Retroperitoneal Liposarcoma: Rational Extent of Surgery Tailored to Grade of Malignancy.

This study was aimed at determining the indications for combined and organ-preserving operations. The study included 190 patients with retroperitoneal liposarcoma (RLPS). The influence of the following factors on the overall survival (OS) and recurrence-free survival (RFS) were studied: involvement of adjacent organs in the tumor, volume of surgical intervention. OS and RFS were worse in pathologically confirmed visceral invasion in the both RLPS low grade and high grade (p = 0.000). In RLPS low grade, there was no significant difference in OS and RFS between the group of patients who underwent combined surgery without confirmed visceral invasion and the group of patients who underwent organ-preserving surgery (p > 0.080). In RLPS high grade, OS and RFS were higher in the group of patients who underwent combined surgery without confirmed visceral invasion than in the group of patients who underwent organ-preserving surgery (p < 0.050). In RLPS low grade, it is advisable to perform organ-preserving operations, including nephrosaving operations. In RLPS high grade, the organ-preserving operations worsen long-term results and prognosis. Combined operations including nephrectomy are justified in RLPS high grade.

Prediction of Recurrence-Free and Overall Survival in Retroperitoneal Well-Differentiated and Dedifferentiated Liposarcoma After Surgery.

This study was aimed at creating an effective model for predicting the course of the disease in retroperitoneal well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcomas after surgery. The study included 111 patients with WDLPS and 74 patients with DDLPS. We developed a methodology for stratification of patients into prognostic groups. Overall survival (OS) and recurrence-free survival (RFS) were analyzed in accordance with it. The highest OS was achieved in the group "favorable prognosis," while the shortest OS was in the group "extremely poor prognosis" (p < 0.001). The median OS in the "favorable prognosis" group was 225 (95% CI, 174, 276) months; "intermediate prognosis" - 130 (95% CI, 115, 145) months; "poor prognosis" - 90 (95% CI, 79, 101) months; and "extremely poor prognosis" - 22 (95% CI, 15, 29) months. The highest RFS was achieved in the group "favorable prognosis," while the shortest RFS was achieved in the group "extremely poor prognosis" (p < 0.001). The median RFS in the "favorable prognosis" group was 80 (95% CI, 65, 95) months; "intermediate prognosis" - 47 (95% CI, 33, 61) months; "poor prognosis" - 26 (95% CI, 24, 28) months; "extremely poor prognosis" - 10 (95% CI, 6, 14) months. The method of predicting recurrence-free and overall survival demonstrates an adequate distribution of patients and the reliability of intergroup differences in the survival rate.

TNM classification of malignant tumors: Eighth edition for retroperitoneal liposarcoma. Ways to improve.

AIM: This study was aimed at assessing the prognostic significance of the "TNM: Classification of Malignant Tumors" eighth edition (TNM8) in the most common retroperitoneal tumors - liposarcoma. METHODS: The study included 192 patients with retroperitoneal liposarcoma (RLPS). The distribution of patients by stages and survival in accordance with the TNM8 were studied. RESULTS: In the TNM8, only the degree of malignancy of the tumor has a prognostic value. The T-category does not reflect the actual size of the RLPS and is considered as T4 in 93%, which leads to inadequate staging. During the 15-year period, there were no cases with stages II and IIIA, and the survival rate was estimated only in patients with stages I and IIIB. The tumor node metastasis (TNM) classification with new values of the T-category was proposed by us, which demonstrated a more adequate distribution of patients by stages and the reliability of intergroup differences in the survival rate. CONCLUSION: It is advisable to create a special TNM classification for RLPS, which makes up more than half of all retroperitoneal sarcomas. The TNM8 does not accurately reflect the prevalence of the tumor and the prognosis in RLPS. Revision of the T-staging is necessary to improve the accuracy of the prognosis in RLPS. The modified by us TNM classification demonstrated a more adequate distribution of patients by stages.

The Correlation of Ten Immune Checkpoint Gene Expressions and Their Association with Gastric Cancer Development.

