Insights into autotaxin- and lysophosphatidate-mediated signaling in the pancreatic ductal adenocarcinoma tumor microenvironment: a survey of pathway gene expression.

Lysophosphatidate (LPA)-mediated signaling is a vital component of physiological wound healing, but the pathway is subverted to mediate chronic inflammatory signaling in many pathologies, including cancers. LPA, as an extracellular signaling molecule, is produced by the enzyme autotaxin (ATX, gene name ENPP2) and signals through six LPA receptors (LPARs). Its signaling is terminated by turnover via the ecto-activity of three lipid phosphate phosphatases (LPPs, gene names PLPP1-3). Many pharmacological developments against the LPA-signaling axis are underway, primarily against ATX. An ATX inhibitor against pancreatic ductal adenocarcinoma (PDAC), a very aggressive disease with limited systemic therapeutic options, is currently in clinical trials, and represents the first in-class drug against LPA signaling in cancers. In the present study, we surveyed the expression of ATX, LPARs, and LPPs in human PDACs and their clinical outcomes in two large independent cohorts, the Cancer Genome Atlas (TCGA) and GSE21501. Correlation among gene expressions, biological function and the cell composition of the tumor microenvironment were analysed using gene set enrichment analysis and cell cyber-sorting with xCell. ENPP2, LPAR1, LPAR4, LPAR5, LPAR6, PLPP1, and PLPP2 were significantly elevated in PDACs compared to normal pancreatic tissue, whereas LPAR2, LPAR3, and PLPP3 where downregulated (all P≤0.003). Only ENPP2 demonstrated survival differences, with overall survival favoring ENPP2-high patients (hazard ration 0.5-0.9). ENPP2 was also the only gene with enriched gene patterns for inflammatory and tissue repair gene sets. Epithelial (cancer) cells had increased LPAR2, LPAR5 and PLPP2 expression, and decreased ENPP2, LPAR1, PLPP1, and PLPP3 gene expression (all P<0.02). Tumor fibroblasts had increased ENPP2, LPAR2, LPAR4, PLPP1, and PLPP3 expression and decreased LPAR2, LPAR5, and PLPP2 expression in both cohorts (all P≤0.01). Immune cell populations were not well correlated to gene expression in PDACs, but across both cohorts, cytolytic scores were increased in high-expressing ENPP2, LPAR1, LPAR6, PLPP1, and PLPP3 tumors (P<0.01). Overall, in PDACs, ENPP2 may switch from an anti-to-pro tumor promoting gene with disease progression. LPAR2 and PLPP2 inhibition are also predicted to have potential therapeutic utility. Future multi-omics investigations are necessarily to validate which LPA signaling components are high-value candidates for pharmacological manipulation in PDAC treatment.

Epidemiology of Adenosquamous Carcinomas.

Background: Adenosquamous carcinomas (ASCs) are a very rare histology containing cancer cells with both glandular-like (adeno) and squamous cell histologies, comprising typically a fraction of a percent of all solid tumors. The bulk of the literature on ASCs is comprised of case reports and small series, with the general finding that ASCs tend to have worse outcomes than either of their parent histologies. However, there is a lack of pan site-comparative studies in the literature that compare ASC clinicodemographic and survival outcomes with those of conventional adenocarcinomas (ACs) and squamous cell carcinomas (SCCs). Methods: In this study, we summarize these outcomes in eight primary sites, comprising 92.7% of all ASC cases diagnosed from 1975 to 2020 in the Surveillance, Epidemiology, and End Results (SEER) database. Results: Lung ASCs comprise 51.5% of all ASC cases, accounting for 1.1% of all lung cancer cases, followed by uterine/cervical cancers at 29.7% of all ASC cases, translating into 1.8% of all cancers in this site. In descending order, the remaining 20% of ASCs arise in pancreatic, oral cavity, biliary, esophageal, colorectal, and gastric sites, comprising between 0.1% and 0.7% of all cancers in these sites. Apart from pancreatic and oral cavity cancers, ASC tumors tended to favor higher rates of regional or distant disease at presentation with poor tumor differentiation compared to either AC or SCC histologies. After multivariable analysis, adjusting for age, sex, detection stage, grade differentiation, surgery, chemotherapy, and radiotherapy, except for oral cavity cancers, ASCs tended to have worse overall survivals compared to ACs (hazard ratios: 1.1 - 1.6) and SCC (1.0 - 1.3), with colorectal ASCs having the worse overall survival compared to colorectal ACs, with a hazard ratio of 1.4 (95% confidence interval: 1.3 - 1.6). Conclusions: Overall, these results suggest that ASC outcomes are site specific, and in general, tend to have worse outcomes than nonvariant ACs and SCCs even after correction for common clinical and epidemiological factors. These cancers have a poorly understood but unique tumor biology that warrants further characterization.

Optimal Practices for Suspected Nodal Melanoma-The Role of the General Surgeon.

This Viewpoint describes results of trials on neoadjuvant checkpoint inhibitor immunotherapy for patients with metastatic melanoma and recommends increased use of this approach.

Progression to pseudomyxoma peritonei in patients with low grade appendiceal mucinous neoplasms discovered at time of appendectomy.

