No abstract

Colorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.

Choledochoduodenostomy (CDD) has been reported as a more effective treatment of CBD stones than T-tube drainage but it is regarded as a last resort or obsolete therapeutic method due to fears of higher mobidity, cholangitis, “sump” syndrome and liver dysfunction. We aimed to assess the aforementioned issues analyzing prospectively our experience from 1976 through Dec.92. Methods: CDD was performed in 89 females and 36 males, aged 60.2±8.7 years, 26 during repeat surgery. Duct stones were the indication in 94, Sphincter of oddi (SO) dysfunction in 23 and obstructive pancreatitis nodule in 8. Peroperative liver biopsies were obtained in 44 patients. The “follow-up” schedule (> 2.5 years in 110) included clinical interview and LFT's on an yearly basis. Ultra sound (USG) was obtained every one or two years. ERC was done in 10 symptomatic patients and in 25 others for protocul purposes. Liver biopsies were taken four to nine years post surgery in 11 patients-five at relaparotomy for non-biliary causes and six percutaneously by fine needle. Ductal mucosa biopsy could safely be performed in one patient 10 years after surgery. The long-term results were classified as excellent, good, fair or poor. Poor meant the need for further invasive therapy (resurgery or EST). Results: There were two operative deaths (1.6%). The long-term results (123 survivors) were considered excellent in 89, good in 22, fair in 9 and poor in three. Three patients died from unrelated causes and eight others ceased the “follow-up” evaluation three to five years post surgery. All of them were considered as having excellent or good results. A widely patent anastomosis of approximately 20 mms without mucosal inflammatory changes was documented in every patient assessed via ERC. food “debris” was detected within the distal duct of four patients yet it was easily flushed through the stoma. Normal tissue patterns were observed in all long-term liver biopsies. Likewise the ductal mucosa biopsy failed to reveal any acute or chronic inflammatory changes. Conclusions: 1) CDD is ahighly effective short and long-term treatment of CBD lithiasis.2) It does not lead to bacterial or “chemical” cholangitis, to “sump” syndrome or to hepatic dysfunction, provided a wide anastomosis is accomplished.3) CDD should only be considered as obsolete after extensive, long-term, prospective, randomized assessments of laparoscopic or combined laparoendoscopic approaches have been shown to be as effective as or superior to CDD.

Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.