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1.
J Surg Res ; 251: 47-52, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32113037

RESUMO

BACKGROUND: Long-gap esophageal atresia (LGEA) precludes immediate primary repair. When delayed primary esophagoesophagostomy (DPE) is not feasible, a reverse gastric tube (RGT) is a potential salvage option. The purpose of this study was to determine if DPE and RGT had both similar short-term and long-term outcomes. METHODS: A retrospective review of all EA patients from 1994 to 2016 was undertaken. Data were stratified by surgical management (DPE versus RGT). Baseline demographics, operative information, postoperative management, and complications were analyzed. Descriptive statistics were used and P-values <0.05 were considered statistically significant. RESULTS: Two hundred and eighteen patients with EA were treated during this period; 37/218 (17%) had LGEA. Mean gap length was 3.3 ± 1.2 cm. Thirty-three patients underwent some form of repair, all of which were managed initially with a gastrostomy tube feeds. Twenty-five patients underwent DPE with 89% of these never requiring revision, and 86% having excellent function with long-term follow-up. In eight patients, esophageal length was never adequate for DPE; therefore, six were reconstructed with RGT, and two underwent gastric transposition. There were no significant differences in complications, revisions, ventilator days, overall length of stay, weight percentiles, or conduit function between children undergoing RGT compared with DPE at a mean follow-up of 5.5 years. CONCLUSIONS: Surgical treatment of LGEA is complex, and controversy exists regarding the optimal repair method when DPE is not feasible. In this series, DPE after gastrostomy tube feeds often allowed for sufficient esophageal lengthening with satisfactory long-term esophageal function. However, when adequate length for DPE was not attainable, these data suggest that RGT is a viable conduit with favorable postoperative outcomes.

2.
J Immunol ; 202(12): 3458-3467, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31036766

RESUMO

Immune checkpoint inhibitors are effective in treating a variety of malignancies, including metastatic bladder cancer. A generally accepted hypothesis suggests that immune checkpoint inhibitors induce tumor regressions by reactivating a population of endogenous tumor-infiltrating lymphocytes (TILs) that recognize cancer neoantigens. Although previous studies have identified neoantigen-reactive TILs from several types of cancer, no study to date has shown whether neoantigen-reactive TILs can be found in bladder tumors. To address this, we generated TIL cultures from patients with primary bladder cancer and tested their ability to recognize tumor-specific mutations. We found that CD4+ TILs from one patient recognized mutated C-terminal binding protein 1 in an MHC class II-restricted manner. This finding suggests that neoantigen-reactive TILs reside in bladder cancer, which may help explain the effectiveness of immune checkpoint blockade in this disease and also provides a rationale for the future use of adoptive T cell therapy targeting neoantigens in bladder cancer.

3.
J Med Genet ; 56(6): 370-379, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30745422

RESUMO

INTRODUCTION: Hereditary diffuse gastric cancer (HDGC) is a cancer syndrome associated with variants in E-cadherin (CDH1), diffuse gastric cancer and lobular breast cancer. There is considerable heterogeneity in its clinical manifestations. This study aimed to determine associations between CDH1 germline variant status and clinical phenotypes of HDGC. METHODS: One hundred and fifty-two HDGC families, including six previously unreported families, were identified. CDH1 gene-specific guidelines released by the Clinical Genome Resource (ClinGen) CDH1 Variant Curation Expert Panel were applied for pathogenicity classification of truncating, missense and splice site CDH1 germline variants. We evaluated ORs between location of truncating variants of CDH1 and incidence of colorectal cancer, breast cancer and cancer at young age (gastric cancer at <40 or breast cancer <50 years of age). RESULTS: Frequency of truncating germline CDH1 variants varied across functional domains of the E-cadherin receptor gene and was highest in linker (0.05785 counts/base pair; p=0.0111) and PRE regions (0.10000; p=0.0059). Families with truncating CDH1 germline variants located in the PRE-PRO region were six times more likely to have family members affected by colorectal cancer (OR 6.20, 95% CI 1.79 to 21.48; p=0.004) compared with germline variants in other regions. Variants in the intracellular E-cadherin region were protective for cancer at young age (OR 0.2, 95% CI 0.06 to 0.64; p=0.0071) and in the linker regions for breast cancer (OR 0.35, 95% CI 0.12 to 0.99; p=0.0493). Different CDH1 genotypes were associated with different intracellular signalling activation levels including different p-ERK, p-mTOR and ß-catenin levels in early submucosal T1a lesions of HDGC families with different CDH1 variants. CONCLUSION: Type and location of CDH1 germline variants may help to identify families at increased risk for concomitant cancers that might benefit from individualised surveillance and intervention strategies.

