Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2+ AML patients with NPM1c mutations.

Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma.

BACKGROUND: Chimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors. METHODS: Glypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry. RESULTS: In this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells. CONCLUSIONS: Our results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.

Overexpression of POU3F2 promotes radioresistance in triple-negative breast cancer via Akt pathway activation.

PURPOSE: POU3F2 is associated with malignant behaviors and poor prognosis in cancer. However, the function and mechanism of POU3F2 in breast cancer remain to be elucidated. Our study aimed to explore the role of POU3F2 in triple-negative breast cancer and radiotherapy. METHODS: POU3F2 expression was examined by RT-PCR and Western blot. The proliferation of cancer cells was measured by MTT assay. Migration of cancer cells was determined by Transwell assay and wound healing assay. To determine which protein interacts with POU3F2, Co-IP was performed. Survival analysis was performed based on the online database GEPIA. DNA damage after radiation was examined by Comet Assay. Radiosensitivity was evaluated with clonogenic survival assays. A tumor xenograft model was established with MDA-MB-231 breast cancer cells in BALB/c nude mice to explore the effect of POU3F2 in vivo. RESULTS: We found that the expression of POU3F2 was significantly elevated in breast cancer cells, especially in TNBC, and higher POU3F2 expression was related to poor prognosis of patients with breast cancer. Functional assays revealed that POU3F2 promoted proliferation, migration, and invasion of triple-negative breast cancer (TNBC) cells in vitro and in vivo. In addition, the knockdown of POU3F2 decreased the radioresistance of TNBC cells in vitro. Furthermore, POU3F2 could enhance the activation of the Akt pathway by interacting with ARNT2, thereby promoting proliferation and radioresistance in TNBC cells. CONCLUSIONS: Our results provide evidence that high expression of POU3F2 promotes radioresistance in triple-negative breast cancer via Akt pathway activation by interacting with ARNT2.

Preoperative prognostic nutritional index predicts postoperative delirium in elderly patients after hip fracture surgery.

BACKGROUND: Postoperative delirium (POD) is a very common complication in elderly patients after hip fracture surgery, which has poorly understood pathophysiology. This study aimed to investigate potential risk factors for POD. METHODS: Elderly patients (aged ≥65 years) scheduled to undergo selective surgery in our hospital were consecutively recruited. Patient characteristics, preoperative laboratory tests and prognostic nutritional index (PNI) levels were compared between patients with or without POD. The risk factors for POD were evaluated by univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive value of PNI and age for POD. RESULTS: Fifty-seven of the 163 enrolled patient had suffered POD within postoperative day 7 with an incidence of 35.0%. Multivariate logistic analyses revealed that an advanced age (cut-off value: 71.5 years, sensitivity: 48.1%, specificity: 75.4%, odds ratio (OR): 3.24, 95% CI: 1.16-8.69, P = 0.026) and lower PNI level (cut-off value: 47.45, sensitivity: 86.0%, specificity: 51.9%, OR: 2.88, 95% CI: 1.25-6.64, P = 0.012) were two independent predictive factors associated with POD. According to the ROC curve analysis, preoperative PNI level was a predictor for POD with an area under the curve of 0.686 (95% CI: 0.604-0.767, P < 0.001). CONCLUSIONS: Advanced age and lower preoperative PNI level were significantly associated with POD in elderly patients after hip fracture surgery.

Comparison of WBRT alone, SRS alone, and their combination in the treatment of one or more brain metastases: Review and meta-analysis.