In the immunotherapy based on immune checkpoint inhibition (IC), additional ICs are being studied to increase its effectiveness. An almost unstudied feature is the possible co-expression of ICs, which can determine the therapeutic efficacy of their inhibition. For the selection of promising ICs, information on the association of their expression with cancer development may be essential. We have obtained data on the expression correlation of ADAM17, PVR, TDO2, CD274, CD276, CEACAM1, IDO1, LGALS3, LGALS9, and HHLA2 genes in gastric cancer (GC). All but one, TDO2, have other IC genes with co-expression at some stage. At the metastatic stage, the expression of the IDO1 does not correlate with any other gene. The correlations are positive, but the expressions of the CD276 and CEACAM1 genes are negatively correlated. The expression of TDO2 and LGALS3 is associated with GC metastasis. The expression of TDO2 four-fold higher in metastatic tumors than in non-metastatic tumors, but LGALS3 was two-fold lower. The differentiation is associated with IDO1. The revealed features of TDO2, with a significant increase in expression at the metastatic stage and the absence of other IC genes with correlated expression indicates that the prospect of inhibiting TDO2 in metastatic GC. IDO1 may be considered for inhibition in low-differentiated tumors.

The Features of Immune Checkpoint Gene Regulation by microRNA in Cancer.

Currently, the search for new promising tools of immunotherapy continues. In this regard, microRNAs (miRNAs) that influence immune checkpoint (IC) gene expression in tumor and T-cells and may be important regulators of immune cells are considered. MiRNAs regulate gene expression by blocking mRNA translation. An important feature of miRNA is its ability to affect the expression of several genes simultaneously, which corresponds to the trend toward the use of combination therapy. The article provides a list of miRNAs acting simultaneously on several ICs and miRNAs that, in addition to IC, can regulate the expression of targeted therapy genes. There is dependence of miRNA interactions with IC genes on the type of cancer. The analysis of the accumulated data demonstrates that only about 14% (95% CI: 9.8-20.1%) of the studied miRNAs regulate the expression of specific IC in more than one type of cancer. That is, there is tumor specificity in the miRNA action on ICs. A number of miRNAs demonstrated high efficiency in vitro and in vivo. This indicates the potential of miRNAs as promising agents for cancer immunotherapy. Additional studies of the miRNA-gene interaction features and the search for an optimal miRNA mimic structure are necessary.

Isolation and Characterization of Extracellular Vesicles from Gastric Juice.

EVs are involved in local and distant intercellular communication and play a vital role in cancer development. Since EVs have been found in almost all body fluids, there are currently active attempts for their application in liquid diagnostics. Blood is the most commonly used source of EVs for the screening of cancer markers, although the percentage of tumor-derived EVs in the blood is extremely low. In contrast, GJ, as a local biofluid, is expected to be enriched with GC-associated EVs. However, EVs from GJ have never been applied for the screening and are underinvestigated overall. Here we show that EVs can be isolated from GJ by ultracentrifugation. TEM analysis showed high heterogeneity of GJ-derived EVs, including those with exosome-like size and morphology. In addition to morphological diversity, EVs from individual GJ samples differed in the composition of exosomal markers. We also show the presence of stomatin within GJ-derived EVs for the first time. The first conducted comparison of miRNA content in EVs from GC patients and healthy donors performed using a pilot sampling revealed the significant differences in several miRNAs (-135b-3p, -199a-3p, -451a). These results demonstrate the feasibility of the application of GJ-derived EVs for screening for miRNA GC markers.

Macrophage Phenotype in Combination with Tumor Microbiome Composition Predicts RCC Patients' Survival: A Pilot Study.

