Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells.

Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, MVP, YB-1, and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018-2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in ABCB1, ABCC1, and ABCG2 expression. We demonstrated strong negative correlations in ABCB1 and ABCG2 expression with SI (Doc) and SI (Doc + Gem), and positive correlation of MVP expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance.

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.

Spontaneous regression of a metastatic carcinoma transmitted by a kidney graft.

Transmission of a malignancy from a donor's organ to the recipient of the graft is a rare event, though it is a severe complication that can result in a poor outcome. Usually, immunosuppressive therapy is discontinued and the allograft is removed. However, treatment of patients with the disseminated cancers implies that after the graft removal and cessation of the immunosuppression, radiotherapy, chemotherapy, or immunotherapy with alpha-interferon (INF-α) or interleukin-2 (IL-2) are required. The case report presents a clinical case of a transmitted kidney graft with multiple metastases (MTS) in a 31-year-old woman with the spontaneous regression of the metastatic cancer after transplantectomy and cancellation of the immunosuppressive therapy. Obviously, the determining factor is the recognition of the tumor by the effectors of the antitumor immunity due to the human leukocyte antigen (HLA) mismatch between the donor and the recipient. Therefore, cancellation of the immunosuppressive therapy in cases of transferal of a malignancy with a transplanted organ allows the effectors of the immune system to distinguish the tumor as a foreign tissue and effectively eliminate this neoplasm.

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.

Soft Tissue Sarcoma Study: Association of Genetic Alterations in the Apoptosis Pathways with Chemoresistance to Doxorubicin.

Soft tissue sarcomas (STS) are heterogeneous cancers with more than 100 histological subtypes, different in molecular alterations, which make its personalized therapy very complex. Gold standard of chemotherapy for advanced STS includes combinations of Doxorubicin and Ifosfamide or Gemcitabine and Docetaxel. Chemotherapy is efficient for less than 50% of patients and it is followed by a fast development of drug resistance. Our study was directed to the search of genetic alterations in cancer cells associated with chemoresistance of undifferentiated pleomorphic and synovial sarcomas to the abovementioned genotoxic drugs. We analyzed chemoresistance of cancer cells in vitro using primary STS cultures and performed genetic analysis for the components of apoptotic signaling. In 27% of tumors, we revealed alterations in TP53, ATM, PIK3CB, PIK3R1, NTRK1, and CSF2RB. Cells from STS specimens with found genetic alterations were resistant to Dox, excluding the only one case when TP53 mutation resulted in the substitution Leu344Arg associated with partial oligomerization loss and did not cause total loss of TP53 function. Significant association between alterations in the components of apoptosis signaling and chemoresistance to Dox was found. Our data are important to elaborate further the therapeutic strategy for STS patients with alterations in apoptotic signaling.

Comprehensive Molecular Genetic Diagnostics of Birt-Hogg-Dube Syndrome in a Russian Patient with Renal Cancer and Lung Cysts: A Case Report.

We report a case of Birt-Hogg-Dube syndrome (BHDS), a rare hereditary syndrome, the main visible sign of which is the development of multiple skin fibrofolliculomas. In our case, there was a manifestation of BHDS consisting in the absence of fibrofolliculomas and presence of other characteristic features of this syndrome: lung cysts and renal cancer. The 26-year-old woman was admitted to a clinic for diagnosis and treatment of a neoplasm of the left kidney and had a history of renal cell cancer (RCC) of the right kidney and spontaneous pneumothorax. Multiple tumors of the left kidney and lung cysts were observed upon clinical and laboratory testing. Tumors of the left kidney were resected and diagnosed by a pathologist as chromophobe RCC. Sequencing of FLCN exons 4-14 from blood DNA revealed the heterozygous germline nonsense mutation c.1429C>T (p.R477*), confirming the diagnosis of BHDS. Several somatic variants were detected by tumor DNA sequencing using the Comprehensive Cancer Panel and Ion S5 platform. Medical-genetic counseling was conducted, and follow-up management was outlined. To our knowledge, this case report is the first comprehensive clinical and genetic examination of a patient with BHDS in Russia. The p.R477* mutation has been described by other authors in patients with fibrofolliculomas and lung cysts, but not in those with RCC, while RCC was the first manifestation of BHDS in our case. The case report may help geneticists, oncologists, and other specialists to better understand the clinical and genetic heterogeneity of BHDS in various populations.