Abstract. The WHO 2010 classification divides gastrointestinal neuroendocrine neoplasms (GI-NENs) into neuroendocrine tumor (NET) G1, NET G2, neuroendocrine carcinoma (NEC) and mixed adenoendocrine carcinoma (MANEC) groups. A total of 136 cases of GI-NENs diagnosed at our hospitals as gastrointestinal carcinoids, endocrine cell carcinomas and NENs over the last 11 years, using the WHO 2010 classification were assessed. Among the 136 cases, 88.2% (120/136) were classified into the NET group (NET G1/G2) and 11.8% (16/136) were classified into the NEC group (NEC/MANEC). The incidences of lymphatic and venous invasions were higher in the NEC group compared with in the NET group (P<0.0001 and P=0.0021, respectively). The immunohistochemical staining of cluster of differentiation 73 (CD73) was evaluated in GI-NENs. CD73 is a potentially useful molecule in tumor immunity. In general, CD73 on the tumor cell membrane converts adenosine monophosphate to adenosine, which restrains the production of interferon-γ and cytocidal activity. Although the association between stem cells of pancreatic NENs and CD73 has been reported, few studies have reported on CD73 expression in GI-NENs. Immunohistochemical CD73 expression on the cytomembrane of neuroendocrine cells was detected in 27.2% (37/136) of the GI-NENs. The positive ratio of CD73 was significantly higher in the NEC group compared with in the NET group (P=0.0015). CD73 is also considered as a potential biomarker of anti-programmed death-1 (PD-1) therapy. The expression of programmed death-ligand 1 (PD-L1) on the cytomembrane of GI-NENs was assessed. The positive ratio of PD-L1 was higher in the NEC group compared with in the NET group (P=0.0011). Furthermore, CD73 expression status was significantly correlated with PD-L1 expression (P<0.0001). These results indicate that CD73 may be an interesting candidate for a biomarker for certain prognostic factors and therapeutics concerning PD-1 therapy.
The purpose of the present study was to report cases of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-naïve patients carrying a mutation associated with acquired resistance to the drug. Gene alterations in 77 lung carcinoma patients were analyzed by collecting and studying curette lavage fluid at the time of diagnosis. PCRs were performed to amplify mutation hotspot regions in EGFR genes. The PCR products were direct-sequenced and the mutations confirmed by resequencing using different primers. Case 1 was a 78-year-old Japanese male diagnosed with stage IB lung adenocarcinoma who was found to have two EGFR mutations, G719S and L747S. Case 2 was a 73-year-old Japanese male diagnosed with stage IV squamous cell lung carcinoma and bone metastasis who had the EGFR mutation, L747S. Case 3 was an 82-year-old Japanese male diagnosed with hyponatremia due to inappropriate secretion of antidiuretic hormone and stage IIIB small cell lung carcinoma (SCLC) who had the EGFR mutation, L747S. Thus, the EGFR mutation L747S associated with acquired EGFR-TKI resistance was detected in two non-small cell lung carcinoma (NSCLC) patients and one SCLC patient, none of whom had ever received EGFR-TKI. The patients were current smokers with stages at diagnosis ranging from IB to IV, and their initial tumors contained resistant clones carrying L747S. L747S may be associated with primary resistance. To the best of our knowledge, this study is the first report of an EGFR mutation associated with resistance to EGFR-TKI in SCLC patients. The early detection of EGFR-TKI resistance mutations may be beneficial in making treatment decisions for lung carcinoma patients, including those with SCLC.
Abstract. Angiogenesis is essential for tumor growth and metastasis. CD105 is reportedly a specific marker for tumor angiogenesis. It has been demonstrated that monoclonal antibodies to CD105 have high affinity for activated endothelial cells. A relationship between metastasis and microvessel density (MVD), as an indicator of neovascularization, has been identified in patients with colorectal cancer as shown by the presence of monoclonal antibodies to CD105. However, data on potentially confounding factors such as lymphatic and vascular infiltration and tumor size are lacking. We further investigated the relationship between MVD and distant metastasis, along with potentially confounding clinicopathological factors, to more precisely characterize this relationship. In this retrospective study, we analyzed colorectal cancer specimens surgically or endoscopically resected from January to September 2009. We defined MVD as the number of microvessels stained by monoclonal antibodies to CD105 per x400 field. Selected clinicopathological factors were analyzed and stepwise multivariate logistic regression was performed to identify independent risk factors for distant metastasis. We analyzed 129 lesions. The median follow-up time was 34 months (range, 6-85 months) in patients with distant metastasis and 61 months (range, 60-86 months) in those without distant metastasis. At the time of resection or during subsequent follow-up, 32 patients had distant metastases. The MVD was significantly greater in patients with than without distant metastases (mean ± standard deviation: 10.4±4.9 vs. 7.6±3.3, P=0.008; Welch's t-test). Stepwise multivariate logistic regression indicated that MVD, regional lymph node metastasis, and tumor size were independent risk factors for distant metastases. Combining assessment of monoclonal antibodies to CD105-positive MVD with assessment of regional lymph node metastasis and tumor size may help to identify patients who need more intensive surveillance after surgery for colorectal cancer.
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