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OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.
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Melanoma , Ganglio Linfático Centinela , Neoplasias Cutáneas , Adulto , Humanos , Adolescente , Niño , Melanoma/diagnóstico por imagen , Melanoma/cirugía , Melanoma/patología , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/cirugía , Ganglio Linfático Centinela/patología , Recurrencia Local de Neoplasia/patología , Escisión del Ganglio Linfático , Biopsia del Ganglio Linfático Centinela , Estudios RetrospectivosRESUMEN
OBJECTIVE: The purpose of this study was to describe management and outcomes from a contemporary cohort of children with Wilms tumor complicated by inferior vena caval thrombus. BACKGROUND: The largest series of these patients was published almost 2 decades ago. Since then, neoadjuvant chemotherapy has been commonly used to manage these patients, and outcomes have not been reported. METHODS: Retrospective review of 19 North American centers between 2009 and 2019. Patient and disease characteristics, management, and outcomes were investigated and analyzed. RESULTS: Of 124 patients, 81% had favorable histology (FH), and 52% were stage IV. IVC thrombus level was infrahepatic in 53 (43%), intrahepatic in 32 (26%), suprahepatic in 14 (11%), and cardiac in 24 (19%). Neoadjuvant chemotherapy using a 3-drug regimen was administered in 82% and postresection radiation in 90%. Thrombus level regression was 45% overall, with suprahepatic level showing the best response (62%). Cardiopulmonary bypass (CPB) was potentially avoided in 67%. The perioperative complication rate was significantly lower after neoadjuvant chemotherapy [(25%) vs upfront surgery (55%); P =0.005]. CPB was not associated with higher complications [CPB (50%) vs no CPB (27%); P =0.08]. Two-year event-free survival was 93% and overall survival was 96%, higher in FH cases (FH 98% vs unfavorable histology/anaplastic 82%; P =0.73). Neither incomplete resection nor viable thrombus cells affected event-free survival or overall survival. CONCLUSIONS: Multimodal therapy resulted in excellent outcomes, even with advanced-stage disease and cardiac extension. Neoadjuvant chemotherapy decreased the need for CPB to facilitate resection. Complete thrombectomy may not always be necessary.
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Neoplasias Renales , Oncología Quirúrgica , Trombosis de la Vena , Tumor de Wilms , Humanos , Niño , Neoplasias Renales/cirugía , Vena Cava Inferior/cirugía , Tumor de Wilms/cirugía , Tumor de Wilms/tratamiento farmacológico , Trombosis de la Vena/patología , Trombectomía/métodos , Estudios Retrospectivos , Nefrectomía/métodosRESUMEN
PURPOSE: Our objectives were to compare overall survival (OS) and pulmonary relapse between patients with metastatic Ewing sarcoma (EWS) at diagnosis who achieve rapid complete response (RCR) and those with residual pulmonary nodules after induction chemotherapy (non-RCR). PATIENTS AND METHODS: This retrospective cohort study included children under 20 years with metastatic EWS treated from 2007 to 2020 at 19 institutions in the Pediatric Surgical Oncology Research Collaborative. Chi-square tests were conducted for differences among groups. Kaplan-Meier curves were generated for OS and pulmonary relapse. RESULTS: Among 148 patients with metastatic EWS at diagnosis, 61 (41.2%) achieved RCR. Five-year OS was 71.2% for patients who achieved RCR, and 50.2% for those without RCR (p = .04), and in multivariable regression among patients with isolated pulmonary metastases, RCR (hazards ratio [HR] 0.42; 95% confidence interval [CI]: 0.17-0.99) and whole lung irradiation (WLI) (HR 0.35; 95% CI: 0.16-0.77) were associated with improved survival. Pulmonary relapse occurred in 57 (37%) patients, including 18 (29%) in the RCR and 36 (41%) in the non-RCR groups (p = .14). Five-year pulmonary relapse rates did not significantly differ based on RCR (33.0%) versus non-RCR (47.0%, p = .13), or WLI (38.8%) versus no WLI (46.0%, p = .32). DISCUSSION: Patients with EWS who had isolated pulmonary metastases at diagnosis had improved OS if they achieved RCR and received WLI, despite having no significant differences in rates of pulmonary relapse.