Whole brain radiotherapy has been a standard treatment of brain metastases. Stereotactic radiosurgery provides more focal and aggressive radiation and normal tissue sparing but worse local and distant control. This meta-analysis was performed to assess and compare the effectiveness of whole brain radiotherapy alone, stereotactic radiosurgery alone, and their combination in the treatment of brain metastases based on randomized controlled trial studies. Electronic databases (PubMed, MEDLINE, Embase, and Cochrane Library) were searched to identify randomized controlled trial studies that compared treatment outcome of whole brain radiotherapy and stereotactic radiosurgery. This meta-analysis was performed using the Review Manager (RevMan) software (version 5.2) that is provided by the Cochrane Collaboration. The data used were hazard ratios with 95% confidence intervals calculated for time-to-event data extracted from survival curves and local tumor control rate curves. Odds ratio with 95% confidence intervals were calculated for dichotomous data, while mean differences with 95% confidence intervals were calculated for continuous data. Fixed-effects or random-effects models were adopted according to heterogeneity. Five studies (n = 763) were included in this meta-analysis meeting the inclusion criteria. All the included studies were randomized controlled trials. The sample size ranged from 27 to 331. In total 202 (26%) patients with whole brain radiotherapy alone, 196 (26%) patients receiving stereotactic radiosurgery alone, and 365 (48%) patients were in whole brain radiotherapy plus stereotactic radiosurgery group. No significant survival benefit was observed for any treatment approach; hazard ratio was 1.19 (95% confidence interval: 0.96-1.43, p = 0.12) based on three randomized controlled trials for whole brain radiotherapy only compared to whole brain radiotherapy plus stereotactic radiosurgery and hazard ratio was 1.03 (95% confidence interval: 0.82-1.29, p = 0.81) for stereotactic radiosurgery only compared to combined approach. Local control was best achieved when whole brain radiotherapy was combined with stereotactic radiosurgery. Hazard ratio 2.05 (95% confidence interval: 1.36-3.09, p = 0.0006) and hazard ratio 1.84 (95% confidence interval: 1.26-2.70, p = 0.002) were obtained from comparing whole brain radiotherapy only and stereotactic radiosurgery only to whole brain radiotherapy + stereotactic radiosurgery, respectively. No difference in adverse events for treatment difference; odds ratio 1.16 (95% confidence interval: 0.77-1.76, p = 0.48) and odds ratio 0.92 (95% confidence interval: 0.59-1.42, p = 71) for whole brain radiotherapy + stereotactic radiosurgery versus whole brain radiotherapy only and whole brain radiotherapy + stereotactic radiosurgery versus stereotactic radiosurgery only, respectively. Adding stereotactic radiosurgery to whole brain radiotherapy provides better local control as compared to whole brain radiotherapy only and stereotactic radiosurgery only with no difference in radiation related toxicities.

MiR-200c inhibits autophagy and enhances radiosensitivity in breast cancer cells by targeting UBQLN1.

Radioresistance is a major challenge during the treatment of breast cancer. A further understanding of the mechanisms of radioresistance could provide strategies to address this challenge. In our study, we compared the expression of miR-200c in four distinct breast cancer cell lines: two representative basal cancer cells (MDA-MB-231 and BT549) vs. two representative luminal cancer cells (MCF-7 and BT474). The results revealed practically lower expression of miR-200c in the two basal cancer cell lines and higher expression of miR-200c in luminal cancer cells compared to the normal breast epithelial cell line MCF-10A. Ectopic expression of miR-200c in MDA-MB-231 cells inhibited irradiation-induced autophagy and sensitized the breast cancer cells to irradiation. We also identified UBQLN1 as a direct functional target of miR-200c involved in irradiation-induced autophagy and radioresistance. In 35 human breast cancer tissue samples, we detected an inverse correlation between the expression of miR-200c vs. UBQLN1 and LC3. These results indicate that the identified miR-200c/UBQLN1-mediated autophagy pathway may help to elucidate radioresistance in human breast cancer and might represent a therapeutic strategy.

IPSC-derived CAR-NK cells for cancer immunotherapy.

