Cancer Cell Small Molecule Secretome Induces the Immune Checkpoint NKG2A and Dysfunction of Human CD8+ T Cells.

PD-1 blockade has been approved for head and neck squamous cell carcinoma (HNSCC) patients. However, many HNSCC patients do not respond to this treatment, and other tumor microenvironmental factors may promote resistance to PD-1 blockade. We previously identified increased expression of the inhibitory receptor NKG2A on CD8+ T cells in HNSCC tumors compared with T cells in matching PBMC samples. Mechanisms that promote NKG2A expression and the role of NKG2A on human T cells in the tumor microenvironment, however, are uncertain. In this study, we show that tumor-conditioned media (TCM) of HNSCC cancer cell lines or ascites fluid from colorectal carcinoma patients is sufficient to induce the expression of NKG2A and other inhibitory receptors on activated CD8+ T cells isolated from PBMCs of healthy donors. Boiling or small molecular mass cutoff filtering did not eliminate the effect of TCM, suggesting that a small molecule promotes NKG2A. T cell activation in TCM decreased the basal and maximal mitochondrial respiration to metabolically restrain CD8+ T cells. Functionally, T cell activation in TCM reduced CD8+ T cell cytotoxicity as shown by lower production of cytokines, granzyme B, and perforin. Furthermore, TCM prevented CD8+ T cells from killing cancer cells in response to an anti-CD19/anti-CD3 bispecific T cell engager. Thus, a small secreted molecule from HNSCC cells can induce NKG2A expression and promote T cell dysfunction. Our findings may lead to targets for novel cancer therapies or biomarkers for NKG2A blockade response and provide a model to study T cell dysfunction and impaired metabolism.

Enteric tube position on preoperative radiographs predicts clinical outcomes in neonatal congenital diaphragmatic hernia with and without prenatal diagnosis.

OBJECTIVE: Congenital Diaphragmatic Hernia (CDH) is diagnosed prenatally in ~60% of cases. Prenatal measures typically guide management and prognostication. Simple postnatal prognosticators are needed when prenatal diagnosis is lacking. We hypothesized that preoperative orogastric tube (OGT) tip position relative to the contralateral diaphragm correlates with defect severity, resource utilization, and clinical outcomes regardless of diagnostic status. STUDY DESIGN: 150 neonates with left-posterolateral CDH were analyzed. Impact of intrathoracic and intraabdominal preoperative tip position on clinical outcomes was compared. RESULTS: Ninety-nine neonates were prenatally diagnosed. Overall, intrathoracic position significantly correlated with larger diaphragmatic defects, advanced postnatal pulmonary support requirements (HFOV, pulmonary vasodilators, and ECMO), operative complexity, longer hospitalization, and poorer survival to discharge. These observations persisted when analyzing only cases lacking prenatal diagnosis. CONCLUSIONS: Preoperative OGT tip position predicts defect severity, resource utilization, and outcomes in CDH. This observation enhances postnatal prognostication and care planning for neonates without a prenatal diagnosis.

Postoperative biliary anastomotic strictures after pancreaticoduodenectomy.

BACKGROUND: Biliary anastomotic stricture (BAS) is an uncommon complication of pancreaticoduodenectomy (PD). As PDs are performed more frequently, BAS may become a more common pathologic entity requiring clinical engagement. The aim of this study was to report the incidence of BAS in the modern era of pancreatic surgery and identify risk factors associated with it. METHODS: Patients undergoing PD at the Johns Hopkins Hospital between 2007 and 2016 were identified using an institutional registry and clinicopathological features were analyzed to identify risk factors associated with BAS. RESULTS: Of 2125 patients identified, 103 (4.9%) developed BAS. Factors independently associated with BAS included laparoscopic approach (HR:2.83,95%CI:1.35-5.92, p = 0.006), postoperative pancreatic fistula (HR:2.45,95%CI:1.56-4.16,p < 0.001), postoperative bile leak (BL) (HR:5.26,95%CI:2.45-11.28,p < 0.001), and administration of adjuvant radiation therapy (HR:6.01,95%CI:3.19-11.34,p < 0.001). Malignant pathology was associated with lower rates of BAS (HR:0.52,95%CI:0.30-0.92, p = 0.025). BL was associated with higher rates of early-BAS (HR:16.49,95%CI:3.28-82.94, p = 0.001) while use of Vicryl suture for biliary enteric anastomosis was associated with lower rates of early-BAS (HR:0.20,95%CI:0.05-0.93, p = 0.041). CONCLUSION: Approximately 5% of patients undergoing PD experience BAS. Multiple factors are associated with the development and timing of BAS.

KRAS mutational status impacts pathologic response to pre-hepatectomy chemotherapy: a study from the International Genetic Consortium for Liver Metastases.

BACKGROUND: A major response to pre-hepatectomy chemotherapy has been associated with improved survival in patients who undergo resection of colorectal liver metastases (CRLM). However, the role of tumor biology, as exemplified by overall and codon-specific KRAS mutational status, in predicting response to chemotherapy is not well defined. METHODS: Pathologic response was characterized as minor or major depending on the percentage of remnant viable cells (>50% vs <50%, respectively). Multivariable logistic regression was used to identify factors associated with major response. RESULTS: 319 patients met inclusion criteria. 229 patients had a KRAS wild-type (wtKRAS) tumor and 90 harbored KRAS mutations (mutKRAS). A major pathologic response was more commonly noted in patients with wtKRAS compared to mutKRAS (48.5% vs 33.3%, P = 0.01) and wtKRAS status remained independently associated with a major response (P = 0.04). On a codon-specific level, major pathologic response occurred less frequently in those with codon 13 mutations (17.7%) compared to those with codon 12 (35.4%), and other KRAS mutations (33.3%). Importantly, codon 13 mutations were independently associated with minor pathologic response (P = 0.023). CONCLUSIONS: Patients with wtKRAS tumors appear to have the highest likelihood of experiencing a major response after preoperative chemotherapy. Future studies in "all-comer" cohorts are needed to confirm these findings and further investigate the response of codon 13 mutations.