4.
Am Surg ; 84(6): 813-819, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29981607

RESUMO

Trauma is a major cause of morbidity and mortality in the pediatric population. However, temporal variations of trauma have not been well characterized and may have implications for appropriate allocation of hospital resources. Data from patients evaluated at an ACS-verified Level I pediatric trauma center between 2011 and 2015 were retrospectively analyzed. Date and time of injury, type of injury (blunt vs penetrating), and postemergency department disposition were reviewed. To assess temporal trends, heatmaps were constructed and a mixed poisson regression model was used to assess statistical significance. Pediatric trauma from blunt and penetrating injuries occurred at significantly higher rates between the hours of 1800 and 0100, on weekends compared with weekdays, and from May to August compared with November to February. These data provide useful information for hospital resource utilization. The emergency department, operating room, and intensive care unit should be prepared for increased trauma-related volume between May and August, weekends, and evening hours by appropriately increasing staff volume and resource availability.


Assuntos
Recursos em Saúde/estatística & dados numéricos , Periodicidade , Centros de Traumatologia/estatística & dados numéricos , Ferimentos não Penetrantes/epidemiologia , Ferimentos Penetrantes/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
5.
Mol Cancer Ther ; 17(9): 2013-2023, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29934340

RESUMO

In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC), and less than 20% will survive 5 years. Positron emission tomography avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits proapoptotic functions. Higher expression in EAC has been associated with improved disease-specific survival, lack of lymph node involvement, reduced perineural invasion, and increased tumor differentiation. We hypothesized that TXNIP may act as a tumor suppressor that sensitizes EAC cells to standard chemotherapeutics. EAC cell lines and a Barrett epithelial cell line were used. qRT-PCR, immunoblot, and immunofluorescence techniques evaluated gene expression. TXNIP was stably overexpressed or knocked down using lentiviral RNA transduction techniques. Murine xenograft methods examined growth following overexpression of TXNIP. Apoptosis and DNA damage were measured by annexin V and γH2AX assays. Activation of the intrinsic apoptosis was quantitated with green fluorescence protein-caspase 3 reporter assay. In cultured cells and an esophageal tissue array, TXNIP expression was higher in Barrett epithelia and normal tissue compared with EAC. Constitutive overexpression of TXNIP decreased proliferation, clonogenicity, and tumor xenograft growth. TXNIP overexpression increased, whereas knockdown abrogated, DNA damage and apoptosis following cisplatin treatment. An HDAC inhibitor, entinostat (currently in clinical trials), upregulated TXNIP and synergistically increased cisplatin-mediated DNA damage and apoptosis. TXNIP is a tumor suppressor that is downregulated in EACC. Its reexpression dramatically sensitizes these cells to cisplatin. Our findings support phase I/II evaluation of "priming" strategies to enhance the efficacy of conventional chemotherapeutics in EAC. Mol Cancer Ther; 17(9); 2013-23. ©2018 AACR.


Assuntos
Adenocarcinoma/tratamento farmacológico , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Proteínas de Transporte/genética , Dano ao DNA , Neoplasias Esofágicas/tratamento farmacológico , Piridinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos Nus , Ativação Transcricional/efeitos dos fármacos
6.
J Pediatr Surg Case Rep ; 22: 47-49, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29130032

RESUMO

This report presents the successful treatment of a child with a solitary metastatic lesion to the calvarium following treatment for Stage III anaplastic Wilms' Tumor.