Adoptive cell therapies (ACT) based on chimeric antigen receptor (CAR)-modified immune cells have made great progress with six CAR-T cell products approved by the U.S. FDA for hematological malignancies. Compared with CAR-T cells, CAR-NK cells have attracted increasing attention owing to their multiple killing mechanisms, higher safety profile, and broad sources. Induced pluripotent stem cell (iPSC)-derived NK (iPSC-NK) cells possess a mature phenotype and potent cytolytic activity, and can provide a homogeneous population of CAR-NK cells that can be expanded to clinical scale. Thus, iPSC-derived CAR-NK (CAR-iNK) cells could be used as a standardized and "off-the-shelf" product for cancer immunotherapy. In this review, we summarize the current status of the manufacturing techniques, genetic modification strategies, preclinical and clinical evidence of CAR-iNK cells, and discuss the challenges and future prospects of CAR-iNK cell therapy as a novel cellular immunotherapy in cancer.

Cancer-associated fibroblasts induce growth and radioresistance of breast cancer cells through paracrine IL-6.

In breast cancer, the most numerous stromal cells are cancer-associated fibroblasts (CAFs), which are associated with disease progression and chemoresistance. However, few studies have explored the function of CAFs in breast cancer cell radiosensitivity. Here, CAF-derived conditioned media was observed to induce breast cancer cell growth and radioresistance. CAFs secrete interleukin 6 (IL-6) which activates signal transducer and activator of transcription 3 (STAT3) signaling pathway, thus promoting the growth and radioresistance of breast cancer cells. Treatment with an inhibitor of STAT3 or an IL-6 neutralizing antibody blocked the growth and radioresistance induced by CAFs. In in vivo mouse models, tocilizumab (an IL-6 receptor monoclonal antibody) abrogated CAF-induced growth and radioresistance. Moreover, in breast cancer, a poor response to radiotherapy was associated with IL-6 and p-STAT3 expression. These results indicated that IL-6 mediates cross-talk between breast cancer cells and CAFs in the tumor microenvironment. Our results identified the IL-6/STAT3 signaling pathway as an important therapeutic target in breast cancer radiotherapy.

Case report: Abolishing primary resistance to PD-1 blockade by short-term treatment of lenvatinib in a patient with advanced metastatic renal cell carcinoma.

Anti-PD-1 immunotherapy has been extensively used in treatment of patients with advanced metastatic renal cell carcinoma (mRCC). Several prospective clinical trials showed that the combined treatment of anti-PD-1 antibody plus lenvatinib, a potent receptor tyrosine kinase inhibitor (TKI), exhibited high response rate compared with single-agent sunitinib. However, whether the patients with primary resistance to PD-1 blockade could benefit from the addition of lenvatinib is still unclear. Herein, we reported a patient with mRCC who was primary resistant to pembrolizumab and achieved a durable complete response after a short-term treatment with lenvatinib. This case report indicates that the patients with primary resistance to anti-PD-1 therapy could benefit from the short-term lenvatinib in combination with anti-PD-1 therapy, and provides a useful paradigm worthy of establishing a clinical trial for mRCC patients with primary resistance to anti-PD-1 therapy.

Assessment and nonpharmacological management for patients with cancer anorexia-cachexia syndrome: a best practice implementation project.

INTRODUCTION AND AIMS: Cancer anorexia-cachexia syndrome (CACS) is a common multifactorial syndrome, which affects up to 80% patients with advanced cancer. At present, evidence to support the benefit of pharmacological intervention in the management of CACS is limited. Patients would benefit from standard procedures for early assessment and identification of cancer anorexia-cachexia, and using nonpharmacological strategies to manage patients with CACS. This best practice implementation project aimed to implement an evidence-based practice in assessing and managing patients with CACS, thereby improving the compliance of clinical practice with the best evidence and the quality of life of patients with CACS. METHODS: This was an evidence-based audit and feedback project that used a three-phase approach at a public hospital in China. Phase 1 included the development of seven evidence-based audit criteria and carrying out a baseline audit on 30 patients using the JBI's Practical Application of Clinical Evidence System in the Department of Radiation Oncology of Nanfang Hospital. Phase 2 utilized the Getting Research into Practice component of the Practical Application of Clinical Evidence System to identify barriers to compliance with best practice principles and developed strategies and resources to improve compliance. Phase 3 involved conducting a follow-up audit using the same sample size and audit criteria to assess the results of interventions implemented to improve practice and identify issues that would be addressed in future audit. RESULTS: The compliance rates of audit criteria 1, 2 and 6 were 100% at both baseline and follow-up audit. After the application of evidence, the compliance rate increased from 0 to 100% for audit criterion 3, from 0 to 76.6% for audit criterion 4, from 23 to 70% for audit criterion 5, and from 0 to 40% for audit criterion 5. CONCLUSION: The best evidence for the assessment and nonpharmacological management of cancer patients with CACS can improve clinical practice, the quality of clinical nursing, and patient satisfaction. The application of electronic informatization promotes the implementation and maintenance of best practice.