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Neoplasias Óseas , Neoplasias Pulmonares , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/mortalidad , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patología , Femenino , Masculino , Niño , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/secundario , Estudios Retrospectivos , Adolescente , Neoplasias Óseas/mortalidad , Neoplasias Óseas/terapia , Neoplasias Óseas/secundario , Neoplasias Óseas/patología , Preescolar , Tasa de Supervivencia , Pronóstico , Estudios de Seguimiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto Joven , Inducción de Remisión , Lactante , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Quimioterapia de InducciónRESUMEN
OBJECTIVE: To evaluate the impact of prophylactic antibiotics on early infectious complications after central venous access device (VAD) placement in children with cancer. SUMMARY OF BACKGROUND DATA: Despite the frequency of VAD procedures in children, the effectiveness of prophylactic antibiotics for reducing infectious complications is unknown. METHODS: This was a retrospective cohort study of children with cancer undergoing central VAD placement identified in the Pediatric Health Information System database between 2017-2021. The primary outcome was the rate of early infectious complications (composite surgical site infections, central line-associated bloodstream infections, and bacteremia). Multivariable logistic regression was used to evaluate factors associated with early infection, and heterogeneity of treatment effect of prophylactic antibiotics was compared across subgroups. RESULTS: 9,216 patients were included (6,058 ports and 3,158 tunneled lines). Prophylactic antibiotics were associated with lower early infectious complications overall (1.3% vs. 2.4%; OR 0.55 [95% C.I. 0.39-0.79], P<0.001), an effect demonstrated for tunneled lines (OR 0.59, 95% C.I.: 0.41-0.84) but not ports (OR 3.01, 95% C.I.: 0.66-13.78). On multivariate analysis, prophylactic antibiotics (OR 0.67, 95% C.I.: 0.45-0.97) and solid tumors (OR 0.38, 95% C.I.: 0.22-0.64) were associated with reduced odds of early infections, while tunneled lines (OR 20.78, 95% C.I.: 9.83-43.93) and acute myelogenous leukemia (OR 2.37, 95% C.I.: 1.58-3.57) had increased odds. CONCLUSIONS: Prophylactic antibiotics are associated with reduced early infectious complications after central VAD placement overall. Despite recommendations from multiple national organizations against prophylactic antibiotics, these findings suggest a benefit in children with malignancy undergoing tunneled line placement.
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Wilms tumor (WT) is the most common renal malignancy in children. Children with favorable histology WT achieve survival rates of over 90%. Twelve percent of patients present with metastatic disease, most commonly to the lungs. The presence of a pleural effusion at the time of diagnosis of WT may be noted on staging imaging; however, minimal data exist regarding the significance and prognostic importance of this finding. The objectives of our study are to identify the incidence of pleural effusions in patients with WT, and to determine the potential impact on oncologic outcomes. A multi-institutional retrospective review was performed from January 2009 to December 2019, including children with WT and a pleural effusion on diagnostic imaging treated at Pediatric Surgical Oncology Research Collaborative (PSORC) participating institutions. Of 1259 children with a new WT diagnosis, 94 (7.5%) had a pleural effusion. Patients with a pleural effusion were older than those without (median 4.3 vs 3.5 years; P = .004), and advanced stages were more common (local stage III 85.9% vs 51.9%; P < .0001). Only 14 patients underwent a thoracentesis for fluid evaluation; 3 had cytopathologic evidence of malignant cells. Event-free and overall survival of all children with WT and pleural effusions was 86.2% and 91.5%, respectively. The rate and significance of malignant cells present in pleural fluid is unknown due to low incidence of cytopathologic analysis in our cohort; therefore, the presence of an effusion does not appear to necessitate a change in therapy. Excellent survival can be expected with current stage-specific treatment regimens.