7.
J Clin Pathol ; 69(9): 826-33, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27406052

RESUMO

AIM: To evaluate possible colon involvement in the 'gastric adenocarcinoma and proximal polyposis of the stomach' (GAPPS) gastrointestinal polyposis syndrome. METHODS: Prospective clinicopathological evaluation of two GAPPS families and expression of nuclear ß-catenin, p53 and Ki67 measured by immunohistochemistry on endoscopic and surgical specimens from patients with GAPPS. RESULTS: Patients with the GAPPS phenotype were more frequently affected by colonic polyps than patients at risk within the same families (p<0.01). Colonic polyps shared immunohistochemical features of fundic gland polyps and gastric cancers including increased expression of nuclear ß-catenin, Ki67 and p53. Both gastric and colonic lesions harboured activating somatic variants of ß-catenin signalling. CONCLUSIONS: Similarities in expression markers in fundic gland and colonic polyps, together with an enrichment of colonic adenomas in family members affected by GAPPS phenotype compared with family members at risk, support mild colonic involvement of this rare cancer syndrome. Colonoscopic screening might be warranted. CLINICAL TRIAL REGISTRATION NUMBER: #09-C-0079; Results.


Assuntos
Adenocarcinoma/metabolismo , Pólipos Adenomatosos/metabolismo , Pólipos do Colo/metabolismo , Neoplasias Gástricas/metabolismo , beta Catenina/metabolismo , Adenocarcinoma/patologia , Pólipos Adenomatosos/patologia , Adulto , Pólipos do Colo/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Prospectivos , Neoplasias Gástricas/patologia , Adulto Jovem
8.
Int J Endocr Oncol ; 3(2): 161-174, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27213037

RESUMO

Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Unlike many other cancers, there has been little improvement in patient outcome over the past several decades. However, as scientific advancements are made and our understanding of the molecular genetics involved in ACC improve then progress may be achieved in this devastating disease. This review focuses on recent literature published in the field of ACC from 2010 to 2015 with an emphasis on improving diagnosis, staging and treatment for ACC.

9.
J Gastrointest Surg ; 20(2): 293-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26553264

RESUMO

INTRODUCTION: The natural history of radiographic strictures of the pancreaticojejunostomy (PJ) after pancreatoduodenectomy (PD) is difficult to characterize. The purpose of this study was to identify the indications for operative revision of PJ strictures after PD for benign and malignant disease and to evaluate its safety and clinical efficacy. METHODS: A retrospective review of all patients undergoing operative revision of PJ strictures following PD at a single academic institution over an 8-year period (2006-2014) was performed. RESULTS: Twenty-seven patients underwent revision of a symptomatic radiographically detectable PJ stricture. The median time from PD to PJ stricture diagnosis was 46 months. The median increase in the main pancreatic duct diameter between the time of PD and PJ revision was 2 mm. The overall morbidity after PJ revision was 26 %. No postoperative mortality occurred. Twenty-one (78 %) patients experienced resolution of symptoms without recurrent acute pancreatitis after PJ revision during a median follow-up of 30 months. Durable symptom resolution was reported among 60 % of patients with chronic pancreatitis. CONCLUSIONS: Surgical revision of pancreaticojejunostomy strictures is technically safe and clinically effective for selected patients who experience recurrent acute pancreatitis after pancreatoduodenectomy for either benign or malignant disease.


Assuntos
Ductos Pancreáticos/patologia , Pancreaticoduodenectomia/efeitos adversos , Pancreaticojejunostomia/efeitos adversos , Pancreatite Crônica/cirurgia , Adulto , Idoso , Constrição Patológica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite Crônica/etiologia , Pancreatite Crônica/patologia , Reoperação , Estudos Retrospectivos , Resultado do Tratamento
10.
J Pediatr Surg ; 46(6): 1029-33, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21683193

RESUMO

PURPOSE: The objective of our study was to quantify mucosal bacterial DNA within specimens from neonates undergoing small bowel resection for necrotizing enterocolitis (NEC). METHODS: We obtained clinical information and pathologic specimens from all infants diagnosed with NEC who underwent surgical treatment at our institution from 1999 to 2008. Bacterial and human DNA were isolated from paraffin-embedded surgical specimens, and real time polymerase chain reaction was used to amplify bacterial and human genes. Linear regression was used to quantify the amount of human and bacterial DNA in our specimens. RESULTS: From a cohort of 50 infants, we identified 23 infants who underwent both surgical resection and subsequent intestinal reanastomosis. Thirteen (59%) of the neonates had Bell stage III NEC, and 9 (41%) had stage II. There was significantly more bacterial DNA in the resection specimens than in the reanastomosis specimens. This corresponds to a median (interquartile range) increase of 1.81 (1.11-4.69)-fold bacterial DNA in the resection specimen compared with the reanastomosis specimen (P < .05). CONCLUSION: There is more bacterial DNA in infants with acute NEC compared with the same infants after the NEC had clinically resolved. These findings underscore the potential relevance of adherent or invasive bacteria across the bowel wall in the pathogenesis of NEC.


