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Congenital melanocytic nevi are present at birth or develop within the first few months of life. Giant congenital melanocytic nevi are a rare variant and may involve the external genitalia with a confluent "bathing trunk" distribution. Rapid growth of proliferative nodules of melanocytic cells may cause disfigurement and anatomical distortion resulting in psychological distress and loss of functionality. We report the case of a neglected 17-year-old nonverbal male who received a resection of a Giant Congenital Melanocytic Nevi (GMN) engulfing the penis and scrotum with final resected dimensions of 36.0×20.0×8.0 cm.
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Nevo Pigmentado , Neoplasias Cutâneas , Recém-Nascido , Humanos , Masculino , Criança , Adolescente , Genitália Masculina , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/cirurgia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgia , PênisRESUMO
BACKGROUND: Management patterns and outcomes are poorly defined in cases of late PUV diagnosis. OBJECTIVE: To compare post-ablation management and clinical outcomes of patients with infantile (<1 year) versus childhood (>5 year) PUV diagnosis to gain insight into the pathologies at opposite ends of the PUV spectrum. STUDY DESIGN: A multicenter retrospective cohort study was conducted using the TriNetX research network between 2006 and 2022. TriNetX synthesizes insurance claims and electronic medical record data for over 110 million patients from 92 healthcare organizations. We defined two cohorts: 1) The <1 year arm had an index diagnosis of PUV and cystoscopy with valve ablation within 1 year of life, 2) the >5 year arm had an index diagnosis of PUV and valve ablation after age 5. We report rates and time-to-first use of antispasmodics, alpha-blockers, CIC, bladder botox, enterocystoplasty or Mitrofanoff or secondary cutaneous vesicostomy, and CKD. RESULTS: We identified 569 patients (323 <1 year; 246 >5 year). Median age at diagnosis was 1 month (median follow-up 8 years) and 9 years (median follow-up 10 years) for the <1 year and >5 year cohorts, respectively. Following ablation, both arms were primarily managed with antispasmodics, with no difference between groups. The >5 year arm was significantly more likely to receive alpha-blockers or bladder botox. The <1 year arm was significantly more likely to be started on CIC, undergo enterocystoplasty, Mitrofanoff or secondary cutaneous vesicostomy, or renal transplantation. The <1 year arm had significantly higher rates and shorter time-to-progression to all stages of CKD. DISCUSSION: Despite higher utilization of conservative strategies among patients with a late PUV diagnosis, these patients had superior renal outcomes and low rates of progression to invasive treatments. Limitations include potential inaccuracies in medical coding as well as variations in thresholds to initiate CIC, perform surgical reconstruction, or proceed with renal transplantation at participating centers. CONCLUSIONS: These findings provide evidence that a late PUV diagnosis reflects an overall milder disease process.
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Rhabdomyosarcoma (RMS) treatment involves surgery, chemotherapy, and radiotherapy. A radioprotective space between the bladder/prostate and rectum reduces postradiation complications, as reported in adult patients. Describe pediatric preradiotherapy perirectal hyaluronic acid (HA) spacer injection for bladder/prostate RMS. We present a case of a 17-month-old male with bladder/prostate RMS. Before radiotherapy, an HA spacer was injected peri-rectally. Under general anesthesia, a transrectal ultrasound was positioned and 1mL of HA spacer was injected into the perirectal space. No complications were reported at 6-month follow-up. This is the first report of pre-radiation therapy spacer injection for pediatric bladder/prostate RMS.
