the clinical importance and prognostic implications of histologic activity on biopsies in Crohn's disease (CD) patients with endoscopic remission are not well defined. The aim of this study was to determine if histologic activity in patients with endoscopic remission is associated with future risk of endoscopic and/or radiologic postoperative recurrence (POR). METHODS: In this multicenter retrospective cohort study, adult patients with CD who underwent ICR between 2009 and 2020 with endoscopic biopsies of ileal mucosa from Rutgeerts i0 on index colonoscopy were included. The composite rate of endoscopic (Rutgeerts score ≥i2b) and radiologic (active inflammation on imaging) recurrence was compared in patients with and without histologic activity using a Kaplan-Meier survival analysis. A multivariable Cox proportional hazard regression model including clinically relevant risk factors of POR, postoperative biologic prophylaxis, and histology activity was designed. RESULTS: A total of 113 patients with i0 disease on index colonoscopy after ICR were included. Of these, 42% had histologic activity. Time to POR was significantly earlier in the histologically active versus normal group ( P = 0.04). After adjusting for clinical risk factors of POR, histologic activity (HR 2.37, 95% CI 1.17-4.79; P = 0.02) and active smoking (HR 2.54, 95% CI 1.02-6.33; P = 0.05) were independently associated with subsequent composite POR risk. DISCUSSION: In patients with postoperative CD, histologic activity despite complete endoscopic remission is associated with composite, endoscopic, and radiographic recurrence. Further understanding of the role of histologic activity in patients with Rutgeerts i0 disease may provide a novel target to reduce disease recurrence in this population.
RESUMO
Background: Fecal calprotectin (FC) is a reliable predictor of active bowel inflammation in postoperative Crohn's disease (CD), but cutoffs vary between studies. Recent guidelines recommend a cutoff of <50 ug/g to avoid routine endoscopy in patients at low pretest probability for CD recurrence. We evaluated the performance of this threshold in a real-world CD cohort after ileocolic resection (ICR). Methods: In this retrospective study, patients with CD post-ICR between 2009 to 2020 with FCâ >â 60 days butâ <â 1 year of surgery were included from a multicenter database. Established risk factors and/or biologic prophylaxis (biologic within 90 days of surgery) defined pretest probability. Those without postoperative colonoscopy were excluded. Rates of endoscopic recurrence, defined as Rutgeerts scoreâ ≥â i2b at any time after surgery, were compared between FCâ <â 50 versus â ≥â 50 ug/g. Student's t-test and Fisher's exact test were utilized for statistical analysis. All postoperative FCs were matched to closest colonoscopy within 1 year to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Thirty-seven patients categorized as either low-risk or high-risk and received biologic prophylaxis and had postoperative colonoscopy were included. Median time to first FC was 217 days (IQR 131-288). 15 (41%) patients had initial FCâ <â 50 ug/g versus 22 (59%) ≥50 ug/g. Median time to first colonoscopy was 234 days (IQR 189-369). Compared to initial FCâ ≥â 50 ug/g, FCâ <â 50ug/g experienced less endoscopic recurrence (0% vs. 36%, Pâ =â .005). Median time to first endoscopic recurrence in FCâ ≥â 50 ug/g was 145 days. There were 39 matched pairs of FC and colonoscopy. At an FC cutoff of 50 ug/g, calculated sensitivity was 90% and NPV was 93%, whereas specificity and PPV were 48% and 38%, respectively. Conclusions: In this real-world cohort, FCâ <â 50 ug/g is a useful cutoff to exclude endoscopic recurrence in a post-ICR CD population that is at low pretest probability of recurrence.