Assuntos
DNA Bacteriano/análise , Enterocolite Necrosante/microbiologia , Enterocolite Necrosante/cirurgia , Mucosa Intestinal/microbiologia , Centros Médicos Acadêmicos , Fatores Etários , Translocação Bacteriana , Biópsia por Agulha , Estudos de Coortes , Enterocolite Necrosante/patologia , Feminino , Hospitais Pediátricos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de Risco , Sensibilidade e Especificidade , Inclusão do Tecido
11.
J Pediatr Surg ; 46(6): 1045-51, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21683196

RESUMO

PURPOSE: In animal models, the small intestine responds to massive small bowel resection (SBR) through a compensatory process termed adaptation, characterized by increases in both villus height and crypt depth. This study seeks to determine whether similar morphologic alterations occur in humans after SBR. METHODS: Clinical data and pathologic specimens of infants who had both an SBR for necrotizing enterocolitis and an ostomy takedown from 1999 to 2009 were reviewed. Small intestine mucosal morphology was compared in the same patients at the time of SBR and at the time of ostomy takedown. RESULTS: For all samples, there was greater villus height (453.6 ± 20.4 vs 341.2 ± 12.4 µm, P < .0001) and crypt depth (178.6 ± 7.2 vs 152.6 ± 6 µm, P < .01) in the ostomy specimens compared with the SBR specimens. In infants with paired specimens, there was an increase of 31.7% ± 8.3% and 22.1% ± 10.0% in villus height and crypt depth, respectively. There was a significant correlation between the amount of intestine resected and the percent change in villus height (r = 0.36, P < .05). CONCLUSION: Mucosal adaptation after SBR in human infants is similar to what is observed in animal models. These findings validate the use of animal models of SBR used to understand the molecular mechanisms of this important response.


Assuntos
Adaptação Fisiológica/fisiologia , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Enterocolite Necrosante/cirurgia , Intestino Delgado/patologia , Intestino Delgado/cirurgia , Estudos de Coortes , Enterocolite Necrosante/patologia , Enterostomia/métodos , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Recém-Nascido , Mucosa Intestinal/patologia , Mucosa Intestinal/cirurgia , Masculino , Estudos Retrospectivos , Estatísticas não Paramétricas , Inclusão do Tecido , Resultado do Tratamento
13.
Semin Pediatr Surg ; 19(1): 35-43, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20123272

RESUMO

The structural and functional changes during intestinal adaptation are necessary to compensate for the sudden loss of digestive and absorptive capacity after massive intestinal resection. When the adaptive response is inadequate, short bowel syndrome (SBS) ensues and patients are left with the requirement for parenteral nutrition and its associated morbidities. Several hormones have been studied as potential enhancers of the adaptation process. The effects of growth hormone, insulin-like growth factor-1, epidermal growth factor, and glucagon-like peptide 2 on adaptation have been studied extensively in animal models. In addition, growth hormone and glucagon-like peptide 2 have shown promise for the treatment of SBS in clinical trials in human beings. Several lesser studied hormones, including leptin, corticosteroids, thyroxine, testosterone, and estradiol, are also discussed.


Assuntos
Adaptação Fisiológica , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Intestino Delgado/efeitos dos fármacos , Hormônios Peptídicos/uso terapêutico , Síndrome do Intestino Curto/tratamento farmacológico , Animais , Proliferação de Células/efeitos dos fármacos , Enterócitos/efeitos dos fármacos , Fator de Crescimento Epidérmico/farmacologia , Fator de Crescimento Epidérmico/uso terapêutico , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Peptídeo 2 Semelhante ao Glucagon/uso terapêutico , Hormônio do Crescimento/farmacologia , Hormônio do Crescimento/uso terapêutico , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Intestino Delgado/citologia , Intestino Delgado/crescimento & desenvolvimento , Hormônios Peptídicos/farmacologia , Ratos , Síndrome do Intestino Curto/patologia , Somatomedinas/farmacologia , Somatomedinas/uso terapêutico
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