BACKGROUND: The discovery of a low grade appendiceal mucinous neoplasm (LAMN) during appendectomy is a rare scenario. These neoplasms can progress to pseudomyxoma peritonei (PMP), however the incidence of progression is not well known. METHODS: The records of all patients with a diagnosis of localized LAMN found during appendectomy were identified, and demographic, tumor, surveillance, and outcome variables were analyzed. RESULTS: Progression to PMP occurred in 20% of patients in an average of 12.4 months after appendectomy with median follow-up of 18 months. Tumor variables such as margin positivity, appendiceal perforation, and presence of extra-appendiceal acellular mucin or mucinous epithelium on the serosal were not significantly associated with progression. CONCLUSIONS: During an average follow-up period of 18 months after surgery, progression to PMP occurred in a fifth of patients. It is difficult to predict which patients will progress, therefore cross-sectional imaging surveillance is recommended for all patients.

Exploration of Lipid Metabolism in Gastric Cancer: A Novel Prognostic Genes Expression Profile.

BACKGROUND: Alterations in lipid metabolism are increasingly being recognized. However, the application of lipid metabolism in the prognosis of gastric cancer (GC) has not yet been explored. METHODS: A total of 204 lipid metabolism relative genes were analyzed in the GC cohort from The Cancer Genome Atlas (TCGA), and four independent cohorts from Gene Expression Omnibus (GEO) and one cohort from Wuhan Union Hospital were applied for external validation. Differential expression and enrichment analyses were performed between GC and normal tissue. The LASSO-Cox proportional hazard regression model was applied to select prognostic genes and to construct a gene expression profile. RESULTS: Our research indicated that higher expression level of AKR1B1, PLD1, and UGT8 were correlated with worse prognosis of GC patients, while AGPAT3 was correlated with better prognosis. Furthermore, we developed a gene profile composed of AGPAT3, AKR1B1, PLD1, and UGT8 suggested three groups with a significant difference in overall survival (OS). The profile was successfully validated in an independent cohort and performed well in the immunohistochemical cohort. Furthermore, we found that ether lipid metabolism, glycerophospholipid metabolism, and glycerolipid metabolism were upregulated, and fatty acid ß-oxidation and other lipid peroxidation processes were reduced in GC. CONCLUSION: Collectively, we found lipid metabolism is reliable and clinically applicable in predicting the prognosis of GC based on a novel gene profile.

Optimal oncologic and perioperative outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy are attainable at a community center.

BACKGROUND: CRS with HIPEC is a complex operation that has shown survival benefit in patients with a variety of primary and metastatic peritoneal surface malignancies. While optimal oncologic and perioperative outcomes have been defined by expert consensus and demonstrated at university-affiliated, academic centers, similar results have never been presented from a non-university-affiliated, community center in the literature to date. METHODS: All cases of CRS with HIPEC performed at a non-university-affiliated, community center were retrospectively reviewed and analyzed. Oncologic and perioperative outcomes were compared Chicago Working Group benchmarks and with results from university-affiliated, academic centers recently published in high-impact-factor, peer-reviewed journals. RESULTS: All 112 cases completed over 5 years were reviewed. 3 were excluded from analysis since they were palliative HIPEC procedures for distressing ascites-related symptoms only without CRS. A wide variety of tumors were treated. Average PCI was 18±9.1. Median PCI was 14. CC 0-1 was achieved in 89% of patients. Average length of stay was 11.6±9.3 days. Serious perioperative morbidity, defined as a Clavien-Dindo Grade III or IV complication, was observed in 22% of patients. The frequency of major complications decreased after the first year. There were no perioperative deaths. CONCLUSIONS: Optimal oncologic and perioperative outcomes of CRS and HIPEC are attainable at a non universityaffiliated, community center. A multidisciplinary team and high clinical volume are necessary to obtain these results.

Cystic Adventitial Disease of the Common Femoral Vein Successfully Treated with Resection, Synthetic Graft Reconstruction, and Fistula Creation.

Cystic adventitial disease (CAD) is a rare, benign disease of blood vessels which most commonly affects the popliteal artery. Less than 50 cases of CAD affecting veins have ever been described in the literature to date. We report the case of a 56-year-old woman who presented with unilateral lower extremity swelling and varicosities due to CAD of her common femoral vein. Resection and reconstruction with a venous interposition graft, employing a polytetrafluoroethylene graft and arteriovenous fistula in order to maintain venous bypass patency, were performed successfully. The patient recovered well without any evidence of recurrence or postoperative complications.

Bilateral adrenal histoplasmosis in an immunocompetent man from Texas.

Disseminated histoplasmosis affecting the adrenal gland(s) of immunocompetent adults is a very rare infection. Here, we present a case of bilateral adrenal histoplasmosis in an immunocompetent, 62-year-old gentleman from Texas along with a brief review of the published literature. Given the risk of patient decompensation secondary to adrenal insufficiency and the wide availability of effective treatments, adrenal histoplasmosis must be considered even in immunocompetent adults who acquire adrenal masses.

Challenges of the information age: the impact of false discovery on pathway identification.

BACKGROUND: Pathways with members that have known relevance to a disease are used to support hypotheses generated from analyses of gene expression and proteomic studies. Using cancer as an example, the pitfalls of searching pathways databases as support for genes and proteins that could represent false discoveries are explored. FINDINGS: The frequency with which networks could be generated from 100 instances each of randomly selected five and ten genes sets as input to MetaCore, a commercial pathways database, was measured. A PubMed search enumerated cancer-related literature published for any gene in the networks. Using three, two, and one maximum intervening step between input genes to populate the network, networks were generated with frequencies of 97%, 77%, and 7% using ten gene sets and 73%, 27%, and 1% using five gene sets. PubMed reported an average of 4225 cancer-related articles per network gene. DISCUSSION: This can be attributed to the richly populated pathways databases and the interest in the molecular basis of cancer. As information sources become enriched, they are more likely to generate plausible mechanisms for false discoveries.