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Neoplasias Renales , Derrame Pleural Maligno , Derrame Pleural , Oncología Quirúrgica , Tumor de Wilms , Niño , Humanos , Incidencia , Neoplasias Renales/epidemiología , Neoplasias Renales/cirugía , Derrame Pleural/epidemiología , Derrame Pleural/etiología , Derrame Pleural Maligno/epidemiología , Derrame Pleural Maligno/etiología , Derrame Pleural Maligno/cirugía , Estudios Retrospectivos , Tumor de Wilms/epidemiología , Tumor de Wilms/cirugíaRESUMEN
PURPOSE: The majority of pediatric patients with choledochal cysts (CDC) are symptomatic prior to undergoing CDC excision. This study investigated the impact of surgical timing of CDC excision on postoperative outcomes among children. METHODS: We performed a retrospective review of 59 patients undergoing open CDC excision with Roux-Y hepaticojejunostomy between 2000 and 2020. Patients were grouped based on whether they underwent an electively scheduled or urgent CDC excision, as defined as CDC excision within the same admission due to CDC-related symptoms. Patient characteristics and perioperative data were compared between the two groups. RESULTS: Patients who underwent an elective surgery were older, had more Todani-type 1 CDC, and had decreased postoperative hospital length of stay and opioid use compared to patients who underwent CDC excision within the same admission due to CDC-related symptoms. No significant differences emerged regarding postoperative complications. Multivariable analysis showed that elective cyst excision (HR = 0.55, p = 0.04; HR = 0.59, p = 0.008) and type 1 CDC (HR = 0.32, p = 0.03; HR = 0.12, p < 0.001) were independently associated with decreased opioid use and postoperative hospital length of stay. CONCLUSIONS: Elective CDC excision is associated with shortened hospital stay and decreased opioid use among children compared to patients who undergo a CDC excision during the same admission for CDC-related symptoms.
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Quiste del Colédoco , Laparoscopía , Analgésicos Opioides , Anastomosis en-Y de Roux , Niño , Quiste del Colédoco/diagnóstico , Quiste del Colédoco/cirugía , Humanos , Laparoscopía/efectos adversos , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: We evaluated the impact of a virtual Pediatric Surgery Bootcamp curriculum on resource utilization, learner engagement, knowledge retention, and stakeholder satisfaction. METHODS: A virtual curriculum was developed around Pediatric Surgery Milestones. GlobalCastMD delivered pre-recorded and live content over a single 10-h day with a concluding social hour. Metrics of learner engagement, faculty interaction, knowledge retention, and satisfaction were collected and analyzed during and after the course. RESULTS: Of 56 PS residencies, 31 registered (55.4%; 8/8 Canadian and 23/48 US; p = 0.006), including 42 learners overall. The virtual BC budget was $15,500 (USD), 54% of the anticipated in-person course. Pre- and post-tests were administered, revealing significant knowledge improvement (48.6% [286/589] vs 66.9% [89/133] p < 0.0002). Learner surveys (n = 14) suggested the virtual BC facilitated fellowship transition (85%) and strengthened peer-group camaraderie (69%), but in-person events were still favored (77%). Program Directors (PD) were surveyed, and respondents (n = 22) also favored in-person events (61%). PDs not registering their learners (n = 7) perceived insufficient value-added and concern for excessive participants. CONCLUSIONS: The virtual bootcamp format reduced overall expenses, interfered less with schedules, achieved more inclusive reach, and facilitated content archiving. Despite these advantages, learners and program directors still favored in-person education. LEVEL OF EVIDENCE: III.
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COVID-19 , Internado y Residencia , Canadá , Niño , Competencia Clínica , Curriculum , Humanos , Evaluación de Programas y Proyectos de SaludRESUMEN
Minimally invasive surgery (MIS) to resect primary and metastatic pediatric embryonal tumors offers the potential for reduced postoperative morbidity with smaller wounds, less pain, fewer surgical site infections, decreased blood loss, shorter hospital stays, and less disruption to treatment regimens. However, significant controversy surrounds the question of whether a high-fidelity oncologic resection of childhood embryonal tumors with gross total resection, negative margins, and appropriate lymph node sampling can be achieved through MIS. This review outlines the diverse applications of MIS to treat definitively pediatric embryonal malignancies, including this approach to metastatic deposits. It outlines specific patient populations and presentations that may be particularly amenable to the minimally invasive approach. This work further summarizes the current evidence supporting the efficacy of MIS to accomplish a definitive, oncologic resection without compromising relapse-free or overall survival. Finally, the review offers technical considerations to consider in order to achieve a safe and complete resection.
