Lung NETs and GEPNETs: One Cancer with Different Origins or Two Distinct Cancers?

Lung neuroendocrine tumors (LNETs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are two distinct types of neuroendocrine tumors (NETs) that have traditionally been treated as a single entity despite originating from different sources. Although they share certain phenotypic characteristics and the expression of neuroendocrine markers, they exhibit differences in their microenvironment, molecular mutations, and responses to various therapeutic regimens. Recent research has explored the genetic alterations in these tumors, revealing dissimilarities in the frequently mutated genes, the role of EGFR in carcinogenesis, the presence of transcription factors, and the immunogenicity of the tumor and its microenvironment. Spread Through Air Spaces (STAS), a phenomenon unique to lung carcinomas, appears to play a crucial role in LNET prognosis. These distinctions are also evident in the cascade response of lung and GI tract neuroendocrine tumors to somatostatin analogs, Peptide Receptor Radionuclide Therapy (PRRT), chemotherapy, and immunotherapy. Identifying similarities and differences between the two groups may improve our understanding of the underlying mechanisms and facilitate the development of more effective treatment strategies.

Hiatal hernia repair with mesh: a survey of SAGES members.

BACKGROUND: Primary repair of large hiatal hernia is associated with a high recurrence rate. The use of mesh may reduce this recurrence rate. The indication for mesh use, the type of mesh to use, and the placement technique are controversial. A survey of surgeon practice was undertaken to obtain a better understanding of the controversies surrounding this clinical problem. METHODS: A questionnaire on the technique and results of mesh hiatal herniorrhaphy was sent to 1,192 members of the Society of Gastrointestinal and Endoscopic Surgeons (SAGES). RESULTS: There were 275 responses; 261 of these were analyzed. A total of 5,486 hiatal hernia repairs with mesh were reported; 77% and 23% were performed laparoscopically vs open, respectively. The most common indication for mesh usage was an increased size hiatal defect (46% of respondents). The most common mesh types were biomaterial (28%), polytetrafluoroethylene (25%), and polypropylene (21%). Suture anchorage was the most common fixation technique (56% of respondents). The findings showed a failure rate of 3%, a stricture rate of 0.2%, and an erosion rate of 0.3%. Biomaterial tended to be associated with failure, whereas nonabsorbable mesh tended to be associated with stricture and erosion. CONCLUSIONS: The use of mesh during hiatal hernia repair resulted in a reported recurrence rate which appeared to be lower than that obtained historically without mesh. No one mesh type was clearly superior in terms of avoiding failure and complication.

Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response.

OBJECTIVE: Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2 gene for functional variants that may influence susceptibility to disease. METHODS AND RESULTS: The promoter of COX-2 was screened for variants in healthy subjects by use of polymerase chain reaction-based methods. Promoter activity was investigated by using reporter expression experiments in human lung fibroblasts. Patients undergoing coronary artery bypass graft surgery, with measurements of plasma markers linked to COX-2 activity, were genotyped for association studies. A common COX-2 promoter variant, -765G>C, was found and shown to be carried by >25% of a group of healthy UK subjects. The -765C allele had significantly lower promoter activity compared with -765G, basally (28+/-3% lower, P<0.005) and in serum-stimulated cells (31+/-2% lower, P<0.005). In patients subjected to coronary artery bypass graft surgery, the magnitude of rise in levels of C-reactive protein (CRP) was strongly genotype dependent. Compared with -765G homozygotes, patients carrying the -765C allele had significantly lower plasma CRP levels at 1 to 4 days after surgery (14% lower at the peak of CRP levels on day 3, P<0.05 for all time points). CONCLUSIONS: For several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed.

Overcoming Resistance to Targeted Therapies in Cancer.

The recent discovery of oncogenic drivers and subsequent development of novel targeted strategies has significantly added to the therapeutic armamentarium of anti-cancer therapies. Targeting BCR-ABL in chronic myeloid leukemia (CML) or HER2 in breast cancer has led to practice-changing clinical benefits, while promising therapeutic responses have been achieved by precision medicine approaches in EGFR mutant lung cancer, colorectal cancer and BRAF mutant melanoma. However, although initial therapeutic responses to targeted therapies can be substantial, many patients will develop disease progression within 6-12 months. An increasing application of powerful omics-based approaches and improving preclinical models have enabled the rapid identification of secondary resistance mechanisms. Herein, we discuss how this knowledge has translated into rational, novel treatment strategies for relapsed patients in genomically selected cancer populations.

Functional prostaglandin-endoperoxide synthase 2 polymorphism predicts poor outcome in sarcoidosis.

RATIONALE: The majority of patients with sarcoidosis resolve their condition; however 5-10% of patients with sarcoidosis develop pulmonary fibrosis with poor prognosis. Prostaglandin-endoperoxide synthase 2 (PTGS2) is a key regulatory enzyme in the synthesis of the antifibrotic agent prostaglandin E(2) and is reduced in sarcoidosis lung. A promoter polymorphism in PTGS2, -765G>C, is reported to reduce its expression. OBJECTIVES: To investigate if -765G>C is associated with susceptibility to, and poorer outcome within, sarcoidosis and to examine a possible mechanism by which -765G>C reduces PTGS2 expression. METHODS: We used a case-control design study and genotyped -765G>C in a white British population of 198 patients with sarcoidosis and 166 control subjects. Patients with sarcoidosis were classified before genotyping as having persistent or nonpersistent disease using clinical criteria that included chest radiography staging, need for treatment, lung function, and longitudinal follow-up. Electrophoretic mobility shift assays were used to identify changes in transcription factor binding caused by the -765G>C polymorphism. RESULTS: Carriage of the -765C allele was strongly associated with susceptibility to sarcoidosis (odds ratio, 2.50; 95% confidence interval, 1.51-4.13; p=0.006) and, within this disease, with poorer outcome (odds ratio, 3.11; 95% confidence interval, 1.35-7.13; p=0.008). The association with sarcoidosis was replicated in a second Austrian population. Electrophoretic mobility shift assays revealed that the -765C allele causes a loss of Sp1/Sp3 transcription factor binding and an increase in Egr-1 binding to the region. CONCLUSION: Our data suggest that the -765G>C polymorphism identifies individuals who are susceptible to sarcoidosis and, more importantly, at risk of pulmonary fibrotic disease. An altered Sp1/Sp3 binding to the -765 region may contribute to the mechanism by which -765G>C reduces PTGS2 expression.