The identification of new prognostic markers of renal cell carcinoma (RCC) is an urgent problem in oncourology. To investigate the potential prognostic significance of tumor microbiome and stromal inflammatory markers, we studied a cohort of 66 patients with RCC (23 clear cell RCC, 19 papillary RCC and 24 chromophobe RCC). The microbiome was analyzed in tumor and normal tissue by 16S rRNA amplicon sequencing. Characterization of the tumor stroma was performed using immunohistochemistry. A significant difference in alpha diversity was demonstrated between normal kidney tissue and all types of RCC. Further, we demonstrated that the bacterial burden was higher in adjacent normal tissue than in a tumor. For the first time, we demonstrated a significant correlation between bacterial burden and the content of PU.1+ macrophages and CD66b+ neutrophils in kidney tumors. Tumors with high content of PU.1+ cells and CD66b+ cells in the stroma were characterized by a lower bacterial burden. In the tumors with high bacterial burden, the number of PU.1+ cells and CD66b+ was associated with a poor prognosis. The identified associations indicate the great prognostic potential of a combined tumor microbiome and stromal cell analysis.

Clinical significance of molecular subtypes of gastrointestinal tract adenocarcinoma.

Adenocarcinomas of the gastrointestinal tract (esophagus, stomach, and colon) represent a heterogeneous group of diseases with distinct etiology, clinical features, treatment approaches, and prognosis. Studies are ongoing to isolate molecular genetic subtypes, perform complete biological characterization of the tumor, determine prognostic groups, and find predictive markers to the effectiveness of therapy. Separate molecular genetic classifications were created for esophageal adenocarcinoma [The Cancer Genome Atlas (TCGA)], stomach cancer (TCGA, Asian Cancer Research Group), and colon cancer (Colorectal Cancer Subtyping Consortium). In 2018, isolation of TCGA molecular genetic subtypes for adenocarcinomas of the gastrointestinal tract (esophagus, stomach, and colon) highlighted the need for further studies and clinical validation of subtyping of gastrointestinal adenocarcinomas. However, this approach has limitations. The aim of our work was to critically analyze integration of molecular genetic subtyping of gastrointestinal adenocarcinomas in clinical practice.

Aberrant Methylation of 20 miRNA Genes Specifically Involved in Various Steps of Ovarian Carcinoma Spread: From Primary Tumors to Peritoneal Macroscopic Metastases.

Our work aimed to differentiate 20 aberrantly methylated miRNA genes that participate at different stages of development and metastasis of ovarian carcinoma (OvCa) using methylation-specific qPCR in a representative set of clinical samples: 102 primary tumors without and with metastases (to lymph nodes, peritoneum, or distant organs) and 30 peritoneal macroscopic metastases (PMM). Thirteen miRNA genes (MIR107, MIR124-2, MIR124-3, MIR125B-1, MIR127, MIR129-2, MIR130B, MIR132, MIR193A, MIR339, MIR34B/C, MIR9-1, and MIR9-3) were hypermethylated already at the early stages of OvCa, while hypermethylation of MIR1258, MIR137, MIR203A, and MIR375 was pronounced in metastatic tumors, and MIR148A showed high methylation levels specifically in PMM. We confirmed the significant relationship between methylation and expression levels for 11 out of 12 miRNAs analyzed by qRT-PCR. Moreover, expression levels of six miRNAs were significantly decreased in metastatic tumors in comparison with nonmetastatic ones, and downregulation of miR-203a-3p was the most significant. We revealed an inverse relationship between expression levels of miR-203a-3p and those of ZEB1 and ZEB2 genes, which are EMT drivers. We also identified three miRNA genes (MIR148A, MIR9-1, and MIR193A) that likely regulate EMT-MET reversion in the colonization of PMM. According to the Kaplan-Meier analysis, hypermethylation of several examined miRNA genes was associated with poorer overall survival of OvCa patients, and high methylation levels of MIR130B and MIR9-1 were related to the greatest relative risk of death.

Blood Plasma Metabolome Profiling at Different Stages of Renal Cell Carcinoma.

