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.

Staging Laparoscopy is Underutilized in the Management of Gastric Adenocarcinoma.

BACKGROUND: Staging laparoscopy (SL) with peritoneal lavage is usually performed on a separate day from the planned resection and is recommended in patients with gastric adenocarcinoma as it can identify radiographically occult metastases and malignant cytology, thus altering prognosis and treatment. SL can be done on the same day as planned resection (SLSR) or with delayed resection (SLDR). The purpose of this study was to determine utilization of SL and factors associated with SLSR and SLDR, among patients diagnosed with gastric adenocarcinoma. METHODS: SEER-Medicare linked data were used to identify patients diagnosed with gastric adenocarcinoma from 2004 through 2013. SL were defined as a laparoscopy that occurred up to 3 months postdiagnosis. Multivariate logistic regression was used to identify factors associated with the utilization of SLSR and SLDR. RESULTS: Of the 5610 patients with gastric adenocarcinoma who underwent a surgical procedure, 733 (13%) had a SL. Utilization of SL increased annually from 6.4% to 22.2% (p < 0.01). Receipt of SL was associated with patient demographics, tumor location, and treatment at a National Cancer Institute (NCI) Designated Cancer Center (CC). Of the 733 patients who underwent SL, 475 (65%) received further surgical procedures; 367 (77%) underwent SLSR, while 108 patients (23%) underwent SLDR. Compared with SLSR, SLDR was more common among patients who were younger, treated at an NCI-Designated CC and had proximal tumors. CONCLUSIONS: SL for optimal preoperative staging remains underutilized in the management of gastric adenocarcinoma. Expanded use of laparoscopy as a distinct procedure could minimize unnecessary interventions.

Recognition of human gastrointestinal cancer neoantigens by circulating PD-1+ lymphocytes.

Tumor-resident lymphocytes can mount a response against neoantigens expressed in microsatellite-stable gastrointestinal (GI) cancers, and adoptive transfer of neoantigen-specific lymphocytes has demonstrated antitumor activity in selected patients. However, whether peripheral blood could be used as an alternative minimally invasive source to identify lymphocytes targeting neoantigens in patients with GI cancer with relatively low mutation burden is unclear. We used a personalized high-throughput screening strategy to investigate whether PD-1 expression in peripheral blood could be used to identify CD8+ or CD4+ lymphocytes recognizing neoantigens identified by whole-exome sequencing in 7 patients with GI cancer. We found that neoantigen-specific lymphocytes were preferentially enriched in the CD8+PD-1+/hi or CD4+PD-1+/hi subsets, but not in the corresponding bulk or PD-1- fractions. In 6 of 7 individuals analyzed we identified circulating CD8+ and CD4+ lymphocytes targeting 6 and 4 neoantigens, respectively. Moreover, neoantigen-reactive T cells and a T cell receptor (TCR) isolated from the CD8+PD-1+ subsets recognized autologous tumor, albeit at reduced levels, in 2 patients with available cell lines. These data demonstrate the existence of circulating T cells targeting neoantigens in GI cancer patients and provide an approach to generate enriched populations of personalized neoantigen-specific lymphocytes and isolate TCRs that could be exploited therapeutically to treat cancer.

Trends in Major Gastrectomy for Cancer: Frequency and Outcomes.

BACKGROUND: Declining incidence of gastric cancer in the USA has presumably resulted in lower rates of major gastrectomy for cancer. The impact on perioperative outcomes remains undefined. The aims of this study were to characterize national trends in frequency of major gastrectomy for cancer, identify factors associated with in-hospital mortality, and examine outcome disparities by race/ethnicity. METHODS: Nationwide inpatient sample data from 1993 to 2013 were queried for procedural and diagnostic codes (ICD-9) relating to total and partial gastrectomy procedures. Gastric resections for cancer were compared to those for peptic ulcer disease for reference. Patient demographics, comorbidity score, mortality, and hospital characteristics were recorded as covariates. RESULTS: A significant decrease in annual rates of partial and total gastrectomy was observed from 1993 to 2013 (p < 0.0001). The change in absolute number and percent decline was greater for partial gastrectomy (- 39.3%) than total gastrectomy (- 19%). There was a 34.0% decrease in gastrectomy for cancer in Whites and a 61.2% increase among Hispanic patients over two decades. In-hospital mortality also significantly decreased over the study period (7.7% to 2.7%). Factors associated with lower mortality rates included male sex and treatment at urban teaching hospitals. Analysis of trends revealed that gastrectomy for cancer was performed with increasing frequency at urban teaching hospitals. CONCLUSIONS: The frequency of major gastric resections in the USA has declined over two decades. Overall, in-hospital mortality rates also have decreased significantly. Declining in-hospital mortality after gastrectomy for cancer is associated with more frequent treatment at urban teaching hospitals.