Blockade of Spinal EphA4 Reduces Chronic Inflammatory Pain in Mice.

Background: Erythropoietin-producing hepatocellular (Ephs) receptor and their ligands, ephrins, orchestrate the induction of cell proliferation and migration, axonal guidance, synaptic genesis and synaptic plasticity in the central nervous system. Previous studies demonstrated that EphBs/ephrinBs participate in the pathophysiology of neuropathic pain, inflammatory pain and bone cancer pain, but the role of EphA4 in the regulation of pain in the spinal cord is unknown. Therefore, we explored the role of EphA4 receptor in regulating chronic inflammatory pain.Methods: We established a mouse model of chronic inflammatory pain through plantar injection of complete freund's adjuvant (CFA) and assessed EphA4 expression in spinal cord by western blotting. EphA4 receptor was blocked by intrathecal injection of EphA4-Fc, an EphA4 antagonist, and pain behaviors were measured by assessing thermal hyperalgesia and mechanical allodynia. Finally, immunohistochemistry was performed to analyze the changes in the expression of Fos protein in spinal cord after blocking EphA4 receptor.Results: Plantar injection of CFA produced persistent thermal hyperalgesia and mechanical allodynia, which was accompanied by significant increases in spinal EphA4 and Fos expression. Blocking spinal EphA4 receptor suppressed CFA-induced pain behaviors and reduced the expression of Fos protein in spinal cord.Conclusions: Our study demonstrated that EphA4 receptor is involved in the generation and maintenance of CFA-induced chronic inflammatory pain and that blocking the spinal EphA4 receptor could relieve persistent pain behaviors in mice.

Implementation of strategies to improve nutritional intervention for patients with cancer treatment-related oral mucositis: a best practice implementation project.

BACKGROUND: Oral mucositis is a common complication after radiotherapy or chemotherapy in cancer patients. Oral mucositis can affect the patient's food intake and their confidence in treatment as patients are more likely to suffer severe pain, experience weight loss, encounter an interruption or change of cancer treatment plan, and are reported to have a reduced survival from the disease. Nutritional intervention is the primary nursing focus in patients with oral mucositis treated by chemoradiotherapy. OBJECTIVES: The current best practice implementation project aimed to establish best practice principles in nutritional interventions for patients with cancer treatment-related oral mucositis. METHODS: This was an evidence-based audit and feedback project that used a three-phase approach at a public hospital in China. Phase 1 involved developing five evidence-based audit criteria informed by current best available evidence, and undertaking a clinical audit of current practice on 50 patients in the Department of Radiation Oncology of Nanfang Hospital using the JBI's Practical Application of Clinical Evidence System. Phase 2 utilized the Getting Research into Practice component of the Practical Application of Clinical Evidence System to identify barriers to compliance with best practice principles and developed strategies and resources to improve compliance. Phase 3 involved conducting a postaudit using the same sample size and audit criteria to re-evaluate compliance with best practice. RESULTS: Baseline results showed that compliance rates were 0% for criteria 1 and 2, 76% for criteria 3 and 5, and 82% for criterion 4. The implementation of strategies, including establishing a multidisciplinary team with a dietitian, creating training and education programs for all staff and patients, utilizing a scale regarding diet to assess patients' current diet, and establishing a nutrition intervention nursing procedure to supervise implementation of the nutritional intervention for patients with cancer treatment-related oral mucositis, increased compliance with best practice, achieving compliance rates of at least 82% for all five audit criteria. CONCLUSION: The implementation of context-specific strategies improved compliance with evidence-based practice in the nutritional intervention for patients with cancer treatment-related oral mucositis. Sustainability of best practice is important, with further audits planned to evaluate the sustainability of these practice changes.