RESUMO
BACKGROUND: Combined injury of the anterior cruciate ligament (ACL) and the medial collateral ligament (MCL) is a common injury pattern and accounts for 20% of all ligamentous knee injuries. Despite advancements in surgical technique, there is no up-to-date consensus regarding the superiority of nonoperative versus operative management in higher-grade MCL tears of combined ACL-MCL injuries. PURPOSE: To interpret recent literature on treatment options and to provide an updated evidence-based approach for management of combined ACL-MCL knee injuries. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: We performed a systematic review on outcomes following treatment of concomitant ACL and MCL injuries. A computerized search was conducted in PubMed, Embase.com, and Scopus.com. Authors independently assessed eligible studies and screened titles and abstracts. Articles reporting on patients with concomitant ACL and MCL injuries with or without concomitant procedures were included. Data regarding study design, sample size, patient age and sex, length of follow-up, timing of surgery, indications, surgical methods, concomitant procedures, outcomes, and complications were recorded. Patient-reported outcomes (PROs) and functional outcomes, including Knee injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scores, Lysholm and Tegner scores, and range of motion, were estimated via meta-analysis and compared statistically by surgical approach. RESULTS: In total, 18 studies were included in the systematic review with level 1 to level 4 evidence, with a total of 1,534 cases, were included in the systematic review. Of these, 16 studies with sufficient statistical reporting including 997 cases with sufficient follow-up were included in meta-analysis. Three different approaches to combined ACL-MCL injuries were identified: ACL reconstruction with (1) nonoperative MCL, (2) MCL repair, and (3) MCL reconstruction. There was no statistical difference between nonoperative versus surgically managed MCL injuries for PROs, range of motion at final follow up, or quadriceps strength. CONCLUSION: Reconstruction of combined injury in a delayed fashion facilitates return of range of motion and may allow time for low-grade MCL tears to heal. If residual valgus or anteromedial rotatory laxity remains after a period of rehabilitation, then concomitant surgical management of ACL and MCL injuries is warranted. Avulsion MCL injuries and Stener-type lesions may benefit from early repair techniques.
Assuntos
Lesões do Ligamento Cruzado Anterior , Traumatismos do Joelho , Ligamento Colateral Médio do Joelho , Humanos , Ligamento Colateral Médio do Joelho/cirurgia , Ligamento Colateral Médio do Joelho/lesões , Resultado do Tratamento , Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/cirurgia , Traumatismos do Joelho/cirurgia , Articulação do Joelho/cirurgiaRESUMO
BACKGROUND & AIMS: Preoperative risk stratification may help guide prophylactic biologic utilization for the prevention of postoperative Crohn's disease (CD) recurrence; however, there are limited data exploring and validating proposed clinical risk factors. We aimed to explore the preoperative clinical risk profiles, quantify individual risk factors, and assess the impact of biologic prophylaxis on postoperative recurrence risk in a real-world cohort. METHODS: In this multicenter retrospective analysis, patients with CD who underwent ileocolonic resection (ICR) from 2009 to 2020 were identified. High-risk (active smoking, ≥2 prior surgeries, penetrating disease, and/or perianal disease) and low-risk (nonsmokers and age >50 y) features were used to stratify patients. We assessed the risk of endoscopic (Rutgeert score, ≥i2b) and surgical recurrence by risk strata and biologic prophylaxis (≤90 days postoperatively) with logistic and time-to-event analyses. RESULTS: A total of 1404 adult CD patients who underwent ICR were included. Of the high-risk factors, 2 or more ICRs (odds ratio [OR], 1.71; 95% CI, 1.13-2.57), active smoking (OR, 1.73; 95% CI, 1.17-2.53), penetrating disease (OR, 1.41; 95% CI, 1.02-1.94), and history of perianal disease alone (OR, 1.99; 95% CI, 1.42-2.79) were associated with surgical but not endoscopic recurrence. Surgical recurrence was lower in high-risk patients receiving prophylaxis vs not (10.2% vs 16.7%; P = .02), and endoscopic recurrence was lower in those receiving prophylaxis irrespective of risk strata (high-risk, 28.1% vs 37.4%; P = .03; and low-risk, 21.1% vs 38.3%; P = .002). CONCLUSIONS: Clinical risk factors accurately illustrate patients at risk for surgical recurrence, but have limited utility in predicting endoscopic recurrence. Biologic prophylaxis may be of benefit irrespective of risk stratification and future studies should assess this.