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Neoplasias de Células Germinales y Embrionarias/cirugía , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Terapia Neoadyuvante , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Neoplasias de Células Germinales y Embrionarias/patología , NeuroblastomaRESUMEN
BACKGROUND: Biliary atresia (BA) is a rare obstructive cholangiopathy that presents in early infancy. The Kasai portoenterostomy (PE) improves survival with the native liver. Epidural analgesia is an appealing option to control pain in this fragile patient population, yet its safety, efficacy, and potential benefits remain unproven. METHODS: Patients undergoing PE for BA between 2001 and 2016 at a single institution were identified by ICD codes. Preoperative laboratories, procedure details, and recovery outcomes were reviewed retrospectively. Outcomes of interest were need for postoperative mechanical ventilation, pain scores, normalized opioid administration, return of bowel function, and length of hospital stay after PE. RESULTS: Of 47 infants undergoing PE for BA, 25 received epidural analgesia, and 22 did not. Infants with epidurals received less systemic opioids over the first 96 h postoperatively than those without (P < 0.001). Epidurals were associated with lower pain scores between 6 and 30 h postoperatively (P = 0.01 to 0.04), during which the highest median 6-h interval pain score was 0.2 (IQR 0-1.3) for patients with epidurals yet 2.1 (IQR 1.2-3.3) for patients without. Patients with epidurals (88%, n = 22) were more commonly extubated before leaving the operating room than those without (59%, n = 13; P = 0.02). No significant difference was observed in time to first bowel movement (P = 0.48) or first oral feed (P = 0.81). However, infants with epidurals had shorter hospital stays after PE than those without (6 d [IQR 5-7] versus 8 d [IQR 6.3-11], P = 0.01). No major complications were associated with epidural catheters. CONCLUSIONS: Epidural analgesia in patients undergoing PE for BA appears safe and effectively controls pain while minimizing the need for systemic opioids. Reduced need for mechanical ventilation postoperatively and shortened hospital stays serve as further evidence for using epidurals to enhance recovery after PE.
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Analgesia Epidural , Analgésicos Opioides/administración & dosificación , Atresia Biliar/cirugía , Portoenterostomía Hepática/rehabilitación , Femenino , Humanos , Lactante , Masculino , Estudios RetrospectivosRESUMEN
Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub-Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub-Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment-resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT-associated genes and evaluated whole-genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow-up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment-resistant.
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Aberraciones Cromosómicas , Genes del Tumor de Wilms , Neoplasias Renales/genética , Tumor de Wilms/genética , Preescolar , Estudios de Cohortes , Femenino , Dosificación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Kenia , Masculino , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
PURPOSE: Wilms tumor is the most common renal neoplasm of childhood. We previously found that restricted activation of the WNT/ß-catenin pathway in renal epithelium late in kidney development is sufficient to induce small primitive neoplasms with features of epithelial Wilms tumor. Metastatic disease progression required simultaneous addition of an activating mutation of the oncogene K-RAS. We sought to define the molecular pathways activated in this process and their relationship to human renal malignancies. MATERIALS AND METHODS: Affymetrix® expression microarray data from murine kidneys with activation of K-ras and/or Ctnnb1 (ß-catenin) restricted to renal epithelium were analyzed and compared to publicly available expression data on normal and neoplastic human renal tissue. Target genes were verified by immunoblot and immunohistochemistry. RESULTS: Mouse kidney tumors with activation of K-ras and Ctnnb1, and human renal malignancies had similar mRNA expression signatures and were associated with activation of networks centered on ß-catenin and TP53. Up-regulation of WNT/ß-catenin targets (MYC, Survivin, FOXA2, Axin2 and Cyclin D1) was confirmed by immunoblot. K-RAS/ß-catenin murine kidney tumors were more similar to human Wilms tumor than to other renal malignancies and demonstrated activation of a TP53 dependent network of genes, including the transcription factor E2F1. Up-regulation of E2F1 was confirmed in murine and human Wilms tumor samples. CONCLUSIONS: Simultaneous activation of K-RAS and ß-catenin in embryonic renal epithelium leads to neoplasms similar to human Wilms tumor and associated with activation of TP53 and up-regulation of E2F1. Further studies are warranted to evaluate the role of TP53 and E2F1 in human Wilms tumor.
