Recommendations for a practical implementation of circulating tumor DNA mutation testing in metastatic non-small-cell lung cancer.

BACKGROUND: Liquid biopsy (LB) is a rapidly evolving diagnostic tool for precision oncology that has recently found its way into routine practice as an adjunct to tissue biopsy (TB). The concept of LB refers to any tumor-derived material, such as circulating tumor DNA (ctDNA) or circulating tumor cells that are detectable in blood. An LB is not limited to the blood and may include other fluids such as cerebrospinal fluid, pleural effusion, and urine, among others. PATIENTS AND METHODS: The objective of this paper, devised by international experts from various disciplines, is to review current challenges as well as state-of-the-art applications of ctDNA mutation testing in metastatic non-small-cell lung cancer (NSCLC). We consider pragmatic scenarios for the use of ctDNA from blood plasma to identify actionable targets for therapy selection in NSCLCs. RESULTS: Clinical scenarios where ctDNA mutation testing may be implemented in clinical practice include complementary tissue and LB testing to provide the full picture of patients' actual predictive profiles to identify resistance mechanism (i.e. secondary mutations), and ctDNA mutation testing to assist when a patient has a discordant clinical history and is suspected of showing intertumor or intratumor heterogeneity. ctDNA mutation testing may provide interesting insights into possible targets that may have been missed on the TB. Complementary ctDNA LB testing also provides an option if the tumor location is hard to biopsy or if an insufficient sample was taken. These clinical use cases highlight practical scenarios where ctDNA LB may be considered as a complementary tool to TB analysis. CONCLUSIONS: Proper implementation of ctDNA LB testing in routine clinical practice is envisioned in the near future. As the clinical evidence of utility expands, the use of LB alongside tissue sample analysis may occur in the patient cases detailed here.

Characterization of novel CD55 isoforms expression in normal and neoplastic tissues.

CD55 (decay-accelerating factor, DAF) is overexpressed in several types of cancer, including colorectal cancer. Because of its inhibitory effect on the complement system, it has been suggested as a possible target for cancer immunotherapy. However, CD55 is also expressed in normal tissues, body fluids and stroma, limiting the use of anti-CD55 therapeutic antibodies. Two novel CD55 splice variants or isoforms have recently been identified. These have been shown to contain part or all of intron 7 (CD55(int7+)), in contrast to the previously identified splice variants (CD55(wt)), which do not contain intron 7. Our aim was to determine the pattern of expression of the CD55(int7+) isoforms in normal and cancer tissues and to compare it to CD55(wt). We found that while CD55's isoforms levels vary directly, CD55(wt) is much more abundant (on average 48 times more) than CD55(int7+). Moreover, colon cancers that express high CD55(wt) mRNA levels tend to upregulate CD55(int7+) to a further extent. Finally, we compared the protein levels of CD55(int7+) to CD55(wt) by immunohistochemistry in various colorectal pathological conditions including neoplasia, and found that the levels of both isoforms were elevated in all types of colonic pathology. These results show that the levels of CD55(int7+) in normal tissue are much lower than CD55(wt), while in tumors it is restricted to the epithelial structures unlike CD55(wt). Thus, CD55(int7+) may be a more suitable target for cancer immunotherapy.

A role for VICKZ proteins in the progression of colorectal carcinomas: regulating lamellipodia formation.

VICKZ proteins are a highly conserved family of RNA binding proteins, implicated in RNA regulatory processes such as intracellular RNA localization, RNA stability, and translational control. During embryogenesis, VICKZ proteins are required for neural crest migration and in adults, the proteins are overexpressed primarily in different cancers. We hypothesized that VICKZ proteins may play a role in cancer cell migration. In patients, VICKZ expression varies with tumour type, with over 60% of colon, lung, and ovarian tumours showing strong expression. In colorectal carcinomas (CRCs), expression is detected at early stages, and the frequency and intensity of staining increase with progression of the disease to lymph node metastases, of which 97% express the protein at high levels. Indeed, in stage II CRC, the level of VICKZ expression in the primary lesion correlates with the degree of lymph node metastasis. In culture, VICKZ proteins rapidly accumulate in processes at the leading edge of PMA-stimulated SW480 CRC cells, where they co-localize with beta-actin mRNA. Two distinct cocktails of shRNAs, each targeting all three VICKZ paralogues, cause a dramatic drop in lamellipodia and ruffle formation in stimulated cells. Thus, VICKZ proteins help to facilitate the dynamic cell surface morphology required for cell motility. We propose that these proteins play an important role in CRC metastasis by shuttling requisite RNAs to the lamellipodia of migrating cells.

[Complex evaluation of endemicity level of the territory affected by hemorrhagic fever with renal syndorome]. / Kompleksnaia otsenka éndemichnosti territorii po gemorragicheskoi likhoradke s pochechnym sindromom.

A new formula for the calculation of the endemicity index of the territory affected by hemorrhagic fever with renal syndrome (HFRS) based on empiric data collected in the Volga region near Saratov in 1982-2000 is proposed. As found in this research 21% of the administrative districts of the region have a high endemicity level (with the average index for several years reaching 35 points), 8% of the districts have a medium enemicity level (20 points) and 71% of the districts--a low endemicity level (9 points). It is pointed out that under conditions of financial constraints territories with high and medium endemicity levels should be first examined for HFRS; these territories should also be given priority in prophylactic deratization in the field and human settlements.