Assuntos
Produtos Biológicos , Doença de Crohn , Adulto , Humanos , Doença de Crohn/prevenção & controle , Doença de Crohn/cirurgia , Doença de Crohn/tratamento farmacológico , Estudos Retrospectivos , Endoscopia/efeitos adversos , Fatores de Risco , Produtos Biológicos/uso terapêutico , Recidiva , Íleo/cirurgiaRESUMO
BACKGROUND: Identifying and targeting established modifiable risk factors has been a successful strategy for reducing the burden of coronary artery disease (CAD) at the population-level. However, up to 1-in-4 patients who present with ST elevation myocardial infarction do so in the absence of such risk factors. Polygenic risk scores (PRS) have demonstrated an ability to improve risk prediction models independent of traditional risk factors and self-reported family history, but a pathway for implementation has yet to be clearly identified. The aim of this study is to examine the utility of a CAD PRS to identify individuals with subclinical CAD via a novel clinical pathway, triaging low or intermediate absolute risk individuals for noninvasive coronary imaging, and examining the impact on shared treatment decisions and participant experience. TRIAL DESIGN: The ESCALATE study is a 12-month, prospective, multicenter implementation study incorporating PRS into otherwise standard primary care CVD risk assessments, to identify patients at increased lifetime CAD risk for noninvasive coronary imaging. One-thousand eligible participants aged 45 to 65 years old will enter the study, which applies PRS to those considered low or moderate 5-year absolute CVD risk and triages those with CAD PRS ≥80% for a coronary calcium scan. The primary outcome will be the identification of subclinical CAD, defined as a coronary artery calcium score (CACS) >0 Agatston units (AU). Multiple secondary outcomes will be assessed, including baseline CACS ≥100 AU or ≥75th age-/sex-matched percentile, the use and intensity of lipid- and blood pressure-lowering therapeutics, cholesterol and blood pressure levels, and health-related quality of life (HRQOL). CONCLUSION: This novel trial will generate evidence on the ability of a PRS-triaged CACS to identify subclinical CAD, as well as subsequent differences in traditional risk factor medical management, pharmacotherapy utilization, and participant experience. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12622000436774. Trial was prospectively registered on March 18, 2022. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=383134.
Assuntos
Doenças Cardiovasculares , Doença da Artéria Coronariana , Humanos , Pessoa de Meia-Idade , Idoso , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Cálcio , Estudos Prospectivos , Qualidade de Vida , Triagem , Austrália , Fatores de Risco , Medição de Risco , Angiografia Coronária/métodos , Estudos Multicêntricos como AssuntoRESUMO
ABSTRACT: A 62-year-old man presented with headache, fever, and malaise. He was diagnosed with Anaplasma phagocytophilum, confirmed by serum polymerase chain reaction, and started on oral doxycycline. After 5 days of treatment, the patient began to experience gait imbalance with frequent falls, as well as myoclonus, and confusion. Examination was notable for opsoclonus-myoclonus-ataxia (OMA) and hypometric saccades. Cerebrospinal fluid (CSF) autoimmune encephalitis panel demonstrated a markedly elevated neuronal intermediate filament (NIF) immunoglobulin G antibody titer of 1:16, with positive neurofilament light- and heavy-chain antibodies. These antibodies were suspected to have been triggered by the Anaplasma infection. Repeat CSF examination 8 days later still showed a positive immunofluorescence assay for NIF antibodies, but the CSF titer was now less than 1:2. Body computed tomography imaging was unrevealing for an underlying cancer. Our patient illustrates a postinfectious mechanism for OMA and saccadic hypometria after Anaplasma infection.