CAR-T cells targeting a nucleophosmin neoepitope exhibit potent specific activity in mouse models of acute myeloid leukaemia.

Therapies employing chimeric antigen receptor T cells (CAR-T cells) targeting tumour-associated antigens (TAAs) can lead to on-target-off-tumour toxicity and to resistance, owing to TAA expression in normal tissues and to TAA expression loss in tumour cells. These drawbacks can be circumvented by CAR-T cells targeting tumour-specific driver gene mutations, such as the four-nucleotide duplication in the oncogene nucleophosmin (NPM1c), which creates a neoepitope presented by the human leukocyte antigen with the A2 serotype (HLA-A2) that has been observed in about 35% of patients with acute myeloid leukaemia (AML). Here, we report a human single-chain variable fragment (scFv), identified via yeast surface display, that specifically binds to the NPM1c epitope-HLA-A2 complex but not to HLA-A2 or to HLA-A2 loaded with control peptides. In vitro and in mice, CAR-T cells with the scFv exhibit potent cytotoxicity against NPM1c+HLA-A2+ leukaemia cells and primary AML blasts, but not NPM1c-HLA-A2+ leukaemia cells or HLA-A2- tumour cells. Therapies using NPM1c CAR-T cells for the treatment of NPM1c+HLA-A2+ AML may limit on-target-off-tumour toxicity and tumour resistance.

CAR-NK cells: A promising cellular immunotherapy for cancer.

Natural Killer (NK) cells and CD8+ cytotoxic T cells are two types of immune cells that can kill target cells through similar cytotoxic mechanisms. With the remarkable success of chimeric antigen receptor (CAR)-engineered T (CAR-T) cells for treating haematological malignancies, there is a rapid growing interest in developing CAR-engineered NK (CAR-NK) cells for cancer therapy. Compared to CAR-T cells, CAR-NK cells could offer some significant advantages, including: (1) better safety, such as a lack or minimal cytokine release syndrome and neurotoxicity in autologous setting and graft-versus-host disease in allogenic setting, (2) multiple mechanisms for activating cytotoxic activity, and (3) high feasibility for 'off-the-shelf' manufacturing. CAR-NK cells could be engineered to target diverse antigens, enhance proliferation and persistence in vivo, increase infiltration into solid tumours, overcome resistant tumour microenvironment, and ultimately achieve an effective anti-tumour response. In this review, we focus on recent progress in genetic engineering and clinical application of CAR-NK cells, and discuss current challenges and future promise of CAR-NK cells as a novel cellular immunotherapy in cancer.

Assessment and management of cough among patients with lung cancer in a radiotherapy department in China: a best practice implementation project.

