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.

High EIF4EBP1 expression reflects mTOR pathway activity and cancer cell proliferation and is a biomarker for poor breast cancer prognosis.

Eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1) is regulated by the mTOR (mammalian target of rapamycin) signaling pathway. Phosphorylated EIF4EBP1 protein leads to pathway activation and correlates with aggressive breast cancer features. However, the clinical relevance of EIF4EBP1 gene expression as a prognostic biomarker in bulk breast tumors is not understood. In this study, EIF4EBP1 expression was analyzed in over 5000 breast cancers from three large independent cohorts, TCGA, METABRIC, and SCAN-B (GSE96058), and expression was dichotomized into low and high groups by the median. We also performed gene set enrichment analysis (GSEA) and cell cybersorting via the xCell algorithm to investigate EIF4EBP1 biology and expression patterns within the tumor microenvironment (TME). We additionally confirmed EIF4EBP1 expression location in the TME via single cell RNA sequencing. EIF4EBP1 expression was highest in both triple negative and high-grade tumors (both P<0.001), and tumor mutational burden scores were highest in the high EIF4EBP1-expression groups (all P<0.001). High EIF4EBP1 expression significantly correlated to worse overall survival in all three cohorts (hazard ratios (HR) 1.4-1.9), and worse distant relapse-free survival in patients treated with neoadjuvant taxane-anthracycline chemotherapy (HR 2.4). GSEA demonstrated enriched mTOR and cell proliferation-related gene sets, including, MYC, G2M checkpoint, and E2F targets across all three bulk tumor and single cell RNA sequencing cohorts. Phenotypically, these pathways were reflected by increased Ki67 gene expression and signaling via pharmacologically-activated mTOR gene sets in EIF4EBP1 high-expressing tumors (all P<0.001). EIF4EBP1 expression was increased in whole breast tumors compared to normal breast tissue (P<0.001), and was expressed predominantly in cancer epithelial cells, particularly in basal epithelial cell subclasses. EIF4EBP1 expression did not correlate to a consistent immune system phenotype across all three cohorts. Overall, these findings support that high EIF4EBP1 gene expression in bulk breast tumors could represent a poor prognostic marker via mTOR signaling pathways activation and upregulation of cell cycling, ultimately leading to increased tumorigenesis.

Malignant Transformation of Long-Standing Ileal Crohn's Disease Likely Favors Signet Ring Cell Adenocarcinoma Histology.

Signet ring cell adenocarcinomas (SRCCs) are a rare and aggressive histological subtype of adenocarcinomas typically with poor prognosis usually secondary to late stage at detection. In the small bowel, they constitute only 1% of all malignancies. In the last decade, there have been multiple case reports and small case series that have identified SRCCs, typically in the ileum, in patients with Crohn's disease. Crohn's disease is a transmural inflammatory condition that normally manifests in the distal ileum and colon, and is known to temporally increase the risk of malignancy. Given the profound rarity of SRCCs, establishing an association between Crohn's disease and SRCC is challenging. In this study, we performed a systematic review of case reports and small case series describing small bowel SRCCs in Crohn's disease patients. Most cases were found in the distal/terminal ileum, at a mean age of 59 years old. Virtually all tumors were locally advanced (pathological T stage 3 and 4), typically with at least N1 nodal disease. Two case studies (one is a case-control study and the other a cohort design) demonstrated that small bowel SRCC, as opposed to conventional adenocarcinoma, was significantly correlated to a history of Crohn's disease (35% vs. 0%, 73.5% vs. 28.5%), with a propensity to arise in the ileum (95% vs. 30%, 66.7% vs. 42.1%), and at earlier mean age (43 vs. 68 years, 53.7 vs. 61.7 years). We additionally used the Surveillance, Epidemiology, and End Results (SEER) database for insights into the clinicoepidemiological characteristics of ileum SRCCs. SRCCs composed 28.1% of all ileal SRCCs, compared to 11.0% for the adenocarcinomas, with a younger age at diagnosis (60.7 vs. 64.6 years), more distant disease at presentation (41.3% vs. 26.4%), and shorter overall median survival time (20 vs. 39 months). In summary, while there is limited direct evidence to support an association between small bowel SRCC and Crohn's disease, the phenomenon has been increasingly documented in the literature in the last decade. Clinicians treating Crohn's disease patients should consider this in their differential diagnosis, particularly when managing disease complications, as early detection and surgical intervention offer the best prognosis.