Assuntos
Anaplasmose , Síndrome de Opsoclonia-Mioclonia , Animais , Ataxia , Humanos , Imunoglobulina G , Filamentos Intermediários , Masculino , Pessoa de Meia-IdadeRESUMO
Significant controversy exists regarding the optimal surgical technique for anterior cruciate ligament (ACL) reconstruction in adolescents with 1 to 3 years of skeletal growth remaining. Graft choice and physeal injury remain primary concerns given significantly elevated rates of failure of hamstring autograft reconstructions in this population, as well as risks of leg-length discrepancy and growth axis deviation. Traditional (more vertical) transtibial drilling of the femoral tunnel can reduce risks of physeal injury but has been shown to have less accuracy restoring the native femoral ACL footprint and associated incomplete knee stabilization. On the other hand, anteromedial and outside-in drilling yields improvements in the tunnel location and biomechanics but at the cost of a more oblique trajectory and greater risk of physeal injury. A hybrid transtibial pin technique using a Pathfinder guide facilitates femoral drilling with the "best of both worlds," allowing for reproduction of the native ACL footprint and a more physeal-respecting femoral tunnel. When combined with an all-soft tissue quadriceps tendon autograft and suspensory fixation, the hybrid transtibial method yields a reliable, safe, and robust construct with promising results for the young athlete. We describe our preferred graft harvest, tunnel drilling, and fixation techniques to minimize physeal risks and optimize outcomes.
RESUMO
Neural stem cells (NSCs) in the dentate gyrus (DG) reside in a specialized local niche that supports their neurogenic proliferation to produce adult-born neurons throughout life. How local niche cells interact at the circuit level to ensure continuous neurogenesis from NSCs remains unknown. Here we report the role of endogenous neuropeptide cholecystokinin (CCK), released from dentate CCK interneurons, in regulating neurogenic niche cells and NSCs. Specifically, stimulating CCK release supports neurogenic proliferation of NSCs through a dominant astrocyte-mediated glutamatergic signaling cascade. In contrast, reducing dentate CCK induces reactive astrocytes, which correlates with decreased neurogenic proliferation of NSCs and upregulation of genes involved in immune processes. Our findings provide novel circuit-based information on how CCK acts on local astrocytes to regulate the key behavior of adult NSCs.
Assuntos
Astrócitos/fisiologia , Colecistocinina/fisiologia , Giro Denteado/fisiologia , Interneurônios/fisiologia , Células-Tronco Neurais/fisiologia , Neurogênese , Neuropeptídeos/fisiologia , Animais , Feminino , Masculino , Potenciais da Membrana , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de SinaisRESUMO
The escalating obesity among adolescents is of major concern, especially among those from an ethnic minority background. The adolescent period offers a key opportunity for the implementation of positive lifestyle behaviours as children transition to adulthood. The objective of this review was to examine the effectiveness of lifestyle interventions for adolescents and their impact in ethnic and racial minorities for the prevention of overweight and obesity. Seven electronic databases were searched from 2005 until March 2019 for randomized controlled trials of lifestyle programs conducted in this population. The main outcome was change in Body Mass Index (BMI) z-score (kg/m2) or change in BMI and secondary outcomes were changes in physical activity and diet. Thirty studies met the inclusion criteria. Seven studies reported and/or conducted subgroup analysis to determine if ethnic/racial group affected weight change. None demonstrated an overall decrease in BMI z-score. However, six of the seven demonstrated changes in secondary measures such as fruit and vegetable intake and screen time. Results did not differ by ethnic/racial group for primary and secondary outcomes. Overweight and obesity prevention among adolescents from ethnic minorities is an area that needs further research. There is a lack of interventions that include analyses of effectiveness in ethnic minorities.
