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Recent clinical trials have shown the promising therapeutic effects of pembrolizumab and nivolumab in patients with advanced gastric cancer. Currently, the programmed death ligand-1 (PD-L1) 22C3 pharmDx assay is the only companion diagnostic assay for assessing the safety and effectiveness of pembrolizumab. The purpose of this study was to compare 22C3 pharmDx and 28-8 pharmDx, a complementary diagnostic assay for nivolumab, in gastric cancer. In this study, 22C3 and 28-8 pharmDx assays were performed on the same formalin-fixed, paraffin-embedded tissue blocks of gastric adenocarcinoma clinical samples (n= 55). The concordance rate was evaluated using combined positive score (CPS) cutoffs of 1, 10, and 50. PD-L1 positivity with CPS ≥ 1 was 45.5% using the 22C3 pharmDx assay and 49.1% using the 28-8 pharmDx assay. At a CPS cutoff of 1, the overall percentage agreement was 96.4%. The positive and negative percentage agreements were 93.3% and 100%, respectively. All cases positive for PD-L1 using the 22C3 pharmDx assay were also positive using the 28-8 pharmDx assay. At a CPS cutoff of 10, the overall percentage agreement was 96.4%. At a CPS cutoff of 50, the two assays exhibited 100% concordance. Nonspecific cytoplasmic staining in the background tissues and tumor cells was often observed in the 28-8 pharmDx assay. When the results of the two assays were matched for response to immunotherapy, the overall response rate was higher in patients with a PD-L1 CPS ≥ 1 than in PD-L1-negative patients (22C3 pharmDx, P= 0.001; 28-8 pharmDx, P= 0.002). In conclusion, PD-L1 22C3 and 28-8 pharmDx assays were highly comparable at CPS cutoffs of 1, 10, and 50 in gastric cancer. These results provide evidence for the potential interchangeability of the two PD-L1 assays in gastric cancer.

Recent clinical trials have shown the promising therapeutic effects of pembrolizumab and nivolumab in patients with advanced gastric cancer. Currently, the programmed death ligand-1 (PD-L1) 22C3 pharmDx assay is the only companion diagnostic assay for assessing the safety and effectiveness of pembrolizumab. The purpose of this study was to compare 22C3 pharmDx and 28-8 pharmDx, a complementary diagnostic assay for nivolumab, in gastric cancer. In this study, 22C3 and 28-8 pharmDx assays were performed on the same formalin-fixed, paraffin-embedded tissue blocks of gastric adenocarcinoma clinical samples (n= 55). The concordance rate was evaluated using combined positive score (CPS) cutoffs of 1, 10, and 50. PD-L1 positivity with CPS ≥ 1 was 45.5% using the 22C3 pharmDx assay and 49.1% using the 28-8 pharmDx assay. At a CPS cutoff of 1, the overall percentage agreement was 96.4%. The positive and negative percentage agreements were 93.3% and 100%, respectively. All cases positive for PD-L1 using the 22C3 pharmDx assay were also positive using the 28-8 pharmDx assay. At a CPS cutoff of 10, the overall percentage agreement was 96.4%. At a CPS cutoff of 50, the two assays exhibited 100% concordance. Nonspecific cytoplasmic staining in the background tissues and tumor cells was often observed in the 28-8 pharmDx assay. When the results of the two assays were matched for response to immunotherapy, the overall response rate was higher in patients with a PD-L1 CPS ≥ 1 than in PD-L1-negative patients (22C3 pharmDx, P= 0.001; 28-8 pharmDx, P= 0.002). In conclusion, PD-L1 22C3 and 28-8 pharmDx assays were highly comparable at CPS cutoffs of 1, 10, and 50 in gastric cancer. These results provide evidence for the potential interchangeability of the two PD-L1 assays in gastric cancer.

Introduction: Concussion affects one’s ability to function in everyday life, and many students who suffer from related symptoms have difficulty adjusting to the academic and social demands of college. The purpose of this study was to examine college students’ knowledge, beliefs, and behaviors regarding concussion. Methods: This cross-sectional study took place at a suburban university in the northeastern United States during fall semester 2019, in a public health elective core curriculum course. Results: A total of 416 students responded (response rate 85%). Regarding having a close experience with concussion, 59.1% of participants had a family member or friend who had sustained a concussion, and 20.7% had a personal history of concussion. Students who reported ever playing a sport were more likely to report a personal history of concussion (p<0.001). Students with a personal or family history of concussion were more likely to report currently playing and having ever played a sport (p≤0.003). Female participants were less likely to report that they engage in contact sports (p<0.001) and more likely to report always being careful with physical activities so as to avoid head injuries (p=0.003). Many students reported never wearing a helmet when engaging in high-risk behaviors, but most students reported they would seek medical treatment for a suspected concussion. Conclusions: Universities would benefit on many levels from an active education and prevention campaign, removing the possible peer stigma associated with admitting to a concussion, and seeking appropriate cognitive, linguistic, and communication treatments and academic accommodations to facilitate ongoing learning.