Location Has Prognostic Impact on the Outcome of Colorectal Mucinous Adenocarcinomas.

Mucinous (colloid) adenocarcinomas (MAs) are a rare histological subtype of tumors defined by extracellular mucin comprising more than 50% of the tumor. These tumors are on a continuum of mucin-producing malignancies with signet ring cell adenocarcinomas (SRCCs), which instead produce intracellular mucin. Mucin-containing cancers occur primarily in the stomach and colon, where for SRCCs, outcomes are relatively worse in the proximal stomach and the rectum. It is not known if MAs have similar outcomes. In this study, we use the Surveillance, Epidemiology, and End Results (SEER) database to examine the effects of tumor localization, age, sex, and stage on colorectal and gastric cancer outcomes for MAs. For right colon cancers, MAs are more common, particularly in females, and have slightly better or equivalent outcomes across all stages and ages compared to conventional adenocarcinomas, but outcomes are progressively worse compared to conventional adenocarcinomas for left colon and rectal cancers. Unlike SRCCs, MAs have similar outcomes to conventional adenocarcinomas in all stomach locations. Overall, these results suggest that MAs have an intrinsically different tumor biology in the left colon and rectum that promotes pathogenesis. Decoding this phenomenon could lead to more effectively tailored patient treatment regimens.

Fumarylacetoacetate hydrolase gene as a knockout target for hepatic chimerism and donor liver production.

A reliable source of human hepatocytes and transplantable livers is needed. Interspecies embryo complementation, which involves implanting donor human stem cells into early morula/blastocyst stage animal embryos, is an emerging solution to the shortage of transplantable livers. We review proposed mutations in the recipient embryo to disable hepatogenesis, and discuss the advantages of using fumarylacetoacetate hydrolase knockouts and other genetic modifications to disable hepatogenesis. Interspecies blastocyst complementation using porcine recipients for primate donors has been achieved, although percentages of chimerism remain persistently low. Recent investigation into the dynamic transcriptomes of pigs and primates have created new opportunities to intimately match the stage of developing animal embryos with one of the many varieties of human induced pluripotent stem cell. We discuss techniques for decreasing donor cell apoptosis, targeting donor tissue to endodermal structures to avoid neural or germline chimerism, and decreasing the immunogenicity of chimeric organs by generating donor endothelium.

Functional characterization of a bioengineered liver after heterotopic implantation in pigs.

Organ bioengineering offers a promising solution to the persistent shortage of donor organs. However, the progression of this technology toward clinical use has been hindered by the challenges of reconstituting a functional vascular network, directing the engraftment of specific functional cell types, and defining appropriate culture conditions to concurrently support the health and phenotypic stability of diverse cell lineages. We previously demonstrated the ability to functionally reendothelialize the vasculature of a clinically scaled decellularized liver scaffold with human umbilical vein endothelial cells (HUVECs) and to sustain continuous perfusion in a large animal recovery model. We now report a method for seeding and engrafting primary porcine hepatocytes into a bioengineered liver (BEL) scaffold previously reendothelialized with HUVECs. The resulting BELs were competent for albumin production, ammonia detoxification and urea synthesis, indicating the presence of a functional hepatocyte compartment. BELs additionally slowed ammonia accumulation during in vivo perfusion in a porcine model of surgically induced acute liver failure. Following explant of the graft, BEL parenchyma showed maintenance of canonical endothelial and hepatocyte markers. Taken together, these results support the feasibility of engineering a clinically scaled functional BEL and establish a platform for optimizing the seeding and engraftment of additional liver specific cells.

Stem Cell-Related Studies and Stem Cell-Based Therapies in Liver Diseases.

Owing to the increasing worldwide burden of liver diseases, the crucial need for safe and effective interventions for treating end-stage liver failure has been a very productive line of inquiry in the discipline of hepatology for many years. Liver transplantation is recognized as the most effective treatment for end-stage liver disease; however, the shortage of donor organs, high medical costs, and lifelong use of immunosuppressive agents represent major drawbacks and demand exploration for alternative treatments. Stem cell-based therapies have been widely studied in the field of liver diseases and are considered to be among the most promising therapies. Herein, we review recent advances in the application of stem cell-related therapies in liver disease with the aim of providing readers with relevant knowledge in this field and inspiration to spur further inquiry.