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Neoplasias Pélvicas , Neoplasias da Próstata , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Neoplasias da Bexiga Urinária , Adulto , Humanos , Masculino , Criança , Lactente , Ácido Hialurônico/uso terapêutico , Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/radioterapia , Rabdomiossarcoma/radioterapiaRESUMO
INTRODUCTION: Posterior urethral valves (PUV) is a leading cause of chronic renal failure in childhood. Bladder and posterior urethral deformity in infants with PUV are highly variable on initial voiding cystourethrogram (VCUG). Some types of deformity may be more important than others in determining the severity of the condition. Identification of specific VCUG features may allow for a simple, early screening assessment for patients. OBJECTIVE: Determine whether morphologic features on the initial VCUG correlate to renal outcomes as measured by the creatinine nadir in the first year after ablation. METHODS: Children with PUV treated by primary valve ablation before 12 months old and followed >1 year were identified. Initial diagnostic VCUG was evaluated for the bladder height to width ratio (HW-B), posterior urethral height to width ratio (HW-PU), and posterior-anterior urethral ratio (PA-UR). A trabeculation grade was assigned by three pediatric urologists, and reflux was noted. Univariable analyses with chi-square and t-test were used to compare bladder and posterior urethral morphology factors among those who obtained a creatinine nadir <0.8 or ≥0.8 mg/dL in the first year after ablation. Linear regression was performed to correlate morphology values with true creatinine nadir. RESULTS: A total of 120 boys were ablated at mean age of 40.5 days (range 0-342) and followed for 5.9 years (± 3.85). Among these, 21 (17.5%) had a creatinine nadir ≥0.8 mg/dL. Mean overall HW-B and mean PA-UR were not significantly different between those with creatinine nadir <0.8 versus ≥0.8 mg/dL. Bladder trabeculation grade was not associated with creatinine nadir. For the entire cohort, only the difference in HW-PU was statistically significant between creatinine nadir groups with a much higher ratio among those with a nadir ≥0.8 (p < 0.001). Linear regression demonstrated a significant positive correlation between the HW-PU and creatinine nadir (R 2 = 0.097, p = 0.002). The presence of bilateral reflux is significantly associated with creatinine nadir ≥0.8 mg/dL (p = 0.001). DISCUSSION: We investigate for the first time the association of morphology features on the initial VCUG with renal outcome in PUV patients. Posterior urethral deformity as quantified by a higher HW-PU ratio is significantly correlated with a higher creatinine nadir, whereas measured bladder morphology metrics are not. HW-PU may be an indirect measure of the severity of obstruction in posterior urethral valves. CONCLUSION: The HW-PU appears to be a meaningful early morphologic metric for renal outcome.
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Falência Renal Crônica , Insuficiência Renal Crônica , Masculino , Criança , Lactente , Humanos , Creatinina , Uretra/diagnóstico por imagem , Uretra/cirurgia , Bexiga Urinária , Estudos RetrospectivosRESUMO
INTRODUCTION: PUV patients managed with primary vesicostomy instead of primary valve ablation (PVA) historically are preterm, low-birth-weight (LBW) infants with inadequate urethral size. We previously described progressive urethral dilation (PUD) as an effective method of enhancing the likelihood of PVA in these infants, allowing equal access to PVA as an initial management method. OBJECTIVE: We aim to characterize renal outcomes in patients managed with PUD + PVA and compare this to outcomes with PVA alone. We also re-examine the effect of LBW and gestational age on renal outcomes in PUV with a cohort treated uniformly by PVA. METHODS: We performed retrospective review of 78 neonates with PUV treated with PVA prior to 10 weeks of age with >1 year of follow up. Before valve ablation, boys either underwent PUD (serial upsizing of a smaller bore urethral catheter to an 8Fr catheter; PUD + PVA) or non-dilation (smaller bore catheter was maintained; PVA-only). PUD + PVA versus PVA-only was compared using chi-square and t-test. Logistic regression was performed to assess the effect of PUD, preterm (<37 weeks), LBW (<2.5 kg), and other predictors on the final outcomes of CKD3+ and ESRD. RESULTS: 31 of 78 patients underwent PUD + PVA. Mean follow up was 5.2 years (SD 3.4), with no significant difference between PUD + PVA and PVA-only. The PUD + PVA group included significantly lower gestational age infants with lower birth weight and ablation weight. There was no significant effect of PUD on final CKD3+ or ESRD outcome on univariable or multivariable analysis. When adjusted for other variables, only Cr nadir >0.5 remained an independent predictor of CKD3+ (OR 41.2; p < 0.001) and ESRD (OR 18.9; p = 0.015). DISCUSSION: We previously demonstrated that PUD is an effective means to achieve PVA in small neonates who might otherwise require vesicostomy. The data herein demonstrates no significant effect of PUD on renal outcomes. In this unique cohort of newborns treated with PVA, only creatinine nadir and not gestational age or an independent predictor of outcomes. CONCLUSION: In small preterm infants who would have been excluded from PVA due to limited urethral size, PUD + PVA confers the same renal outcomes as PVA alone in larger infants. This novel data will assist in the risk-benefit analysis of using PUD before PVA in newborns diagnosed with PUV. When primary intervention is uniformly PVA, preterm birth and LBW are not independent predictors of renal outcomes.