T-Cell Transfer Therapy Targeting Mutant KRAS in Cancer.

We identified a polyclonal CD8+ T-cell response against mutant KRAS G12D in tumor-infiltrating lymphocytes obtained from a patient with metastatic colorectal cancer. We observed objective regression of all seven lung metastases after the infusion of approximately 1.11×1011 HLA-C*08:02-restricted tumor-infiltrating lymphocytes that were composed of four different T-cell clonotypes that specifically targeted KRAS G12D. However, one of these lesions had progressed on evaluation 9 months after therapy. The lesion was resected and found to have lost the chromosome 6 haplotype encoding the HLA-C*08:02 class I major histocompatibility complex (MHC) molecule. The loss of expression of this molecule provided a direct mechanism of tumor immune evasion. Thus, the infusion of CD8+ cells targeting mutant KRAS mediated effective antitumor immunotherapy against a cancer that expressed mutant KRAS G12D and HLA-C*08:02.

Expression of MAGE-A and NY-ESO-1 in Primary and Metastatic Cancers.

Melanoma-associated antigen-A (MAGE-A) and New York esophageal squamous cell cancer-1 (NY-ESO-1) are 2 cancer testis antigens (CTA) demonstrating potential for use in targeted immunotherapy. Clinical trials in melanoma and synovial sarcomas targeting these antigens in immune-based therapies have demonstrated durable tumor regression. Although protein expression of NY-ESO-1 has been assessed in a variety of cancer types, the expression of MAGE-A has not been studied in depth. In this study we analyzed MAGE-A and NY-ESO-1 expression in 314 melanoma specimens from 301 melanoma patients, 38 patients with squamous cell cancers and 111 patients with adenocarcinomas. Our results demonstrated higher expression of MAGE-A compared with NY-ESO-1 in melanomas (32% vs. 13%) and squamous cell carcinomas (45% vs. 7.9%), and higher expression of both CTAs in metastatic versus primary tumors. CTA expression in adenocarcinomas was low (MAGE-A: 10%, NY-ESO-1: 0.9%). In addition, we looked at concordance of expression among metastatic melanoma lesions within the same patient and found concordant expression in 38 of 47 patients for MAGE-A and 43 of 47 patients for NY-ESO-1. Our study demonstrated that the MAGE-A family may be of greater utility than NY-ESO-1 for targeted immunotherapy in a variety of cancer histologies, in particular metastatic melanomas and squamous cell carcinomas.

Cyclin D1 splice variants: polymorphism, risk, and isoform-specific regulation in prostate cancer.

PURPOSE: Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged. EXPERIMENTAL DESIGN: First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies. RESULTS: Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism. CONCLUSIONS: These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism.

High density lipoprotein-associated sphingosine 1-phosphate promotes endothelial barrier function.

High density lipoproteins (HDL) are major plasma carriers of sphingosine 1-phosphate (S1P). Here we show that HDL increases endothelial barrier integrity as measured by electric cell substrate impedance sensing. S1P was implicated as the mediator in this process through findings showing that pertussis toxin, an inhibitor of Gi-coupled S1P receptors, as well as antagonists of the S1P receptor, S1P1, inhibited barrier enhancement by HDL. Additional findings show that HDL stimulates endothelial cell activation of Erk1/2 and Akt, signaling pathway intermediates that have been implicated in S1P-dependent endothelial barrier activity. HDL was also found to promote endothelial cell motility, a process that may also relate to endothelial barrier function in the context of a vascular injury response. The effects of HDL on endothelial cell Erk1/2 and Akt activation and motility were suppressed by pertussis toxin and S1P1 antagonists. However, both HDL-induced barrier enhancement and HDL-induced motility showed a greater dependence on Akt activation as compared with Erk1/2 activation. Together, the findings indicate that HDL has endothelial barrier promoting activities, which are attributable to its S1P component and signaling through the S1P1/Akt pathway.