Assuntos
Etnicidade , Estilo de Vida , Obesidade Infantil , Aumento de Peso , Adolescente , Austrália , Feminino , Humanos , Grupos Minoritários , Obesidade Infantil/prevenção & controleRESUMO
Patellar instability is a common problem in the active pediatric population. When nonoperative treatment of the instability fails, growth-respecting surgical stabilization techniques are required. As the incidence of medial patellofemoral ligament (MPFL) reconstruction has increased, techniques have improved to avoid physeal injury to the distal femur. These techniques are technically demanding because of the small size of the distal femoral epiphysis in children, as well as the relatively large socket size (7-8 mm in diameter, >20 mm in length) required for sound fixation with a tenodesis screw as originally described. The size of the femoral tunnel for interference fixation puts the surrounding structures at risk of damage. We present a modification of the epiphyseal socket technique for anatomic growth-sparing MPFL reconstruction using a small soft anchor for femoral graft fixation. This has the proposed advantages of diminishing volumetric bony removal from the epiphysis; increasing the margin of safety with respect to notch, trochlear, and/or physeal damage; and reducing the risk of thermal damage to the physis during socket reaming. This technique is technically simple and can be easily learned by surgeons familiar with adult MPFL reconstruction techniques.
RESUMO
BACKGROUND: Primary shoulder stabilization is successful, but there continues to be a risk of recurrence after operative repair, particularly in the young athlete. It is important for surgeons to understand the outcomes after various revision stabilization techniques to best counsel patients and manage expectations. PURPOSE: To analyze recurrent instability and revision surgery rates in patients who underwent revision anterior glenohumeral stabilization procedures with either arthroscopic repair, open repair, coracoid transfer, free bone block, or capsular reconstruction. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: We performed a systematic review of level 2 to 4 evidence studies using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical studies of revision anterior glenohumeral stabilization (arthroscopic repair, open repair, coracoid transfer, free bone block, or capsular reconstruction) with a minimum 2-year follow-up were analyzed. The rate of recurrent instability, rate of revision surgery, patient-reported outcomes, and range of motion were extracted and reported. Study methodological quality was evaluated using the Downs and Black quality assessment score. RESULTS: A total of 37 studies met inclusion criteria and were available for analysis: 20 studies evaluated arthroscopic repair, 8 evaluated open repair, 5 evaluated Latarjet procedure, 3 evaluated bone block, and 2 evaluated capsular reconstruction. There was 1 study included in both arthroscopic and Latarjet procedures, for a total of 1110 revision cases. There was 1 level 2 study, and the remainder were level 3 or 4 with poor Downs and Black scores. Participants analyzed were most commonly young (weighted mean age, 26.1 years) and male (78.4%). The weighted mean clinical follow-up after revision surgery was 47.8 months. The weighted mean rate of recurrent instability was 3.8% (n = 245) after the Latarjet procedure, 13.4% (n = 260) after open repair, 16.0% (n = 531) after arthroscopic repair, 20.8% (n = 72) after bone block, and 31.0% (n = 35) after capsular reconstruction. The weighted mean rate of additional revision surgery was 0.0% after bone block, 0.02% after the Latarjet procedure, 9.0% after arthroscopic repair, 9.3% after open repair, and 22.8% after capsular reconstruction. Patient-reported outcomes and objective measures of range of motion and strength improved with all revision techniques. CONCLUSION: The current review identifies a deficiency in the literature pertaining to consistent meaningful outcomes and the effect of bone loss after revision shoulder stabilization. Published studies demonstrate, however, that revision shoulder stabilization using arthroscopic, open, coracoid transfer, or bone block techniques yielded satisfactory objective and patient-reported outcomes. The Latarjet procedure exhibited the lowest recurrent instability rate. This study confirms that recurrent instability remains a common problem, despite revision shoulder stabilization. The quality of research in revision shoulder stabilization remains poor, and higher quality studies are needed to establish best practices for treatment of this complex problem.