Administrative database provides valuable information for large cohort studies, especially when tissue diagnosis is rather difficult such as the diagnosis for bile duct cancer (BDC). The aim of this study was to evaluate the diagnostic accuracy of administrative database for BDC by International Classification of Diseases (ICD)-10 codes in a tertiary institute.

Hypointense nodules without arterial hyperenhancement at gadoxetic acid–enhanced MRI correspond to hepatocellular carcinoma or premalignant hepatocellular nodules.

Epstein–Barr virus–associated gastric carcinoma (EBVaGC) is characterized by prominent tumor-infiltrating lymphocytes (TILs) and has a favorable prognosis. Tertiary lymphoid structures (TLS), characterized by ectopic aggregated lymphocytes with high-endothelial venules (HEV), are associated with favorable outcomes in various solid tumors. We hypothesized that EBVaGC, characterized by intense TILs, may be closely associated with TLS or HEV. To test this hypothesis, we digitally analyzed the TLS, HEV, and TILs in 73 surgically resected advanced EBVaGCs. For HEV, dual MECA-79 and CD31 dual immunohistochemistry were performed, and the ectopic expression of MECA-79 in tumor cells was measured. In 73 patients with EBVaGC, a high-TLS ratio was found in 29 (39.7%) cases, high-tumor-associated HEV density in 44 (60.3%) cases, and high-CD8+TIL density in 38 (52.1%) cases. Ectopic tumor expression of MECA-79 was observed in 36 patients (49.3%) cases. A low-TLS ratio and tumor-associated HEV density were significantly associated with lymph node metastasis (P =.005 and.042, respectively). Ectopic MECA-79 expression was significantly associated with lymph node metastasis (P =.003). Patients with a low-TLS ratio (P =.038), low-HEV density (P =.042), and ectopic tumor MECA-79 expression (P =.032) had significantly worse prognoses. In conclusion, TLS ratio and HEV density affect the survival of patients with EBVaGC and may be related to the immune response that interrupts lymph node metastasis.

AimsThis multi-institutional study and a re-evaluation of the TCGA cohort explores the morphological spectrum, genetics and outcome of GI (gastrointestinal) hepatoid tumours, tumours expressing alpha-fetoprotein (AFP) and fetal-type (FT) GI adenocarcinomas.Methods44 tumours with evidence of hepatocellular differentiation were evaluated for morphology as well as by immunohistochemistry for AFP, HepPar1, glypican-3 and arginase-1 and by in situ hybridisation for albumin. Three categories were defined: type I (hepatoid: morphological evidence of hepatocellular differentiation), type II (FT GI adenocarcinoma: tubular profiles and subnuclear vacuolisation, resembling fetal intestine) and type III: positive for at least two hepatocyte-specific markers but lacking morphological evidence of hepatocellular differentiation. GI adenocarcinomas in the TCGA cohort were also evaluated (n=829).Results18 cases were classified as type I, 19 as FT GI adenocarcinomas and 7 as type III (resembling conventional gastrointestinal carcinomas). Serum AFP was elevated in 92% of cases. 93% of tumours were positive for glypican-3, 90% for albumin and 89% for AFP. Arginase-1 was restricted to 35% of type 1 tumours. TCGA gastric tumours with elevated AFP expression showed morphological features of FT GI adenocarcinoma (70%) and were exclusively MSI stable. TCGA gastric adenocarcinomas with high AFP expression showed inferior survival on univariate and multivariate analysis.ConclusionsFT GI adenocarcinomas show a distinctive morphological and immunohistochemical profile. Gastric adenocarcinomas with elevated expression of AFP morphologically resemble FT GI adenocarcinomas, demonstrate aggressive behaviour, independent of grade and stage, and a distinct genetic profile.

Gastrointestinal neurofibroma usually develops as diffuse gastrointestinal involvement in neurofibromatosis type 1 patients. Only 4 cases of sporadic colonic neurofibroma in a patient without neurofibromatosis type 1 have been reported in the English literature. A 26-year-old female patient underwent colonoscopy, and a 4-cm-sized polypoid mass was identified in the sigmoid colon. Wedge resection of the mass showed a yellowish, hard submucosal tumor. Microscopically, the tumor was composed of wavy spindle cells, fibroblasts, and strands of collagen; the stroma showed scattered myxoid areas. The differential diagnoses included gastrointestinal stromal tumor, schwannoma, and neurofibroma. Immunohistochemistry for c-Kit, DOG (discovered on gastrointestinal stromal tumors)-1, smooth muscle actin, S-100 protein, and CD34 was performed. The tumor cells were diffusely positive for CD34 and S-100 protein, while they were completely negative for c-Kit, DOG-1, and smooth muscle actin. The final diagnosis was neurofibroma. Sporadic colonic neurofibroma is very rare. Given the diffuse positivity for CD34 and its rarity, colonic neurofibroma can be easily misdiagnosed as gastrointestinal stromal tumor. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis and unnecessary treatment.