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Falência Renal Crônica , Nascimento Prematuro , Obstrução Uretral , Lactente , Masculino , Feminino , Recém-Nascido , Humanos , Recém-Nascido Prematuro , Obstrução Uretral/etiologia , Obstrução Uretral/cirurgia , Uretra/cirurgia , Estudos Retrospectivos , CatéteresRESUMO
OBJECTIVE: B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and in ectopic GCs in rheumatoid arthritis (RA) synovium that may be tumor necrosis factor (TNF) and lymphotoxin (LT) dependent. This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti-TNF therapy in RA. METHODS: Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n = 43) or adalimumab (n = 20) for 24 weeks. Eligible participants met the American College of Rheumatology 1987 criteria for RA, had clinically active disease (Disease Activity Score in 28 joints >4.4), and were receiving stable doses of methotrexate. The primary mechanistic end point was the change in switched memory B cell fraction from baseline to week 12 in each treatment group. RESULTS: B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to blockade of TNF alone with adalimumab did not translate into significant differences in clinical response. The frequencies of multiple activated B cell populations, including CD21- double-negative memory and activated naive B cells, were higher in RA nonresponders at all time points, and CD95+ activated B cell frequencies were increased in patients receiving anti-TNF treatment in the nonresponder group. In contrast, frequencies of transitional B cells-a putative regulatory subset-were lower in the nonresponders. CONCLUSION: Overall, our results support the notion that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.
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Adalimumab/farmacologia , Antirreumáticos/farmacologia , Artrite Reumatoide/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/fisiologia , Etanercepte/farmacologia , Inibidores do Fator de Necrose Tumoral/farmacologia , Adalimumab/uso terapêutico , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Etanercepte/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Inibidores do Fator de Necrose Tumoral/uso terapêuticoRESUMO
BACKGROUND: Posterior urethral valve (PUV) is a leading cause of chronic kidney failure in children. Studies have shown that a creatinine nadir above historical cutoff values of 0.8 or 1.0 mg/dL correlates with worse kidney outcomes. The ability to use nadir creatinine more discriminately as a test of kidney outcomes is otherwise limited. METHODS: We performed a retrospective review of 102 infants treated with primary valve ablation prior to 1 year of age. Patient factors including creatinine at presentation (Cr-P), nadir within 6 weeks after ablation (Cr-6 W), and nadir within 1 year after ablation (Cr-1Y) were assessed as predictors of final chronic kidney disease (CKD) severity. An optimal threshold for four CKD levels was defined in incremental fashion using binary outcome with receiver operating characteristic (ROC). Multivariable logistic regression models compared Cr-P, Cr-6 W, and Cr-1Y while adjusting for patient factors. RESULTS: Boys were ablated at mean age of 36.3 days and followed for 6.6 years (± 3.7). When compared to other demographics, only creatinine remained independently predictive of CKD outcomes on multivariable analysis. ROC analysis demonstrated excellent diagnostic accuracy for Cr-6 W and Cr-1Y (p < 0.001) and acceptable accuracy for Cr-P (p < 0.005). Using the Cr-6 W and Cr-1Y models, high sensitivity and specificity creatinine nadir cutoffs were determined to predict each CKD outcome. CONCLUSIONS: The severity of childhood CKD can be predicted with high accuracy using the creatinine nadir within 6 weeks of ablation. The cutoff values described can be incorporated into a clinical setting for patient counseling and individual risk stratification.
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Doença Enxerto-Hospedeiro , Falência Renal Crônica , Insuficiência Renal Crônica , Obstrução Uretral , Adulto , Criança , Creatinina , Doença Enxerto-Hospedeiro/complicações , Humanos , Lactente , Falência Renal Crônica/complicações , Masculino , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/etiologia , Estudos Retrospectivos , Uretra , Obstrução Uretral/complicaçõesRESUMO
Antibodies offer a powerful means to interrogate specific proteins in a complex milieu. However, antibody availability and reliability can be problematic, whereas epitope tagging can be impractical in many cases. To address these limitations, the Protein Capture Reagents Program (PCRP) generated over a thousand renewable monoclonal antibodies (mAbs) against human presumptive chromatin proteins. However, these reagents have not been widely field-tested. We therefore performed a screen to test their ability to enrich genomic regions via chromatin immunoprecipitation (ChIP) and a variety of orthogonal assays. Eight hundred eighty-seven unique antibodies against 681 unique human transcription factors (TFs) were assayed by ultra-high-resolution ChIP-exo/seq, generating approximately 1200 ChIP-exo data sets, primarily in a single pass in one cell type (K562). Subsets of PCRP mAbs were further tested in ChIP-seq, CUT&RUN, STORM super-resolution microscopy, immunoblots, and protein binding microarray (PBM) experiments. About 5% of the tested antibodies displayed high-confidence target (i.e., cognate antigen) enrichment across at least one assay and are strong candidates for additional validation. An additional 34% produced ChIP-exo data that were distinct from background and thus warrant further testing. The remaining 61% were not substantially different from background, and likely require consideration of a much broader survey of cell types and/or assay optimizations. We show and discuss the metrics and challenges to antibody validation in chromatin-based assays.