RESUMO
The visualization of regulatory networks is becoming increasingly important in order to understand molecular mechanisms and diseases. MicroRNAs (miRNAs) are small noncoding RNAs (ncRNAs) responsible of the post-transcriptional regulation of messenger RNAs (mRNAs) and other ncRNAs. MiRNAs are involved in numerous biological processes including development, cell proliferation, and apoptosis. They are also key molecules in major complex diseases such as cancer and cardiovascular diseases. A single miRNA can regulate many targets, making the analysis and visualization of these complex networks challenging. Here, we present standard and advanced visualization approaches to represent networks with a special focus on miRNA-target interactions.
Assuntos
Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , MicroRNAs/genética , RNA Mensageiro/genética , Software , Biologia Computacional/métodos , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo , RNA Mensageiro/metabolismoRESUMO
PURPOSE: Most chromosome abnormality patients require long-term clinical care. Awareness of mosaicism and comorbidities can potentially guide such health care. Here we present a population-wide analysis of direct and inverse comorbidities affecting patients with chromosome abnormalities. METHODS: We extracted direct and inverse comorbidities for the 11 most prevalent chromosome abnormalities from the Danish National Patient Registry (covering 6.9 million patients hospitalized between 1994 and 2015): trisomy 13, 18, and 21, Klinefelter (47,XXY), triple X, XYY, Turner (45,X), Wolf-Hirschhorn, Cri-du-chat, Angelman, and Fragile X syndromes (FXS). We also performed four sub-analyses for male/female Down syndrome (DS) and FXS and non-mosaic/mosaic DS and Turner syndrome. RESULTS: Our data cover 9,003 patients diagnosed with at least one chromosome abnormality. Each abnormality showed a unique comorbidity signature, but clustering of their profiles underlined common risk profiles for chromosome abnormalities with similar genetic backgrounds. We found that DS had a decreased risk for three inverse cancer comorbidities (lung, breast, and skin) and that male FXS and non-mosaic patients have a much more severe phenotype than female FXS and mosaic patients, respectively. CONCLUSION: Our study underlines the importance of considering mosaicism, sex, and the associated comorbidity profiles of chromosome abnormalities to guide long-term health care of affected patients.
Assuntos
Transtornos Cromossômicos/epidemiologia , Comorbidade , Aberrações Cromossômicas , Dinamarca/epidemiologia , Feminino , Humanos , Cariotipagem , Masculino , Mosaicismo , Sistema de Registros , Aberrações dos Cromossomos Sexuais , TrissomiaRESUMO
Although many diseases are associated with cancer, the full spectrum of temporal disease correlations across cancer types has not yet been characterized. A population-wide study of longitudinal disease trajectories is needed to interrogate the general medical histories of patients with cancer. Here we performed a retrospective study covering a 20-year period, using 6.9 million patients from the Danish National Patient Registry linked to 0.7 million patients with cancer from the Danish Cancer Registry. Statistical analysis identified all significant disease associations occurring prior to cancer diagnoses. These associations were used to build frequently occurring, longitudinal disease trajectories. Across 17 cancer types, a total of 648 significant diagnoses correlated directly with a cancer, while 168 diagnosis trajectories of time-ordered steps were identified for seven cancer types. The most common diseases across cancer types involved cardiovascular, obesity, and genitourinary diseases. A comprehensive, publicly available web tool of interactive illustrations for all cancer disease associations is provided. By exploring the precancer landscape using this large dataset, we identify disease associations that can be used to derive mechanistic hypotheses for future cancer research. SIGNIFICANCE: This study offers an innovative approach to examine prediagnostic disease and cancer development in a large national population-based setting and provides a publicly available tool to foster additional cancer surveillance research.