FGFR2gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoform-specific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r=0.79) and FISH (r=1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs3% and 75% vs47%, respectively; P<0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P=0.01) and higher N stage (P=0.006). FGFR2b overexpression with H-score ≥150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034–3.261; P=0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2amplification. Given the low frequency of FGFR2amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors.

FGFR2 gene amplification, and resulting FGFR2 protein overexpression, is rare in gastric cancer patients, and development of an accurate and widely available method for mass screening to identify patients who may respond to treatment with fibroblast growth factor receptor (FGFR) inhibitors is important. We first screened 312 gastric cancer patients with known copy number variations by FGFR2b immunohistochemistry using FPR2-D, an isoform-specific antibody. Next, we performed immunohistochemistry on tissue microarrays from 1574 gastric cancer patients. Selected cases were analyzed for FGFR2 amplification by FISH. In addition, FGFR2b overexpression was studied in 88 matched primary and metastatic gastric cancers. In the first cohort, FGFR2b immunohistochemistry results correlated very well with those of copy number variation (r=0.79) and FISH (r=1.0). In total, FGFR2b overexpression was identified in 73 of 1974 gastric cancers (4%). The concordance between immunohistochemistry and FISH was extremely high; all 2+ and 3+ cases identified by immunohistochemistry were FGFR2 amplified. In the matched primary and metastatic gastric cancer pairs, the positivity and percentage of positive tumor cells were significantly higher in metastatic gastric cancers than in primary gastric cancers (8% vs 3% and 75% vs 47%, respectively; P<0.001). FGFR2b overexpression was significantly more frequent in gastric cancers with diffuse subtype (P=0.01) and higher N stage (P=0.006). FGFR2b overexpression with H-score ≥150 were independent prognostic factors for overall survival with hazard ratio of 1.836 (95% confidence interval, 1.034–3.261; P=0.038). FGFR2b positivity in immunohistochemistry was strongly correlated with FGFR2 amplification. Given the low frequency of FGFR2 amplification in gastric cancers, FGFRb2 immunohistochemistry is an accurate screening tool to detect FGFR2 amplification, and both primary and metastatic gastric cancer tissues should be tested to select gastric cancer patients for treatment with FGFR2 inhibitors.

Background:Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs. Material and Methods:Between January 2012 and June 2015, 40 BTC patients’ samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid. Genome analysis using targeted panel sequencing as well as digital multiplexed gene analysis was applied to PDCs as well as primary tumors. Results:Extrahepatic cholangiocarcinoma (N=15, 37.5%), intrahepatic cholangiocarcinoma (N=10, 25.0%), gallbladder cancer (N=14, 35.0%), and ampulla of Vater cancer (N=1, 2.5%) were included. We identified 15 mutations with diverse genetic alterations in 19 cases of BTC from primary tumor specimens. The most common molecular alterations were in TP53 (8/19, 42.1%), including missense mutations such as C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L. We also detected two NRAS mutations (G12C and Q61L), two KRAS mutations (G12A and G12S), two ERBB2 mutations (V777L and pM774delinsMA) and amplification, and three PIK3CA mutations (N345K, E545K, and E521K). PDC models were successfully established in 27 of 40 samples (67.5%), including 22/24 from body fluids (91.7%) and 5/16 from tissue specimens (31.3%). Conclusions:PDC models are promising tools for uncovering driver mutations and identifying rational therapeutic strategies in BTC. Application of this model is expected to inform clinical trials of drugs for molecular-based targeted therapy.

The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324–2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227–2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.

The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situhybridization confirmed the presence of METgene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high METmRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of METgene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324–2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227–2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.

Little is known about the histopathology and prognosis of persistent pure ground-glass opacity nodules (GGNs) of ≥ 10 mm in diameter. We aimed to compare the morphologic features of persistent pure GGNs of ≥ 10 mm in diameter at thin-section CT (TSCT) scan with histopathology and patient prognosis.

Notch signaling is critical to physiologic angiogenesis and has been implicated in tumor angiogenesis and metastasis. Notch signaling was reported to exert either oncogenic or tumor-suppressive function in hepatocellular carcinoma (HCC) tumorigenesis. However, the prognostic significance of Notch receptors in HCC remains uncertain. In this study, we investigated the roles of Notch receptors in the prognosis of HCC.

Progression of hepatocellular carcinoma (HCC) often leads to vascular invasion and intrahepatic metastasis, which correlate with recurrence after surgical treatment and poor prognosis. HCC may be an unusual cancer affected by continuous inflammation that can lead to consistent upregulation of transforming growth factor-β (TGF-β). Chronic inflammation shifts hepatocytic TGF-β signaling from the tumor-suppressive pSmad3C pathway to the oncogenic pSmad3L pathway. In this study, we investigated the functional roles of Smad3 and its phosphoisoforms in the progression of HCC.