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Sequenciamento de Cromatina por Imunoprecipitação , Fatores de Transcrição , Sítios de Ligação , Imunoprecipitação da Cromatina , Humanos , Indicadores e Reagentes , Reprodutibilidade dos Testes , Fatores de Transcrição/metabolismoRESUMO
Inflammatory myofibroblastic tumors (IMT) are rare and poorly understood inflammatory neoplasms. Most commonly occurring in the liver and gastrointestinal tract, cases of bladder involvement have been rarely reported. Bladder IMT generally presents with gross hematuria and can be differentiated from other bladder tumors by expression of anaplastic lymphoma kinase. We report the occurrence of an Bladder IMT detected following lower urinary tract reconstruction with bladder augmentation.
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Canal Anal/anormalidades , Esôfago/anormalidades , Cardiopatias Congênitas/cirurgia , Rim/anormalidades , Deformidades Congênitas dos Membros/cirurgia , Miofibroma/diagnóstico , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Neoplasias da Bexiga Urinária/diagnóstico , Actinas/metabolismo , Canal Anal/cirurgia , Quinase do Linfoma Anaplásico/metabolismo , Criança , Esôfago/cirurgia , Hematúria/etiologia , Humanos , Rim/cirurgia , Masculino , Miofibroma/complicações , Miofibroma/metabolismo , Coluna Vertebral/cirurgia , Traqueia/cirurgia , Bexiga Urinária/cirurgia , Neoplasias da Bexiga Urinária/complicações , Neoplasias da Bexiga Urinária/metabolismo , Bexiga Urinaria Neurogênica/complicaçõesRESUMO
PURPOSE: Primary valve ablation is preferred to vesicostomy in the initial management of posterior urethral valves. However, some neonates have a prohibitively small urethra. We describe our experience with a preoperative urethral catheter regimen to enhance the likelihood of neonatal valve ablation. MATERIALS AND METHODS: We performed a retrospective review of 126 neonates with posterior urethral valves treated between 2003 and 2019 with valve ablation prior to 10 weeks of age. The preoperative indwelling catheter either was gradually upsized to an 8Fr (progressive urethral dilation), was not upsized (nondilated) or was initially larger bore (8Fr only). The primary outcome was the ability to perform primary ablation by neonatal resectoscope. The secondary objective was to establish the parameters for considering progressive urethral dilation as well as its associated risks. RESULTS: Overall 97% could be ablated. The progressive urethral dilation group had the lowest mean weight (p <0.001). Only a larger catheter at the time of ablation was significantly associated with feasible ablation (p <0.001) and not urethral dilation, the infant's weight or his gestational age. Progressive urethral dilation was associated with a longer duration of catheterization as well as double the rate of febrile urinary tract infections (8.5%) over the nondilated group (3.6%). CONCLUSIONS: A much higher rate of primary ablation is feasible (97%) than previously reported (82%). More important than the infant's weight is whether a 6Fr to 8Fr catheter is in place at ablation. If an initial 6Fr to 8Fr catheter cannot be placed, urethral dilation to 8Fr should be performed before attempting ablation. This is both a technique and preoperative assessment that is useful for operative planning.