OBJECTIVES: This project aimed to implement an evidence-based practice to assess and manage lung cancer-associated cough, thereby relieving patients' physical pain and psychological challenges and improving their quality of life. INTRODUCTION: Cough is one of the most common symptoms experienced by patients with lung cancer. If a cough is not proactively managed, patients may develop decreased compliance with treatments and experience a reduced quality of life. Cough assessment and management are essential components of nursing practice that should include evidence-based interventions. METHODS: Seven evidence-based audit criteria were developed from current evidence. The JBI Practical Application of Clinical Evidence System (PACES) was used to perform a baseline audit on 30 patients and 20 nurses in the Department of Radiotherapy of Nanfang Hospital. The Getting Research into Practice (GRiP) component of PACES was used to identify barriers, strategies, resources and outcomes. Following implementation of strategies to improve compliance, a post-audit was conducted using the same sample size and audit criteria. RESULTS: The seven evidence-based audit criteria were as follows: 1) Clinicians have received training on the assessment and management of lung cancer-associated cough; 2) In patients with lung cancer-associated cough, a comprehensive assessment was conducted to identify any co-existing causes linked to cough; 3) Any reversible causes of cough were treated according to evidence-based guidelines; 4) A validated scale was used to assess the frequency and severity of cough and distress experienced by the patients; 5) Patients (and their caregivers) have received education regarding management of cough; 6) Patients (and their caregivers) have received training on cough suppression exercises; 7) For symptomatic therapy, a stepwise approach was followed according to evidence-based guidelines. The baseline results showed that compliance rates were 0% for criteria 1, 4 and 5; 70% for criterion 6; 80% for criterion 7; 90% for criterion 3 and 93% for criterion 2. The implementation of strategies to increase compliance with best practice, including establishing training and education programs for nursing staff and patients, utilizing some validated scales to assess the frequency and severity of cough and the distress caused to the patients, and establishing a quality control team to supervise implementation of the assessment and management of cough, achieved ≥ 93% compliance rate for all seven audit criteria. CONCLUSION: An evidence-based and nurses-oriented best practice for cough assessment and management was successfully established among patients with lung cancer-associated cough.

Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy.

BACKGROUND: Current checkpoint immunotherapy has shown potential to control cancer by restoring or activating the immune system. Nevertheless, multiple mechanisms are involved in immunotherapy resistance which limits the clinical benefit of checkpoint inhibitors. An immunosuppressive microenvironment is an important factor mediating the original resistance of tumors to immunotherapy. A previous report by our group has demonstrated that local angiotensin II (AngII) predominantly exists in a tumor hypoxic microenvironment where hypoxic tumour cells produced AngII by a hypoxia-lactate-chymase-dependent mechanism. RESULTS: Here, using 4T1 and CT26 syngeneic mouse tumor models, we found that local AngII in the tumor microenvironment was involved in immune escape of tumour cells and an AngII signaling blockage sensitized tumours to checkpoint immunotherapy. Furthermore, an AngII signaling blockage reversed the tumor immunosuppressive microenvironment, and inhibition of angiotensinogen (AGT, a precursor of AngII) expression strongly triggered an immune-activating cytokine profile in hypoxic mouse cancer cells. More importantly, AGT silencing combined with a checkpoint blockage generated an abscopal effect in resistant tumors. CONCLUSION: Our study demonstrated an important role of local AngII in the formation of a tumor immunosuppressive microenvironment and its blockage may enhance tumor sensitivity to checkpoint immunotherapy. The combination of an AngII signaling blocker and an immune-checkpoint blockage could be a promising strategy to improve tumors responses to current checkpoint immunotherapy.

Preoperative C-Reactive Protein as a Risk Factor for Postoperative Delirium in Elderly Patients Undergoing Laparoscopic Surgery for Colon Carcinoma.

BACKGROUND: Postoperative delirium (POD) is a very common complication in operative disciplines, especially in those elderly patients after cardiac surgery. This study aimed to investigate the relationship between C-reactive protein (CRP) and POD in elderly patients undergoing laparoscopic surgery for colon carcinoma. METHODS: 160 elderly patients scheduled to undergo selective laparoscopic surgery for colon carcinoma were prospectively recruited in this present study. The preoperative demographic and medical characteristics, intraoperative variables, and postoperative complications were all recorded in detail. POD assessment was performed once a day for the first 3 days and at 7th day after surgery, respectively. CRP concentrations preoperatively and on postoperative days 1, 2, and 3 were measured by using human enzyme linked immunosorbent assay (ELISA). RESULTS: Of all the 160 enrolled patients, 39 had suffered POD with a POD incidence of 24.4% within the first week after the operation. The univariate analysis and multiple logistic regression analysis suggested preoperative CRP concentrations as the only independent predicator for POD in patients undergoing laparoscopic surgery for colon carcinoma (OR: 5.87; 95% CI: 2.22-11.4; P = 0.018). CONCLUSIONS: This present study highlighted the predictive role of preoperative CRP concentrations for POD in elderly patients undergoing laparoscopic surgery for colon carcinoma.