Early diagnostics significantly improves the survival of patients with renal cell carcinoma (RCC), which is the prevailing type of adult kidney cancer. However, the absence of clinically obvious symptoms and effective screening strategies at the early stages result to disease progression and survival rate reducing. The study was focused on revealing of potential low molecular biomarkers for early-stage RCC. The untargeted direct injection mass spectrometry-based metabolite profiling of blood plasma samples from 51 non-cancer volunteers (control) and 78 patients with different RCC subtypes and stages (early stages of clear cell RCC (ccRCC), papillary RCC (pRCC), chromophobe RCC (chrRCC) and advanced stages of ccRCC) was performed. Comparative analysis of the blood plasma metabolites between the control and cancer groups provided the detection of metabolites associated with different tumor stages. The designed model based on the revealed metabolites demonstrated high diagnostic power and accuracy. Overall, using the metabolomics approach the study revealed the metabolites demonstrating a high value for design of plasma-based test to improve early ccRCC diagnosis.

Thyroid cancer overdiagnosis revisited.

BACKGROUND: Evidence has accumulated showing that an increase in thyroid cancer incidence reflects overdiagnosis of clinically unimportant lesions due to the rise in the use of neck ultrasonography. In the manuscript we examine the hypothesis that the rise in thyroid cancer incidence in Russia is largely caused by overdiagnosis. MATERIALS AND METHODS: Incidence and mortality rates of thyroid cancer for Russia overall and its administrative regions were abstracted from the statistical database of the Ministry of Health of Russia. For incidence trends, we calculated the percentage change, linear regression coefficient and p-value. The calculation of excess cases was based on expected age-specific distributions assuming that the incidence of thyroid cancer increases exponentially with age, as predicted by the multistage model of carcinogenesis. FINDINGS: Over the study period (1989-2015) the age standardized incidence of thyroid cancer has tripled in Russian women and doubled in men. Strong support for the hypothesis that the increase in thyroid cancer incidence may be artificial is evident from age-specific incidence trends: increases in incidence in middle age but not in older ages, thereby altering the age curves from the expected exponential shape to an "inverted U" shape. The number of observed cases of thyroid cancer exceeded the expected number by 138, 325 or 70 % of all cases diagnosed with thyroid cancer. We attribute the excess cases to detection by ultrasonography clinically unimportant lesions. This is supported by a very high incidence -to-mortality ratio, low case fatality, high and growing prevalence of thyroid cancer. CONCLUSION: Although there is an evidence that exposure to iodine 131 (131I) is an important cause of the increase in incidence of thyroid cancer in high-risk populations, we have shown that this increase could largely be attributed to overdiagnosis associated with ultrasonography screening. Overdiagnosis is the only explanation of the increase in thyroid cancer incidence in low-risk regions.

Oncobox Bioinformatical Platform for Selecting Potentially Effective Combinations of Target Cancer Drugs Using High-Throughput Gene Expression Data.

Sequential courses of anticancer target therapy lead to selection of drug-resistant cells, which results in continuous decrease of clinical response. Here we present a new approach for predicting effective combinations of target drugs, which act in a synergistic manner. Synergistic combinations of drugs may prevent or postpone acquired resistance, thus increasing treatment efficiency. We cultured human ovarian carcinoma SKOV-3 and neuroblastoma NGP-127 cancer cell lines in the presence of Tyrosine Kinase Inhibitors (Pazopanib, Sorafenib, and Sunitinib) and Rapalogues (Temsirolimus and Everolimus) for four months and obtained cell lines demonstrating increased drug resistance. We investigated gene expression profiles of intact and resistant cells by microarrays and analyzed alterations in 378 cancer-related signaling pathways using the bioinformatical platform Oncobox. This revealed numerous pathways linked with development of drug resistant phenotypes. Our approach is based on targeting proteins involved in as many as possible signaling pathways upregulated in resistant cells. We tested 13 combinations of drugs and/or selective inhibitors predicted by Oncobox and 10 random combinations. Synergy scores for Oncobox predictions were significantly higher than for randomly selected drug combinations. Thus, the proposed approach significantly outperforms random selection of drugs and can be adopted to enhance discovery of new synergistic combinations of anticancer target drugs.

Preoperative chemotherapy in patients with resectable esophageal carcinoma: a single center Phase II study.