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Cateteres de Demora , Endoscopia , Cuidados Pré-Operatórios , Uretra/anormalidades , Uretra/cirurgia , Obstrução Uretral/etiologia , Obstrução Uretral/cirurgia , Cateterismo Urinário , Técnicas de Ablação , Humanos , Recém-Nascido , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Procedimentos Cirúrgicos Urológicos Masculinos/métodosRESUMO
The regulation of gene expression catalyzed by RNA polymerase II (Pol II) requires a host of accessory factors to ensure cell growth, differentiation, and survival under environmental stress. Here, using the auxin-inducible degradation (AID) system to study transcriptional activities of the bromodomain and extraterminal domain (BET) and super elongation complex (SEC) families, we found that the CDK9-containing BRD4 complex is required for the release of Pol II from promoter-proximal pausing for most genes, while the CDK9-containing SEC is required for activated transcription in the heat shock response. By using both the proteolysis targeting chimera (PROTAC) dBET6 and the AID system, we found that dBET6 treatment results in two major effects: increased pausing due to BRD4 loss, and reduced enhancer activity attributable to BRD2 loss. In the heat shock response, while auxin-mediated depletion of the AFF4 subunit of the SEC has a more severe defect than AFF1 depletion, simultaneous depletion of AFF1 and AFF4 leads to a stronger attenuation of the heat shock response, similar to treatment with the SEC inhibitor KL-1, suggesting a possible redundancy among SEC family members. This study highlights the usefulness of orthogonal acute depletion/inhibition strategies to identify distinct and redundant biological functions among Pol II elongation factor paralogs.
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Expressão Gênica/genética , Fatores de Alongamento de Peptídeos/metabolismo , RNA Polimerase II/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Células HCT116 , Resposta ao Choque Térmico , Humanos , Fatores de Alongamento de Peptídeos/genética , Proteínas/genética , Proteínas/metabolismo , RNA Polimerase II/genética , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Trimethylaminuria (TMAU) (OMIM #602079) is a rare inherited metabolic condition. TMAU is associated with decreased hepatic trimethylamine N-oxidation, which leads to an excess of the volatile trimethylamine (TMA) instead of substrate conversion to trimethylamine N-oxide (TMAO). TMA is a tertiary amine derived from the enterobacterial metabolism of precursors such as choline and phosphatidylcholine present in the diet, and is also a bacterial metabolite of TMAO, a normal constituent of saltwater fish. When the involved enzyme flavin mono-oxygenase 3 is deficient, TMA builds up and is released in the person's sweat, urine, and breath, giving off a strong body odor. We have recently reported the biochemical and genetic characteristics of 13 Irish adult patients with TMAU attending the main Irish Reference Center. Research on the behavioral and psychosocial aspects of this condition is limited. This study explores the patients' perspectives of living with TMAU in Ireland. METHODS: A qualitative descriptive phenomenological approach was used. Six adults participated in this study. Data were gathered through semi-structured interviews, which were transcribed and analyzed. RESULTS: The results suggest that the participants experienced a negative journey to diagnosis. Fear, anxiety, paranoia, and dysfunctional thinking are a constant struggle. Participants reported using avoidant coping mechanisms and strategic planning to navigate daily life. CONCLUSION: It is considered that the results from this study will inform future interventions with this unique patient cohort.
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BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is associated with transcriptional dysregulation driven by H3K27 mutation. The super elongation complex (SEC) is required for transcriptional elongation through release of RNA polymerase II (Pol II). Inhibition of transcription elongation by SEC disruption can be an effective therapeutic strategy of H3K27M-mutant DIPG. Here, we tested the effect of pharmacological disruption of the SEC in H3K27M-mutant DIPG to advance understanding of the molecular mechanism and as a new therapeutic strategy for DIPG. METHODS: Short hairpin RNAs (shRNAs) were used to suppress the expression of AF4/FMR2 4 (AFF4), a central SEC component, in H3K27M-mutant DIPG cells. A peptidomimetic lead compound KL-1 was used to disrupt a functional component of SEC. Cell viability assay, colony formation assay, and apoptosis assay were utilized to analyze the effects of KL-1 treatment. RNA- and ChIP-sequencing were used to determine the effects of KL-1 on gene expression and chromatin occupancy. We treated mice bearing H3K27M-mutant DIPG patient-derived xenografts (PDXs) with KL-1. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival. RESULTS: Depletion of AFF4 significantly reduced the cell growth of H3K27M-mutant DIPG. KL-1 increased genome-wide Pol II occupancy and suppressed transcription involving multiple cellular processes that promote cell proliferation and differentiation of DIPG. KL-1 treatment suppressed DIPG cell growth, increased apoptosis, and prolonged animal survival with H3K27M-mutant DIPG PDXs. CONCLUSIONS: SEC disruption by KL-1 increased therapeutic benefit in vitro and in vivo, supporting a potential therapeutic activity of KL-1 in H3K27M-mutant DIPG.