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Modelos Animales de Enfermedad , Factor de Transcripción E2F1/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Renales/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteína p53 Supresora de Tumor/genética , Tumor de Wilms/genética , beta Catenina/genética , Animales , Genotipo , Riñón/metabolismo , Ratones , Ratones Mutantes , Análisis de Secuencia por Matrices de Oligonucleótidos , Activación Transcripcional/genética , Transcriptoma/genética , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: The 2013 Children's Oncology Group (COG) blueprint for renal tumor research challenges investigators to develop new, risk-specific biological therapies for unfavorable histology and higher-risk Wilms tumor (WT) in an effort to close a persistent survival gap and to reduce treatment toxicities. As an initial response to this call from the COG, we used imaging mass spectrometry to determine peptide profiles of WT associated with adverse outcomes. MATERIALS AND METHODS: We created a WT tissue microarray containing 2-mm punches of formalin-fixed, paraffin-embedded specimens archived from 48 sequentially treated WT patients at our institutions. Imaging mass spectrometry was performed to compare peptide spectra between three patient groups as follows: unfavorable versus favorable histology, treatment success versus failure, and COG higher- versus lower-risk disease. Statistically significant peptide peaks differentiating groups were identified and incorporated into a predictive model using a genetic algorithm. RESULTS: One hundred thirty-one peptide peaks were differentially expressed in unfavorable versus favorable histology WT (P < 0.05). Two hundred three peaks differentiated treatment failure from success (P < 0.05). Seventy-one peaks differentiated COG higher-risk disease from the very-low, low, and standard-risk groups (P < 0.05). These peaks were used to develop predictive models that could differentiate among patient groups 98.49%, 94.46%, and 98.55% of the time, respectively. Spectral patterns were internally cross-validated using a leave-20% out model. CONCLUSIONS: Peptide spectra can discriminate adverse behavior of WT. After future external validation and refinement, these models could be used to predict WT behavior and to stratify intensity of chemotherapy regimens. Furthermore, peptides discovered in the model could be sequenced to identify potential risk-specific drug targets.
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Neoplasias Renales/metabolismo , Péptidos/metabolismo , Tumor de Wilms/metabolismo , Niño , Preescolar , Femenino , Humanos , Riñón/patología , Neoplasias Renales/patología , Neoplasias Renales/terapia , Masculino , Pronóstico , Estudios Retrospectivos , Análisis de Matrices Tisulares , Insuficiencia del Tratamiento , Tumor de Wilms/patología , Tumor de Wilms/terapiaRESUMEN
BACKGROUND: Survival from Wilms tumor (WT) in sub-Saharan Africa remains dismal as a result of on-therapy mortality and treatment abandonment. Review of patients diagnosed from 2008 to 2011 in our Kenyan Wilms Tumor Registry showed a loss to follow up (LTFU) rate approaching 50%. The purpose of this study was to trace those LTFU, estimate the survival rate, and identify risk factors for treatment abandonment. PROCEDURE: We administered a comprehensive survey to parents of patients with WT at the two largest referral hospitals in Kenya to identify barriers to care. We also telephoned families who had abandoned care to determine vital status and identify risk factors for treatment abandonment. RESULTS: Of 136 registered patients, 77 were confirmed dead (56.7%), 38 remained alive (27.9%), and the vital status of 21 patients remains unknown (15.4%). After contacting 33 of the patients who either abandoned curative treatment (n = 34) or did not attend off-therapy visits (n = 20), the best estimate of 2-year overall survival of patients with WT in Kenya approaches 36%. Sixty-three percent of parents misunderstood treatment plans and 55% encountered financial barriers. When asked how to increase comfort with the child's treatment, 27% of parents volunteered improving inefficient services and 26% volunteered reducing drug-unavailability. CONCLUSIONS: Treatment abandonment remains a significant problem contributing to increased mortality from WT in developing countries. This multi-center survey identified the barriers to treatment completion from the parental perspective to be lack of education about WT and treatment, financial constraints, need for quality improvement, and drug-unavailability. Pediatr Blood Cancer 2015;62:252-256. © 2014 Wiley Periodicals, Inc.