A rapid and systemic complete response to stereotactic body radiation therapy and pembrolizumab in a patient with metastatic renal cell carcinoma.

Stereotactic body radiation therapy (SBRT) of local tumor would induce an abscopal effect that has been observed in several kinds of human cancers; one important mechanism may involve the improved activation of the host immune system. The immune checkpoint inhibitor can overcome immune tolerance and enhance the activation of antitumor T cells. The combined treatment of SBRT and checkpoint inhibitor may represent a new promising therapeutic approach. Herein, we reported a patient with metastatic renal cell carcinoma (RCC) treated with concurrent SBRT and anti-PD-1 antibody, pembrolizumab, by which the patient achieved an amazingly systemic complete response in only 2.2 months after starting treatment. This case report indicates that the advanced RCC may benefit from the combining treatment of local SBRT and PD-1 inhibitor and provide a useful paradigm worthy of establishing a clinical trial for patients with advanced renal cell carcinoma.

Prognostic value of 18F-FDG-PET/CT in patients with nasopharyngeal carcinoma: a systematic review and meta-analysis.

BACKGROUND: The prognostic role of 18F-fluorodeoxyglucose positron emission tomography CT (18F-FDG PET/CT) parameters is still controversial in nasopharyngeal carcinoma patients. We sought to perform a systematic review and meta-analysis to explore the prognostic value of maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on event-free survival (EFS) and overall survival (OS) in nasopharyngeal carcinoma patients. RESULTS: Fifteen studies comprising 1,938 patients were included in this study. The combined hazard ratios (HRs) for EFS were 2.63 (95%CI 1.71-4.05) for SUVmax, 2.55 (95%CI 1.49-4.35) for MTV, and 3.32 (95%CI 1.23-8.95) for TLG. The pooled HRs for OS were 2.07 (95%CI 1.54-2.79) for SUVmax, 3.86 (95%CI 1.85-8.06) for MTV, and 2.60 (95%CI 1.55-4.34) for TLG. The prognostic role of SUVmax, MTV and TLG remained similar in the sub-group analyses. METHODS: A systematic literature search was performed to identify studies which associated 18F-FDG PET/CT to clinical survival outcomes of nasopharyngeal carcinoma patients. The summarized HRs for EFS and OS were estimated by using fixed- or random-effect models according to heterogeneity between trials. CONCLUSIONS: The present meta-analysis confirms that high values of SUVmax, MTV and TLG predicted a higher risk of adverse events or death in patients with nasopharyngeal carcinoma, despite clinically heterogeneous nasopharyngeal carcinoma patients and the various methods adopted between these studies.

Hypoxia-induced angiotensin II by the lactate-chymase-dependent mechanism mediates radioresistance of hypoxic tumor cells.

The renin-angiotensin system (RAS) is a principal determinant of arterial blood pressure and fluid and electrolyte balance. RAS component dysregulation was recently found in some malignancies and correlated with poor patient outcomes. However, the exact mechanism of local RAS activation in tumors is still unclear. Here, we find that the local angiotensin II predominantly exists in the hypoxic regions of tumor formed by nasopharyngeal carcinoma CNE2 cells and breast cancer MDA-MB-231 cells, where these tumor cells autocrinely produce angiotensin II by a chymase-dependent rather than an angiotensin converting enzyme-dependent mechanism. We further demonstrate in nasopharyngeal carcinoma CNE2 and 5-8F cells that this chymase-dependent effect is mediated by increased levels of lactate, a by-product of glycolytic metabolism. Finally, we show that the enhanced angiotensin II plays an important role in the intracellular accumulation of HIF-1α of hypoxic nasopharyngeal carcinoma cells and mediates the radiation-resistant phenotype of these nasopharyngeal carcinoma cells. Thus, our findings reveal the critical role of hypoxia in producing local angiotensin II by a lactate-chymase-dependent mechanism and highlight the importance of local angiotensin II in regulating radioresistance of hypoxic tumor cells.