Identification of Neoantigen-Reactive Tumor-Infiltrating Lymphocytes in Primary Bladder Cancer.

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.

Outcomes for Correction of Long-Gap Esophageal Atresia: A 22-Year Experience.

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.

Associations of CDH1 germline variant location and cancer phenotype in families with hereditary diffuse gastric cancer (HDGC).

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.

A Comparison of Commonly Utilized Diagnostic Biopsy Techniques for Pediatric Patients With Cancer: A Systematic Review by the APSA Cancer Committee.

BACKGROUND: Historically, surgical biopsy (SB) for diagnosis of pediatric solid tumors was considered necessary to provide adequate tissue for histologic and molecular analysis. Less invasive biopsy techniques such as image-guided core needle biopsy (CNB), have shown comparable accuracy with decreased morbidity in some adult studies. However, data regarding the safety and efficacy of CNB in pediatric tumors is limited. This study's aim was to assess the overall rate of successful diagnosis and safety of CNB compared to SB in children with malignancies. METHODS: A PRISMA compliant systematic review was performed in MEDLINE via PubMed, Embase and CINAHL Plus database searches from 2010 to 2023. Studies were included with relevance to the following clinical question: For children with concern for malignancy requiring biopsy for diagnosis, how does CNB compare to open or laparoscopic/thoracoscopic SB in terms of safety and diagnostic efficacy? Data for patients ≤21 years requiring biopsy for diagnosis of liver tumors, neuroblastoma (NB), soft tissue sarcoma (STS), and lymphoma were included. RESULTS: Twenty-seven studies including 2477 patients met inclusion criteria, with 2065 undergoing CNB and 412 SB. Of the 2477 patients, 820 patients had NB, 307 liver tumors, 96 STS, 151 lymphoma, and 1103 patients were from studies that included multiple diagnoses. The average complication rate for CNB was 2.9% compared to 21.4% for SB (p < 0.001). Bleeding was the most common complication in both groups, but significantly higher after SB (22.1% vs 2.3%) (p < 0.001). CNB was diagnostic in 90.8% of patients compared to 98.8% who underwent SB (p < 0.001). CONCLUSIONS: Rates of successful diagnosis were greater than 90% for both CNB and SB, though significantly higher for SB. Conversely, complication rates were close to ten times higher after SB compared to CNB. Given its relatively lower risk profile, CNB can be a safe and useful diagnostic tool for children with solid malignancies. Research focused on enhancing CNB's diagnostic accuracy while maintaining low morbidity should be further explored. LEVEL OF EVIDENCE: Treatment study, Level III.

Evaluating the management timeline of tracheoesophageal fistulas secondary to button batteries: A systematic review.

INTRODUCTION: During the SARS-CoV-2 pandemic, the incidence of pediatric button battery (BB) ingestions has risen. Children have spent more time at home from school, while many parents try to balance working from home and childcare. Additionally, the amount of electronics powered by BB has increased. Tracheoesophageal fistula (TEF) secondary to a retained aerodigestive BB is a devastating development. Management is challenging, and the clinical timeline of watchful waiting versus surgical intervention for TEF is poorly defined in the literature. METHODS: In accordance with PRISMA guidelines, databases searched include PubMed, Scopus, and CINAHL from database date of inception through August 13, 2021. All study designs were included, and no language, publication date, or other restrictions were applied. Case series and reports of TEFs secondary to BBs were included. Clinical risk factors and outcomes were compared between the spontaneous closure and surgical repair groups. RESULTS: A total of 79 studies with 105 total patients were included. Mortality was 11.4%. There were 23 (21.9%) TEFs that spontaneously closed and 71 (67.6%) that underwent surgical repair. Median time to spontaneous closure compared to surgical repair was significantly different (8.0 weeks [IQR 4.0-18.4] vs. 2.0 weeks [IQR 0.1-3.3], p<0.001). Smaller TEFs were more likely to spontaneously close versus being surgically repaired (9.3 mm ± 3.5 vs. 14.9 mm ± 8.3, p=0.022). Duration of symptoms before BB discovery, BB size, time between BB removal and TEF discovery, and location of the TEF were not statistically different between the spontaneous closure and surgical repair groups. CONCLUSION: A TEF secondary to BB ingestion is a potentially deadly complication. Timing of reported TEF spontaneous closure varies significantly. While smaller TEFs may be amenable to healing without surgical repair, no other significant factors were identified that may be associated with spontaneous closure. If clinical status permits, these data suggest a period of observation of at least 8 weeks prior to surgical intervention may be practical for many BB-induced TEFs.

Temporal Variations in Pediatric Trauma: Rationale for Altered Resource Utilization.

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.

Induction of Thioredoxin-Interacting Protein by a Histone Deacetylase Inhibitor, Entinostat, Is Associated with DNA Damage and Apoptosis in Esophageal Adenocarcinoma.

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.

SUCCESSFUL TREATMENT OF A SOLITARY SKULL METASTASIS IN A CHILD WITH WILMS' TUMOR.

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.

Adrenocortical carcinoma: modern management and evolving treatment strategies.

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.

Pancreaticojejunostomy Stricture After Pancreatoduodenectomy: Outcomes After Operative Revision.

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.