Lessons Learned This study showed that carefully selected patients with locally advanced and metastatic forms of malignant melanoma and renal cell carcinoma could potentially have long‐term disease control with a tag‐7 gene‐modified tumor cells‐based vaccine. Randomized clinical trials in patients whose tumors produce low amounts of immunosuppressive factors are needed to confirm this hypothesis in both the adjuvant and metastatic settings. Background Immunotherapy may produce long‐lasting effects on survival and toxicity. The magnitude of efficacy may be dependent on immune factors. We analyzed the results of a phase I/II study of a tag‐7 gene‐modified tumor cells‐based vaccine (GMV) in patients with malignant melanoma (MM) or renal cell carcinoma (RCC) with biomarker analysis of immunosuppressive factors (ISFs) production by their tumor cells. Methods From 2001 to 2014, 80 patients received GMV: 68 with MM and 12 with RCC. Treatment in the metastatic setting included 61 patients (MM, 51; RCC, 10), and treatment in the adjuvant setting (after complete cytoreduction) included 19 patients (MM, 17; RCC, 2). Twenty‐six patients were stage III (33%), and 54 (67%) were stage IV. The patients’ tumor samples were transferred to culture, transfected with tag‐7 gene, and inactivated by radiation. The produced product was injected subcutaneously every 3 weeks until progression or 2 years of therapy. ISFs were measured in the supernatants of the tumor cell cultures and used as predictive factors. Results No major safety issues or grade 5 adverse events (AEs) were seen. One grade 4 and two grade 3 AEs were registered. No AEs were registered in 89.4% of treatment cycles. No delayed AE was found. The 5‐year overall survival (OS) in the intention‐to‐treat population was 25.1%. There were no differences between MM OS and RCC OS (log rank, p = .44). Median OS in the metastatic setting was 0.7 years and in the adjuvant setting was 3.1 years. Classification trees were built on the basis of ISF production (Fig. 1). The median OS was 6.6 years in the favorable prognosis (FP) group (major histocompatibility complex class I polypeptide‐related sequence A [MICA] level ≤582 pg/mL, n = 15) and 4.6 months in the unfavorable (UF) group (MICA level >582 pg/mL, n = 12; p < .0001). No significant differences were found between classification trees based on ISFs (transforming growth factor β1 [TGF‐β1], interleukin‐10 [IL‐10], and vascular endothelial growth factor [VEGF]). In patients with stage III–IV MM with FP, median OS was 2.3 years, with 31% patients alive at 10 years (Fig. 2) in the UF group (0.4 years; log rank, p = 1.94E−5). No FP patients received modern immunotherapy. Conclusion GMV showed high results in carefully selected patients with low ISF (TGF‐β1, IL‐10, and VEGF) production. The method should be further investigated in patients with FP.
Background. Various tumor control genes and microRNAs (miRNa) play an important role in the development and progression of colorectal cancer (CRC). the expression of these genes can differ significantly in tumor and adjacent healthy tissues. there is no exact data at what distance from the tumor the adjacent healthy tissue is located in terms of gene expression.The aim of the investigation was to study the tumor control genes (E2F3, TGFB, NFKB, KLF-12, EGFR and MMP9), as well as the microRNA genes (microRNA-15, -16, -21 and -210) expression profiles in tumor and adjacent healthy tissues.Material and methods. the study included 19 patients diagnosed with colorectal cancer. the tumor control genes (E2F3, TGFB, NFKB, KLF-12, EGFR and MMP9), as well as the miRNA genes (miRNA-15, -16, -21 and -210) expression levels were investigated in tumor and adjacent normal tissue samples taken during colonoscopy.Results. a decrease in the level of expression of E2F3 (median 3,73, Q1-Q3 2,64 Reu vs. median 6.5, Q1-Q3 6,39 REU, p=0,01) and miRNA-16 (median 2,83, Q1-Q3 4,74 REU vs. median 4,29, Q1-Q3 3,73 REU, p=0,027) and an increase in the expression level of miRNA-21 (median 2,64, Q1-Q3 1,38 REU vs. median 1,41, Q1-Q3 1,21 REU, p<0,001) were found in tumor tissue compared to normal tissue of patients with CRC.Conclusion. significant differences in the E2F3, miRNA-16 and miRNA-21 gene expressions were revealed. an increased level of E2F3 and miRNA-16 expressions at a distance of 1–2 cm from the tumor may be a predictor of tumor recurrence and progression, and an increased miRNA-21 expression in tumor tissue as compared to adjacent tissue may be a negative prognostic factor. this information can be used in further clinical research.