Assuntos
Recidiva Local de Neoplasia/diagnóstico , Neoplasias/diagnóstico , Lesões Pré-Cancerosas/diagnóstico , Sistema de Registros/estatística & dados numéricos , Idoso , Dinamarca/epidemiologia , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Neoplasias/epidemiologia , Vigilância da População , Lesões Pré-Cancerosas/epidemiologia , Prognóstico , Estudos RetrospectivosRESUMO
INTRODUCTION: Epidermal growth factor receptors EGFR and ErbB2 are overexpressed in schwannomas and meningiomas. Preclinical and clinical data indicate that lapatinib, an EGFR/ErbB2 inhibitor, has antitumor activity against vestibular schwannomas in neurofibromatosis type 2 (NF2) patients. Its antitumor activity against meningiomas, however, is unknown. METHODS: We conducted a retrospective review of patients with NF2 and progressive vestibular schwannomas treated on a phase 2 clinical trial with lapatinib (NCT00973739). We included patients with at least one volumetrically measurable meningioma (> 0.5 cm3) who received at least five 28-day courses of treatment. Patients received lapatinib 1500 mg daily. Meningioma response was assessed using 3-dimensional MRI volumetrics. Progressive meningioma growth and response were defined as + 20 and - 20% change in tumor volume from baseline, respectively. Off-treatment was defined as any period > 5 months without lapatinib. RESULTS: Eight patients (ages: 20-58 years) who met criteria had 17 evaluable meningiomas with a combined volume of 61.35 cc at baseline, 61.17 cc during treatment, and 108.86 cc (+ 77.44% change) off-treatment, p = 0.0033. Median time on-treatment and off-treatment was 15.5 and 16.7 months, respectively. On-treatment mean and median annualized growth rates were 10.67 and 1.32%, respectively. Off-treatment mean and median annualized growth rates were 20.05 and 10.42%, respectively. The best volumetric response was - 26.1% after 23 months on lapatinib. Two tumors increased > 20% volumetrically on-treatment, compared to eight tumors off-treatment. CONCLUSIONS: These data suggest that lapatinib may have growth-inhibitory effects on meningiomas in NF2 patients, and support prospective studies of lapatinib for NF2 patients with progressive meningiomas.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Meníngeas/tratamento farmacológico , Meningioma/tratamento farmacológico , Neurofibromatose 2/tratamento farmacológico , Quinazolinas/uso terapêutico , Adulto , Feminino , Humanos , Imageamento Tridimensional , Lapatinib , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/complicações , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/complicações , Meningioma/diagnóstico por imagem , Pessoa de Meia-Idade , Neurofibromatose 2/complicações , Neurofibromatose 2/diagnóstico por imagem , Neuroma Acústico/complicações , Neuroma Acústico/tratamento farmacológico , Estudos Retrospectivos , Adulto JovemRESUMO
We report a case of a Puerto Rican male with advanced AIDS who presented with multiple falls and pancytopenia. Magnetic resonance imaging (MRI) of the brain, as initial workup, revealed 2 ring-enhancing brain lesions. Initial cerebrospinal fluid analysis revealed minimal cells, mildly elevated protein, and no organism seen on gram stain. Due to prohibitive thrombocytopenia, brain biopsy was deferred. He had neither clinical nor radiographic improvement despite empiric therapy for both toxoplasmosis and bacterial abscesses. Indicated by pancytopenia, bone marrow (BM) aspiration was performed. Culture of BM aspirate grew Histoplasma capsulatum. Urine histoplasma antigen was markedly elevated. He was treated with liposomal amphotericin B (LamB) for progressive disseminated histoplasmosis with probable central nervous system involvement. Cerebrospinal fluid histoplasma antigen obtained after 2 months of LamB was detected. After prolonged course of LamB, he took itraconazole. Brain MRI at 7-month follow-up revealed significant improvement from baseline study.
RESUMO
Quiescent neural stem cells (qNSCs) with radial morphology are the only proven source of new neurons in the adult mammalian brain. Our understanding of the roles of newly generated neurons depends on the ability to target and manipulate adult qNSCs. Although various strategies have been developed to target and manipulate adult hippocampal qNSCs, they often suffer from prolonged breeding, low recombination efficiency, and non-specific labeling. Therefore, developing a readily manufactured viral vector that allows flexible packaging and robust expression of various transgenes in qNSCs is a pressing need. Here, we report a recombinant adeno-associated virus serotype 4 (rAAV4)-based toolkit that preferentially targets hippocampal qNSCs and allows for lineage tracing, functional analyses, and activity manipulation of adult qNSCs. Importantly, targeting qNSCs in a non-Cre-dependent fashion opens the possibility for studying qNSCs in less genetically tractable animal species and may have translational impact in gene therapy by preferentially targeting qNSCs.
