New model of methodological support of processes modernization in the college

The article deals with the current problems of the development of STRs associated with the introduction of FSES (Federal state educational standard). A new model of methodological support of training is described. The article presents a view on the system of informal training in the vocational schoolВ статье рассматриваются актуальные проблемы развития СПО, связанные с введением ФГОС. Описывается новая модель методического обеспечения подготовки кадров. Изложен взгляд на систему неформального повышения квалификации в техникум

Mesenchymal Stem Cells Modified with a Single-Chain Antibody against EGFRvIII Successfully Inhibit the Growth of Human Xenograft Malignant Glioma

Glioblastoma multiforme is the most lethal brain tumor with limited therapeutic options. Antigens expressed on the surface of malignant cells are potential targets for antibody-mediated gene/drug delivery.In this study, we investigated the ability of genetically modified human mesenchymal stem cells (hMSCs) expressing a single-chain antibody (scFv) on their surface against a tumor specific antigen, EGFRvIII, to enhance the therapy of EGFRvIII expressing glioma cells in vivo. The growth of U87-EGFRvIII was specifically delayed in co-culture with hMSC-scFvEGFRvIII. A significant down-regulation was observed in the expression of pAkt in EGFRvIII expressing glioma cells upon culture with hMSC-scFvEGFRvIII vs. controls as well as in EGFRvIII expressing glioma cells from brain tumors co-injected with hMSC-scFvEGFRvIII in vivo. hMSC expressing scFvEGFRvIII also demonstrated several fold enhanced retention in EGFRvIII expressing flank and intracranial glioma xenografts vs. control hMSCs. The growth of U87-EGFRvIII flank xenografts was inhibited by 50% in the presence of hMSC-scFvEGFRvIII (p<0.05). Moreover, animals co-injected with U87-EGFRvIII and hMSC-scFvEGFRvIII intracranially showed significantly improved survival compared to animals injected with U87-EGFRvIII glioma cells alone or with control hMSCs. This survival was further improved when the same animals received an additional dosage of hMSC-scFvEGFRvIII two weeks after initial tumor implantation. Of note, EGFRvIII expressing brain tumors co-injected with hMSCs had a lower density of CD31 expressing blood vessels in comparison with control tumors, suggesting a possible role in tumor angiogenesis.The results presented in this study illustrate that genetically modified MSCs may function as a novel therapeutic vehicle for malignant brain tumors

Assessment of a staging system for sigmoid colon cancer based on tumor deposits and extramural venous invasion on computed tomography

Importance: Pre-operative TNM stratification of colon cancer on computed tomography (CT) at present does not identify patients at high risk of recurrence that could be selected for pre-operative treatment. Objective: To evaluate the prognostic importance of CT imaging features of sigmoid colon cancer. Design: Retrospective database analysis performed April 2019. Setting Tertiary centre receiving international and national referrals for colorectal cancer. Participants: Patients undergoing bowel resection for sigmoid colon cancer between 2006 and 2015. Main Outcome and Measures: Cox regression analysis was performed to investigate CT risk factors associated with recurrence. Kaplan Meier survival plots were calculated for disease free survival (DFS) using CT staging systems. Results: Among the 414 patients included with sigmoid cancer with a median follow up of 61 months, 122 patients developed recurrence (29.5%). On multivariate analysis, nodal disease was not prognostic and only TDs (HR 1.90) and EMVI (HR 1.97) on CT were associated with recurrence. Significant differences in DFS were found by CT-T3 substage classification (HR 1.88, 95% CI(1.32-2.68)) but not CT-TNM (HR 1.55, 95% CI(0.94-255)). The presence of EMVI or TDs on CT (HR 2.45, 95% CI(1.68-3.56)) best identified poor outcome. Conclusions and Relevance: T3 substaging and detection of TDs or EMVI on CT were prognostic factors for DFS, whereas TNM and nodal staging on CT held no prognostic value. TDV staging of sigmoid colon cancer is superior to TNM on CT and could be used to pre-operatively identify patients at high risk of recurrence

Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13Rα2-positive Glioma

Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13Rα2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13Rα2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13Rα2, they also recognize IL13Rα1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13Rα2-specific CARs that contain the IL13Rα2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.ζ (IL13Rα2-CARs). IL13Rα2-CAR T cells recognized IL13Rα2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13Rα1. However, only IL13Rα2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13Rα2-CARs with short spacer regions and CD28.ζ, 41BB.ζ, and CD28.OX40.ζ endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13Rα2-CAR T cells hold the promise to improve current IL13Rα2-targeted immunotherapy approaches for GBM and other IL13Rα2-positive malignancies

Diagnostic accuracy of high-resolution MRI as a method to predict potentially safe endoscopic and surgical planes in patients with early rectal cancer.

