Co-expression patterns of cancer associated fibroblast markers reveal distinct subgroups related to patient survival in oropharyngeal squamous cell carcinoma

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in high income countries due to its association with persistent high-risk human papilloma virus (HPV) infection. Recent scientific advances have highlighted the importance of the tumor microenvironment in OPSCC. In this study, including 216 OPSCC patients, we analyze the composition of four established markers of cancer associated fibroblasts (CAFs) in the context of intratumoral CD8 T-cell infiltration.Methods: Immunohistochemical staining for fibroblast activation protein (FAP), platelet-derived growth factor receptor beta (PDGFRb), periostin, alpha smooth muscle actin (α-SMA) and CD8 were analyzed digitally and their association with survival, tumor- and patient characteristics was assessed.Results: Co-expression of CAF markers was frequent but not associated with HPV status. FAPhigh and PDGFRbhigh expression were associated with increased CD8 T-cell infiltration. Low expression of PDGFRb improved patient survival in female patients but not in male patients. We identified PDGFRblow periostinlow α-SMAlow status as an independent predictor of improved survival (hazard ratio 0.377, p = 0.006).Conclusion: These findings elucidate the co-expression of four established CAF markers in OPSCC and underscore their association with T-cell infiltration and patient survival. Future analyses of CAF subgroups in OPSCC may enable the development of individualized therapies

Cytokine release syndrome

During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome

Hand-Assisted Retroperitoneoscopic Donor Nephrectomy Compared to Anterior Approach Open Donor Nephrectomy: Improved Long-Term Physical Component Score in Health-Related Quality of Life in Living Kidney Donors

Background. Health-related quality of life (HRQL), fatigue, anxiety, and depression are crucial for the living kidney donor (LKD). Follow-up data for HRQL of LKDs comparing surgical techniques, especially regarding hand-assisted retroperitoneoscopic donor nephrectomy (HARP), are sparse. The aim of this study was to evaluate the influence of abdominal wall trauma minimized by HARP in comparison to open anterior approach donor nephrectomy (AA) on HRQL and additional psychosocial aspects of LKDs during the long-term follow-up. Material and Methods. This is a cross-sectional study comparing psychosocial aspects of LKD between HARP and AA. Results. This study included 100 LKDs (68 HARP, 28 AA, and 4 were excluded secondary to incomplete data). The time to follow-up was 22.6 +/- 11.7 (HARP) vs 58.7 +/- 13.9 (AA) months (P = 3a degrees due to Clavien-Dindo classification was 0% in both groups. There were higher scores in all physical aspects for HARP donors vs AA donors at that time (physical function: 89.8 +/- 14.6 vs 80.0 +/- 19.9, P =.008, and the physical component score: 53.9 +/- 7.6 vs 48.6 +/- 8.5, P =.006). One year later (follow-up time + 12 months), HRQL for HARP donors was still higher. Mental items showed no significant differences. HARP donors showed better physical scores compared to the age-matched nondonor population (AA donors had lower scores). Neither the Multidimensional Fatigue Inventory-20 (MFI-20) or the Hospital Anxiety and Depression Scale (HADS) showed any differences between the 2 groups. Fatigue scores were higher for HARP and for AA compared to the age-matched population. Conclusions. LKDs undergoing HARP showed better physical performance as part of HRQL in the long-term follow-up

Web-Based Immersive Patient Simulator as a Curricular Tool for Objective Structured Clinical Examination Preparation in Surgery: Development and Evaluation