Assuntos
Células-Tronco Adultas/citologia , Dependovirus/genética , Vetores Genéticos/genética , Hipocampo/citologia , Células-Tronco Neurais/citologia , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/genética , Ratos , Ratos Sprague-Dawley , Transgenes/genéticaRESUMO
Methods that integrate molecular network information and tumor genome data could complement gene-based statistical tests to identify likely new cancer genes; but such approaches are challenging to validate at scale, and their predictive value remains unclear. We developed a robust statistic (NetSig) that integrates protein interaction networks with data from 4,742 tumor exomes. NetSig can accurately classify known driver genes in 60% of tested tumor types and predicts 62 new driver candidates. Using a quantitative experimental framework to determine in vivo tumorigenic potential in mice, we found that NetSig candidates induce tumors at rates that are comparable to those of known oncogenes and are ten-fold higher than those of random genes. By reanalyzing nine tumor-inducing NetSig candidates in 242 patients with oncogene-negative lung adenocarcinomas, we find that two (AKT2 and TFDP2) are significantly amplified. Our study presents a scalable integrated computational and experimental workflow to expand discovery from cancer genomes.
Assuntos
Carcinogênese/genética , Biologia Computacional/métodos , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Proteínas de Neoplasias/genética , Neoplasias/genética , Humanos , MutaçãoRESUMO
The co-occurrence of diseases can inform the underlying network biology of shared and multifunctional genes and pathways. In addition, comorbidities help to elucidate the effects of external exposures, such as diet, lifestyle and patient care. With worldwide health transaction data now often being collected electronically, disease co-occurrences are starting to be quantitatively characterized. Linking network dynamics to the real-life, non-ideal patient in whom diseases co-occur and interact provides a valuable basis for generating hypotheses on molecular disease mechanisms, and provides knowledge that can facilitate drug repurposing and the development of targeted therapeutic strategies.
Assuntos
Comorbidade , Biologia Computacional/métodos , Doença/genética , Redes e Vias Metabólicas , Humanos , Biologia de Sistemas/métodosRESUMO
OBJECTIVES: To determine the association of adjuvant radiotherapy and outcomes of women with stage III node-positive uterine cancer. METHODS: All patients with surgically-staged stage III node-positive uterine cancer from the Surveillance Epidemiology and End Results database of the US National Cancer Institute from 1988 to 2001 were identified. Data were analyzed using Kaplan-Meier and logistic regression methods. RESULTS: Of 943 women, the median age was 64 years (range: 28-93). 82.1%, 8.6%, and 6.8% were White, Black, and Asian respectively. The median number of removed nodes was 11. 54.9% had a single positive node and 45.1% had 2-5 positive nodes. Endometrioid, papillary serous, sarcomas, and clear cell carcinomas comprised of 69.7%, 16.3%, 9.9%, and 4.1% of histologies, respectively. 67.3% of the women underwent adjuvant radiotherapy with a 5-year disease-specific survival of 67.9% compared to 53.4% in those without radiotherapy (p<0.001). Adjuvant radiotherapy improved the survival from 54.4% to 74.3% (p<0.001) in those with a single positive node and from 52.4% to 59.7% (p=0.089) in those with 2-5 positive nodes. On multivariate analysis, older age, non-endometrioid histology, and lack of adjuvant radiotherapy remained as significant independent prognostic factors for worsened survival. CONCLUSIONS: Our data suggest that adjuvant radiotherapy is associated with a significant survival benefit in women with single-positive node endometrioid uterine cancers. Prospective clinical trials are warranted to confirm these findings.