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Costo de Enfermedad , Tumor de Wilms/mortalidad , Tumor de Wilms/terapia , Privación de Tratamiento/estadística & datos numéricos , Humanos , Kenia , Encuestas y Cuestionarios , Tasa de SupervivenciaRESUMEN
BACKGROUND: The Yes-associated-protein-1 (YAP1) is a novel, direct regulator of stem cell genes both in development and cancer. FAT4 is an upstream regulator that induces YAP1 cytosolic sequestering by phosphorylation (p-Ser 127) and therefore inhibits YAP1-dependent cellular proliferation. We hypothesized that loss of FAT4 signaling would result in expansion of the nephron progenitor population in kidney development and that YAP1 subcellular localization would be dysregulated in Wilms tumor (WT), an embryonal malignancy that retains gene expression profiles and histologic features reminiscent of the embryonic kidney. METHODS: Fetal kidneys from Fat4(-/-) mice were harvested at e18.5 and markers of nephron progenitors were investigated using immunohistochemical analysis. To examine YAP1 subcellular localization in WT, a primary WT cell line (VUWT30) was analyzed by immunofluorescence. Forty WT specimens evenly distributed between favorable and unfavorable histology (n = 20 each), and treatment failure or success (n = 20 each) was analyzed for total and phosphorylated YAP1 using immunohistochemistry and Western blot. RESULTS: Fat4(-/-) mouse fetal kidneys exhibit nuclear YAP1 with increased proliferation and expansion of nephron progenitor cells. In contrast to kidney development, subcellular localization of YAP1 is dysregulated in WT, with a preponderance of nuclear p-YAP1. By Western blot, median p-YAP1 quantity was 5.2-fold greater in unfavorable histology WT (P = 0.05). CONCLUSIONS: Fetal kidneys in Fat4(-/-) mice exhibit a phenotype reminiscent of nephrogenic rests, a WT precursor lesion. In WT, YAP1 subcellular localization is dysregulated and p-YAP1 accumulation is a novel biomarker of unfavorable histology.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/fisiología , Embrión de Mamíferos/patología , Regulación del Desarrollo de la Expresión Génica , Riñón/embriología , Riñón/patología , Fosfoproteínas/metabolismo , Fosfoproteínas/fisiología , Tumor de Wilms/patología , Animales , Western Blotting , Proteínas de Ciclo Celular , Núcleo Celular/metabolismo , Núcleo Celular/patología , Proliferación Celular , Células Cultivadas , Preescolar , Embrión de Mamíferos/metabolismo , Femenino , Células HeLa , Humanos , Técnicas para Inmunoenzimas , Riñón/metabolismo , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Ratones , Ratones Noqueados , Nefronas/metabolismo , Nefronas/patología , Fosforilación , Transporte de Proteínas , Células Madre/metabolismo , Células Madre/patología , Fracciones Subcelulares , Factores de Transcripción , Tumor de Wilms/metabolismo , Proteínas Señalizadoras YAPAsunto(s)
Neoplasias Renales , Tumor de Wilms , Niño , Humanos , Oncología Médica , Recurrencia Local de Neoplasia , Estudios RetrospectivosRESUMEN
Introduction: Achalasia among children often fails endoscopic management (e.g., dilation, botulinum toxin). Laparoscopic esophagocardiomyotomy (L-ECM) is a standard intervention to relieve obstruction but can induce gastroesophageal reflux (GER). Concurrent anterior fundoplication (A-fundo) has been evaluated in randomized trials among adults, demonstrating mixed results on controlling postoperative GER without exacerbating dysphagia. Furthermore, evidence for the best approach among children remains sparse. We hypothesized that, among children undergoing L-ECM without mucosal violation, routine A-fundo would not improve postoperative GER control while exacerbating dysphagia. Materials and Methods: Observational data of 47 