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Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Animais , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/genética , Linhagem Celular Tumoral , Glioma/tratamento farmacológico , Glioma/genética , Histonas , CamundongosRESUMO
OBJECTIVE: To report diagnosis, treatment, and outcomes of vaginal yolk sac tumor (YST) cases at a single institution and review literature on vaginal YST to outline advancements in diagnosis, treatment, and survival. DESIGN: Retrospective chart review of female patients less than 21 years of age with pathologic diagnosis of vaginal YST treated at a large children's hospital, and summary of a 100-year review of the literature on vaginal yolk sac tumor. SETTING: Children's Healthcare of Atlanta, a tertiary center in Atlanta, GA. PARTICIPANTS: Female patients less than 21 years of age diagnosed with vaginal YST. RESULTS: Two cases of vaginal YST at our institution are outlined. Both patients presented within the first 2 years of life with vaginal bleeding and were treated successfully with chemotherapy alone. After review of the literature, 137 cases of vaginal YST were found. The mean age at diagnosis was 11 months, and all patients presented with vaginal bleeding. Before 2000, more radical treatments were pursued, and 40% resulted in death. Since the year 2000, treatment has shifted toward chemotherapy and more conservative surgical management, with 51% of vaginal YST cases treated with chemotherapy alone with 92% of patients alive at time of publication. CONCLUSION: Our cases contribute to the limited literature demonstrating the efficacy of conservative management of rare cases of vaginal YST with chemotherapy alone. This case series and review of the literature provide mounting evidence that vaginal YST should be in the differential diagnosis in young girls with vaginal tumors, and conservative management of vaginal YST has excellent outcomes.
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Tumor do Seio Endodérmico , Neoplasias Vaginais , Tratamento Conservador , Tumor do Seio Endodérmico/diagnóstico , Tumor do Seio Endodérmico/tratamento farmacológico , Feminino , Humanos , Lactente , Estudos Retrospectivos , Hemorragia Uterina/etiologia , Neoplasias Vaginais/diagnóstico , Neoplasias Vaginais/tratamento farmacológicoRESUMO
Structural anomalies of the female reproductive tract, known as Mullerian anomalies, can occur in isolation or in association with anomalies of other organ systems. Due to shared embryology, the most common association in up to 40% of patients is with renal, ureteral, and bladder anomalies. Affected girls can have a wide range of genitourinary symptoms with urologists playing an integral role in their diagnosis and treatment. To facilitate the recognition and management of these conditions, we provide a review of Mullerian anomalies including the embryology, classifications, syndromes, evaluation, and treatments with attention to their urologic applicability.
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Ductos Paramesonéfricos/anormalidades , Anormalidades Urogenitais/complicações , Transtornos 46, XX do Desenvolvimento Sexual/complicações , Malformações Anorretais/complicações , Anus Imperfurado/complicações , Anormalidades Congênitas , Feminino , Genitália Feminina/embriologia , Hérnia Umbilical/complicações , Humanos , Escoliose/complicações , Sistema Urinário/embriologia , Anormalidades Urogenitais/classificação , Anormalidades Urogenitais/diagnóstico , Anormalidades Urogenitais/terapiaRESUMO
Actively transcribed genes in mammals are decorated by H3K79 methylation, which is correlated with transcription levels and is catalyzed by the histone methyltransferase DOT1L. DOT1L is required for mammalian development, and the inhibition of its catalytic activity has been extensively studied for cancer therapy; however, the mechanisms underlying DOT1L's functions in normal development and cancer pathogenesis remain elusive. To dissect the relationship between H3K79 methylation, cellular differentiation, and transcription regulation, we systematically examined the role of DOT1L and its catalytic activity in embryonic stem cells (ESCs). DOT1L is dispensable for ESC self-renewal but is required for establishing the proper expression signature of neural progenitor cells, while catalytic inactivation of DOT1L has a lesser effect. Furthermore, DOT1L loss, rather than its catalytic inactivation, causes defects in glial cell specification. Although DOT1L loss by itself has no major defect in transcription elongation, transcription elongation defects seen with the super elongation complex inhibitor KL-2 are exacerbated in DOT1L knockout cells, but not in catalytically dead DOT1L cells, revealing a role of DOT1L in promoting productive transcription elongation that is independent of H3K79 methylation. Taken together, our study reveals a catalytic-independent role of DOT1L in modulating cell-fate determination and in transcriptional elongation control.