Background: Objective Structured Clinical Examination is a standard method of testing declarative and process knowledge in clinical core competencies. It is desirable that students undergo Objective Structured Clinical Examination training before participating in the exam. However, establishing Objective Structured Clinical Examination training is resource intensive and therefore there is often limited practice time. Web-based immersive patient simulators such as ALICE (Artificial Learning Interface of Clinical Education) can possibly fill this gap as they allow for the training of complex medical procedures at the user's individual pace and with an adaptable number of repetitions at home. ALICE has previously been shown to positively influence knowledge gain and motivation. Objective: Therefore, the aim of this study was to develop a Web-based curriculum that teaches declarative and process knowledge and prepares students for a real Objective Structured Clinical Examination station. Furthermore, we wanted to test the influence of ALICE on knowledge gain and student motivation. Methods: A specific curriculum was developed in order to implement the relevant medical content of 2 surgical Objective Structured Clinical Examination stations into the ALICE simulator framework. A total of 160 medical students were included in the study, where 100 students had access to ALICE and their performance was compared to 60 students in a control group. The simulator performance was validated on different levels and students' knowledge gain and motivation were tested at different points during the study. Results: The curriculum was developed according to the Kern cycle. Four virtual clinical cases were implemented with different teaching methods (structured feedback, keynote speech, group discussion, and debriefing by a real instructor) in order to consolidate declarative and process knowledge. Working with ALICE had significant impact on declarative knowledge gain and Objective Structured Clinical Examination performance. Simulator validation was positive for face, content, construct, and predictive validity. Students showed high levels of motivation and enjoyed working with ALICE. Conclusions: ALICE offers Web-based training for Objective Structured Clinical Examination preparation and can be used as a selective didactic intervention as it has positive effect on knowledge gain and student motivation

Glucose transporters 1, 3, 6, and 10 are expressed in gastric cancer and glucose transporter 3 is associated with UICC stage and survival

Background Due to proliferation and increased metabolism, cancer cells have high glucose requirements. The glucose uptake of cells is influenced by a group of membrane proteins denoted the glucose transporter family (Glut-1 to -12). Whereas increased expression and a negative correlation with survival have been described for Glut-1 in several types of cancer, the impact of other glucose transporters on tumor biology is widely unknown. In this retrospective study, gastric cancer specimens of 150 patients who underwent total gastrectomy between 2005 and 2010 were stained for Glut-1, -3, -6, and -10 by immunohistochemistry. Expression of Glut-1, -3, -6, and 10 was correlated to prognosis as well as clinical and pathological parameters. Glut-1, Glut-3, Glut-6, and Glut-10 were expressed in 22.0, 66.0, 38.0, and 43.3 % of the analyzed samples. Whereas Glut-1, -6, and -10 did not show a correlation with prognosis, positive staining for Glut-3 was associated with higher UICC stage and inferior prognosis. The mean overall survival was 38.6 months for Glut-3 positive patients, as compared to 51.2 months for Glut-3 negative patients (p < 0.05). Coexpression of two or more of the analyzed glucose transporters was correlated to inferior prognosis. Glut-3 and UICC stage were significant prognostic factors in multivariate analysis. All of the analyzed glucose transporters were expressed in a significant proportion of the gastric cancer samples. Glut-3 was associated with higher UICC stage and inferior prognosis. These findings are relevant to therapeutic approaches that target glucose metabolism as well as to imaging using radioactively labeled glucose

Using Antigen-Specific B Cells to Combine Antibody and T Cell-Based Cancer Immunotherapy

Cancer immunotherapy by therapeutic activation of T cells has demonstrated clinical potential. Approaches include checkpoint inhibitors and chimeric antigen receptor T cells. Here, we report the development of an alternative strategy for cellular immunotherapy that combines induction of a tumordirected T-cell response and antibody secretion without the need for genetic engineering. CD40 ligand stimulation of murine tumor antigen-specific B cells, isolated by antigenbiotin tetramers, resulted in the development of an antigenpresenting phenotype and the induction of a tumor antigenspecific T-cell response. Differentiation of antigen-specific B cells into antibody-secreting plasma cells was achieved by stimulation with IL21, IL4, anti-CD40, and the specific antigen. Combined treatment of tumor-bearing mice with antigenspecific CD40-activated B cells and antigen-specific plasma cells induced a therapeutic antitumor immune response resulting in remission of established tumors. Human CEA or NYESO- 1-specific B cells were detected in tumor-draining lymph nodes and were able to induce antigen-specific T-cell responses in vitro, indicating that this approach could be translated into clinical applications. Our results describe a technique for the exploitation of B-cell effector functions and provide the rationale for their use in combinatorial cancer immunotherapy. (C) 2017 AACR