consecutive achalasia patients ≤18 years who received L-ECM (2002-2023) at a single academic institution were collected. Patient records were culled for demographics, achalasia characteristics, and outcomes. Two L-ECM groups were identified: with or without A-fundo. Patients were screened for postoperative dysphagia (additional procedures) and GER (new antireflux medications). Univariate independence testing was conducted to identify statistically significant variables. Results: Among 47 patients undergoing L-ECM, 28 (59.6%) received concurrent A-fundo. Compared with patients undergoing L-ECM alone, patients with L-ECM/A-fundo had significantly longer hospital stays (P < .01) without statistically different rates of postoperative dysphagia (P = .81) or GER (P = .51). Five children (10.6%) experienced mucosal injury with L-ECM: 4 recognized intraoperatively received A-Fundo without subsequent leak; 1 mucosal injury was missed and did not receive A-Fundo, which subsequently leaked. Conclusion: In this largest observation of pediatric achalasia patients, A-fundo appeared clinically insignificant when determining contributors to control GER or exacerbate postoperative dysphagia. A-fundo should not be routinely adopted in children having L-ECM for achalasia without further multicenter analysis but appears beneficial in cases having inadvertent mucosal violation.
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Trastornos de Deglución , Acalasia del Esófago , Fundoplicación , Reflujo Gastroesofágico , Laparoscopía , Complicaciones Posoperatorias , Humanos , Acalasia del Esófago/cirugía , Fundoplicación/métodos , Femenino , Masculino , Niño , Complicaciones Posoperatorias/etiología , Reflujo Gastroesofágico/cirugía , Laparoscopía/métodos , Laparoscopía/efectos adversos , Trastornos de Deglución/etiología , Adolescente , Preescolar , Estudios Retrospectivos , Resultado del Tratamiento , Cardias/cirugía , Esófago/cirugíaRESUMEN
INTRODUCTION: Predicted 1-year survival of children with trisomy 18 (T18) has increased to 59.3%. We aimed to systematically review the characteristics, management, and outcomes of children with T18 and hepatoblastoma. METHODS: A systematic literature review of the PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases was performed according to the PRISMA 2020 statement (end-of-search date: 03/03/2024). RESULTS: Fifty studies reporting on 70 patients were included. The median age at diagnosis was 11.5 months, 85.9% were female (n = 55/64), and 15.0% had mosaic T18 (n = 6/40). Diagnosis was made during symptom evaluation (most commonly hepatomegaly or abdominal mass) in 45.5% (n = 15/33), incidentally in 24.2% (n = 8/33), during surveillance with abdominal ultrasound in 18.2% (n = 6/33), and at autopsy in 12.1% (n = 4/33). The median tumor size was 6.4 cm, 33.3% had multiple tumors (n = 14/42), and metastasis was present in one patient (3.8%; n = 1/26). Neoadjuvant chemotherapy was administered in 42.6% (n = 26/61) and adjuvant chemotherapy in 31.6% (n = 18/57). Surgical treatment was performed in 64.2% (n = 43/67). Of the patients not diagnosed on autopsy, overall mortality was 35.5% (n = 22/62) over a median follow-up of 11.0 months. Among the 26 deceased patients (including those diagnosed on autopsy), the most common causes of death were cardiopulmonary disease (38.5%, n = 10/26) and tumor progression (30.8%, n = 8/26). CONCLUSIONS: T18 does not preclude resection with curative intent for hepatoblastoma. Combination of surgery and chemotherapy should be considered in children on an individualized basis depending on tumor characteristics and underlying cardiopulmonary comorbidities. Locoregional modalities may have a role in the setting of severe comorbidities. LEVEL OF EVIDENCE: Level IV evidence.