OBJECTIVE: The role of preoperative chemotherapy in squamous cell esophageal carcinoma remains controversial. A prospective trial was initiated to investigate whether preoperative chemotherapy followed by surgery results in increased progression-free survival in patients with resectable thoracic esophageal carcinoma. METHODS: Patients with Stage IIb-IIIa/b resectable esophageal carcinoma were eligible for the study. They received two cycles of FLEP regimen chemotherapy (cisplatin, etoposide, leucovorine, 5-fluorouracil) followed by transthoracic extended 2- or 3-field esophagectomy. Two-year progression-free survival was the primary endpoint. To evaluate the potential benefit of the dual-modality approach we compared these results with the outcome of patients who were treated in our center in the same period of time and were non-randomly allocated to surgery alone. RESULTS: From 2001 to 2008, 63 patients were included in the study (bimodality group) and 58 patients into the surgery-alone group. Median follow-up was 68 (range, 4-123) months. Squamous cell carcinoma had 93% patients. Two-year progression-free survival for all patients was 45.3 and 30.7% (hazard ratio 0.71, 95% confidence interval 0.46-1.08) and median overall survival was 26.5 months and 18.0 months (hazard ratio 0.67, 95% confidence interval 0.41-1.01) in bimodality- and surgery-alone groups, respectively. Patients who underwent R0-resection after bimodality treatment had significantly better overall survival (40.9 months) than after surgery alone (19.0 months, hazard ratio 0.51, 95% confidence interval 0.30-0.81). CONCLUSIONS: Two cycles of preoperative chemotherapy did not improve progression-free survival of patients with resectable thoracic esophageal carcinoma in intent-to-treat population. However, significantly better results of bimodality approach was seen in R0-resected patients which warrants further trials with more effective chemotherapy combinations.

Subtotal esophagectomy with extended 2-field lymph node dissection for thoracic esophageal cancer.

OBJECTIVE: To examine the efficacy of the Ivor Lewis esophagectomy with extended 2-field lymph node dissection for thoracic esophageal carcinoma we reviewed our experience. METHODS: We analyzed the cases of 147 consecutive patients who underwent subtotal esophagectomy with extended 2-field lymph node dissection through Ivor Lewis approach for esophageal cancer from January 1996 through December 2000. Eighty-six patients were operated on for cancer of the midthoracic esophagus, 48 for cancer of the lower thoracic esophagus, and 13 for cancer of the aortal segment of the esophagus. No patient had received chemotherapy or radiotherapy before operation. RESULTS: There were 113 men (76.9%) and 34 women. Median age was 57 years (range 51-65 years). Postsurgical pathological studies revealed squamous cell carcinoma in 139 patients (94.6%), adenocarcinoma in five (3.4%), and adenosquamous carcinoma in three (2%). Positive abdominal and/or mediastinal lymph nodes were found in 122 patients (82.9%). At mean 43 nodes (range from 32 up to 75) were studied for each patient. Even in T(1)-T(2) tumors mediastinal or abdominal lymph nodes are involved in up to 80% of cases. However, in T(3)-T(4) stages the frequency of lymph node involvement is significantly higher (P<0.05). Postsurgical staging was as follows: stage I in three patients (2%), stage IIa in 20 (13.6%), stage IIb in 29 (19.7%), stage III in 54 (36.8%), and stage IV in 41 (27.9%). All distant metastases were lymphogenous. The operative mortality rate was 6.1%, and complications occurred in 62 patients (42.1%). The overall 5-year survive rate was 28.8% (median survival 36.1 months). The 5-year survival rate for patients in stage IIa was 59%; for those in stage IIb, 39.5%; for patients in stage III, 26.7%; and 0% for patients in stage IV. CONCLUSIONS: Subtotal esophagectomy with extended 2-field lymph node dissection through Ivor Lewis approach for esophageal cancer is a safe operation. Long-term survival is stage dependent. Effective multimodality treatment may be helpful for patients with advanced disease.