Conclusions: Our study showed that EOCRC patients had more frequently BMI < 18.5, primary tumor located at transverse colon and ECOG 0, along with a statistically significant higher PFS in first line and higher OS than the rest of CRC patients.Legal entity responsible for the study: The authors.
The review presents the data on the specifics of mechanism of action, classification, and clinical manifestations of neurotoxicity effect. The most significant features of specific side effects when using taxanes in different treatment regimens, including cumulative doses, are considered. The proven methods of treatment and prevention of neuropathy caused by anticancer drugs are discussed.
Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический)», Санкт-Петербург, Россия РЕЗЮМЕ В обзоре представлены данные о классификации, механизмах развития и клинических проявлениях нейротоксичности. Проанализированы основные особенности нейротоксичности при использовании таксанов, включая кумулятивные дозы. Рассмотрены доказанные методы лечения и профилактики нейропатии, вызванной цитостатическими препаратами.
Challenges in cancer detection, prognosis and management are currently being solved by determining circulating tumor DNA (ctDNA). The assessment of this marker has acquired particular importance in metastatic colorectal cancer (mCRC), the systemic treatment of which depends on the RAS gene status, which has prognostic and predictive value. However, the possibilities of taking samples from the primary or metastatic lesion for pathomorphological and molecular analysis in CRC are often limited. The determination of ctDNA using liquid biopsy has an advantage over standard biopsy due to its low invasiveness and high availability of the method. Analysis of mutations using ctDNA as well as changes in the level of this marker is a criterion for the effectiveness of systemic treatment, as well as a factor that determines the risk of disease progression. Currently, the potential of using ctDNA to monitor effectiveness of first-and second-line chemotherapy, as well as to predict the development of secondary resistance to EGFR inhibitors (cetuximab and panitumumab) in the first-line treatment and assessment of RAS status for returning to therapy with EGFR inhibitors in the third-line treatment of mCRC is being studied. Several pilot studies have provided evidence of the efficacy of EGFR re-treatment. The modern literature data published in leading peer-reviewed journals in Russian and international scientific citation databases, such as Medline, Elibrary, and PubMed were analyzed. Of the 138 analyzed publications, 56 were used to write this review.
e14022 Background: Immunotherapy may produce long lasting effects on survival.Magnitude of efficacy may be depended from immune factors. We evaluated the overall survival (OS) in pts treated with GMV with biomarker analysis of immunosuppressive factors (ISF) production by their tumor cells. Methods: Since 2001 to 2014 80 pts received GMV: 68 with MM and 12 pts with RCC. Treatment was given in the metastatic setting in 61 pts (MM-51, RCC – 10) and in the adjuvant (after complete cytoreduction) setting in 19 pts (MM-17, RCC-2). Stage 3 was in 26 (33%) pts, stage 4 in 54 (67%). Pt’s tumor samples were transferred to culture, transfected with TAG7and inactivated by radiation. Produced product was injected SC every 3 weeks until progression or 2y of therapy. ISF (MICA, TGF-β1, IL-10 and VEGF) were measured in the supernatants of the tumor cell cultures and used as predictive factors. Results: The 5-yr OS in intention to treat population was 25.1%. There was no differences in MM and RCC OS (Log-rank p = 0.44). Median OS in metastatic setting was 0,7 y, in adjuvant – 3,1 y. Classification trees were built on the basis of ISF production. The median OS was 6.6 y in favorable prognosis (FP) group (MICA level ≤582 pg/ml, n = 15), 4.6 mo in unfavorable (UF) group (MICA level > 582 pg/ml, n = 12) (p < 0.0001). No significant differences were found between classification trees based on the other ISF (TGF-β1, IL-10 and VEGF). In stage 3-4 MM pts with FP median OS was 2,3 y with 31% pts alive in 10y, in UF group – 0,4 y; log-rank p = 1,94E-5. No FP pts received modern immunotherapy. Conclusions: GMV shows high results in carefully selected pts with low ISF production. Method should be further investigated in pts with FP. [Table: see text]
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