Introduction: Early rectal cancer (ERC) assessment should include prediction of the potential excision plane to safely remove lesions with clear deep margins and feasibility of organ preservation. Method: MRI accuracy for differentiating ≤T1sm2 (partially preserved submucosa) or ≤T2 (partially preserved muscularis) versus >T2 tumours was compared with the gold standard of pT stage T1sm1/2 versus ≤pT2 versus >pT2. N stage was also compared. The MRI protocol employed a standard surface phased array coil with a high resolution (0.6×0.6×3 mm resolution). The staging data were analysed from a prospectively recorded database of all ERC (≤mrT3b) treated by primary surgery. Results: Of 65 0.7 suggesting good agreement. 44 out of 65 patients underwent radical surgery and 22 out of 44 were ≤mrT2. MRI accuracy to predict lymph node status was 84% (95% CI 70% to 92%), PPV 71% and NPV 90%. Among the 21 out of 65 (32%) patients undergoing local excision or TEM, 20 out of 21 were staged as MR≤T2 and confirmed as such by pathology. On follow-up, none had relapse. If the decision had been made to offer local excision on MRI TN staging rather than clinical assessment, a significant increase in organ preservation surgery from 32% to 60% would have been observed (difference 23%, 95% CI 9% to 35%). Conclusions: MRI is a useful tool for multidisciplinary teams (MDTs) wishing to optimise treatment options for ERC; these study findings will be validated in a prospective multicentre trial

A genetically modified adenoviral vector with a phage display-derived peptide incorporated into fiber fibritin chimera prolongs survival in experimental glioma

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as “GliomaFF.” We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy

Anal cancer with large metastases into the perirectal fat: differential diagnosis and treatment policy

Selected squamous-cell anal carcinoma (SCAC) patients are initially presented with large pararectal lymph node metastases.The aim of this study was to investigate safety, efficacy and long-term outcome of chemoradiotherapy in this patient group.Materials and methods. SCAC patients, initially referred with gastrointestinal stromal tumors, rectal cancer diagnosis or patients with regional metastatic lymph nodes more than twice the size of the primary tumour were included in this retrospective analysis. Previous treatment, diagnostic and clinical mistakes of primary care specialists, short- and long-term outcome of chemoradiotherapy were analyzed.Results. 6 patients were included. Primary tumour size varied between 0.5 and 6.5 cm (median – 1.7 cm), metastatic lymph node size varied between 4.2 and 7.4 cm (median – 6.4 cm). All patients received radical doses of chemoradiation. All patients developed grade 3 toxicities, 2 patients developed grade 4 toxicities. Median followup was 15.5 months. 5 out of 6 patients had persistent complete clinical response. 1 patient died of disease progression (incomplete response and metachronous distant metastases).Conclusion. SCAC patients with large regional lymph node metastases have equal prognosis with the rest of the patient group of adequate treatment was carried out

Transgenic expression of IL15 improves antiglioma activity of IL13Rα2-CAR T cells but results in antigen loss variants

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is virtually incurable with conventional therapies. Immunotherapy with T cells expressing GBM-specific chimeric antigen receptors (CAR) is an attractive approach to improve outcomes. Although CAR T cells targetingGBMantigens, such as IL13 receptor subunit α2 (IL13Rα2), HER2, and EGFR variant III (EGFRvIII), have had antitumor activity in preclinical models, early-phase clinical testing has demonstrated limited antiglioma activity. Transgenic expression of IL15 is an appealing strategy to enhance CAR T-cell effector function. We tested this approach in our IL13Rα2-positive glioma model in which limited IL13Rα2-CAR T-cell persistence results in recurrence of antigenpositive gliomas. T cells were genetically modified with retroviral vectors encoding IL13Rα2-CARs or IL15 (IL13Rα2-CAR.IL15 T cells). IL13Rα2-CAR.IL15 T cells recognized glioma cells in an antigen-dependent fashion, had greater proliferative capacity, and produced more cytokines after repeated stimulations in comparison with IL13Rα2-CAR T cells. No autonomous IL13Rα2-CAR. IL15 T-cell proliferation was observed; however, IL15 expression increased IL13Rα2-CAR T-cell viability in the absence of exogenous cytokines or antigen. In vivo, IL13Rα2-CAR.IL15 T cells persisted longer and had greater antiglioma activity than IL13Rα2-CAR T cells, resulting in a survival advantage. Gliomas recurring after 40 days after T-cell injection had downregulated IL13Rα2 expression, indicating that antigen loss variants occur in the setting of improved T-cell persistence. Thus, CAR T cells for GBM should not only be genetically modified to improve their proliferation and persistence, but also to target multiple antigens. Summary: Glioblastoma responds imperfectly to immunotherapy. Transgenic expression of IL15 in T cells expressing CARs improved their proliferative capacity, persistence, and cytokine production. The emergence of antigen loss variants highlights the need to target multiple tumor antigens. Cancer Immunol Res; 5(7); 571-81

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity. Keywords: siRNA; lipopolymeric nanoparticle; glioblastoma transcription factor; brain tumor-initiating; cells; convection-enhanced deliver

Session 2: Extramural vascular invasion and extranodal deposits: should they be treated the same?

Professor Nagtegaal has already highlighted that lymph nodes are probably not responsible for the development of liver metastases. If they are not, then is there another mechanism? Professor Haboubi addresses the question of extranodal deposits - their frequency and their importance in the development of metastatic disease. The experts review the evidence and discuss whether this information will alter treatment decisions and staging systems in the future