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BACKGROUND: Between 2005 and 2014, Ghana's Wilms tumor (WT) 2-year disease-free survival of 44% trailed behind that of high-income countries. This study aimed to uncover social determinants of health leading to preventable WT death in Ghana. METHODS: WT patient records (2014-2022) at Korle-Bu Teaching Hospital (KBTH; Ghana) were reviewed retrospectively. Demographics, clinical course, tumor characteristics, and survival were evaluated using t-tests, Pearson Chi-square, and multivariate Cox logistic regression. RESULTS: Of 127 patients identified, 65 were female. Median age was 44 months [IQR 25-66]. Forty-eight patients (38%) presented with distant metastasis (75% lung, 25% liver), which associated with hypoalbuminemia (p = 0.009), caregiver informal employment (p = 0.04), and larger tumors (p = 0.002). Despite neoadjuvant chemotherapy shrinking 84% of tumors, larger initial size associated with incomplete resection (p = 0.046). Of 110 nephrectomies, 31 patients had residual disease, negatively impacting survival (p = 2.7 × 10-5). Twenty-two patients (17%) abandoned treatment (45% before nephrectomy; 55% after nephrectomy), with seven patients ultimately lost to follow-up (LTFU). Decedents represented 43% of stage IV patients compared to 28% in other stages. Event-free survival (EFS) was 60% at 4 years with overall survival (OS) at 67%. CONCLUSIONS: Although Ghana's WT survival has improved, informal employment and distance from KBTH predisposed patients to delayed referral, greater tumor burden, hypoalbuminemia, and lower survival. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: II.
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Neoplasias Renales , Nefrectomía , Tumor de Wilms , Humanos , Tumor de Wilms/terapia , Tumor de Wilms/mortalidad , Tumor de Wilms/patología , Tumor de Wilms/cirugía , Ghana/epidemiología , Femenino , Masculino , Estudios Retrospectivos , Preescolar , Neoplasias Renales/terapia , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Neoplasias Renales/cirugía , Carga Tumoral , Lactante , Niño , Supervivencia sin Enfermedad , Determinantes Sociales de la Salud , Terapia Neoadyuvante/estadística & datos numéricosRESUMEN
BACKGROUND: To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2. STUDY DESIGN: For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups. RESULTS: Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321. CONCLUSIONS: Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients.
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Neoplasias Renales , Tumor de Wilms , Niño , Humanos , Anaplasia , Etnicidad , Hispánicos o Latinos , Neoplasias Renales/terapia , Neoplasias Renales/patología , Tumor de Wilms/genética , Tumor de Wilms/terapia , Negro o Afroamericano , Grupos Raciales , Tasa de SupervivenciaRESUMEN
BACKGROUND: The current research environment for academic surgeons demands that extramural funding be obtained. Financial support from the National Institutes of Health (NIH) is historically the gold standard for funding in the biomedical research community, with the R01 funding mechanism viewed as indicator of research independence. The NIH also supports a mentor-based career development mechanism (K-series awards) in order to support early-stage investigators. The goal of this study was to investigate the grants successfully awarded to pediatric surgeon-scientists and then determine the success of the K-series award recipients at achieving research independence. METHODS: In July 2012, all current members of the American Pediatric Surgery Association (APSA) were queried in the NIH database from 1988-2012 through the NIH Research Portfolio Online Reporting Tools. The following factors were analyzed: type of grant, institution, amount of funding, and funding institute or center. RESULTS: Among current APSA members, there have been 83 independent investigators receiving grants, representing 13% of the current APSA membership, with 171 independent grants funded through various mechanisms. Six percent currently have active NIH funding, with $7.2 million distributed in 2012. There have been 28 K-series grants awarded. Of the recipients of expired K08 awards, 39% recipients were subsequently awarded an R01 grant. A total of 63% of these K-awarded investigators transitioned to an independent NIH award mechanism. CONCLUSIONS: Pediatric surgeon-scientists successfully compete for NIH funding. Our data suggest that although the K-series funding mechanism is not the only path to research independence, over half of the pediatric surgeons who receive a K-award are successful in the transition to independent investigator.