Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells.

Oncolytic viruses (OVs) are an emerging class of anti-cancer agents that replicate selectively within malignant cells and generate potent immune responses. Their potential efficacy has been shown in clinical trials, with talimogene laherparepvec (T-VEC or IMLYGIC®) now approved both in the United States and Europe. In healthy individuals, NK cells provide effective surveillance against cancer and viral infections. In oncolytic viral therapy, NK cells may render OV ineffective by rapid elimination of the propagating virus but could also improve therapeutic efficacy by preferential killing of OV-infected malignant cells. Existing evidence suggests that the overall effect of NK cells against OV is context dependent. In the past decade, the understanding of cancer and OV biology has improved significantly, which helped refine this class of treatments in early-phase clinical trials. In this review, we summarised different strategies that have been evaluated to modulate NK activities for improving OV therapeutic benefits. Further development of OVs will require a systematic approach to overcome the challenges of the production and delivery of complex gene and cell-based therapies in clinical settings.

Comparison of women with possible endocervical and non-cervical glandular neoplasms detected in liquid-based cervical cytology- incidence, clinical characteristics and outcomes: A cohort study.

OBJECTIVE: To compare the incidence, demographics and clinical outcomes of women presenting with possible non-cervical (NC) and endocervical (EC) glandular neoplasms in their cervical smears. STUDY DESIGN: Retrospective analysis of a prospective cohort within the NHS Greater Glasgow and Clyde- the largest health organisation in Scotland, UK. METHODS: Cases identified from the Scottish Cervical Call Recall System between January 2013 and December 2017. Incidence and clinical trajectories of NC and EC were reviewed. RESULTS: Two-hundred-and-thirty cases (NC = 41; EC = 189) from 486,240 smears were evaluated. The incidence was 8.4 and 38.9 per 100,000 smear-year for NC and EC, respectively. Compared to women with EC, women with NC were significantly older (p < 0.0001), had higher body mass index (p < 0.0001), more likely to present with symptoms (58.5 % vs 10.5 %; p < 0.0001), had cancers (48.8 % vs 13.8 %; p < 0.0001) and died from their diseases (9.8 % vs 0.5 %; p < 0.0001). Even in the asymptomatic screen-detected NC group, almost a quarter (23.5 %) had endometrial cancer. Age was not associated with high-risk histology (p = 0.289). High-risk colposcopic appearance had good positive predictive value (90.0 %; 95 %CI: 81.2-95.6 %) for high-risk histology, but poor negative predictive value (41.3 %; 95 %CI: 29-54 %). Negative excision margin was associated with favourable outcomes. CONCLUSIONS: NC and EC are rare, but they are distinct and should be reported separately in future studies. The risks of malignancies are high, particularly in women with NC, even if they are asymptomatic. Thus, prompt and thorough investigations and treatments are required to prevent and treat malignancies.

NK Cells Augment Oncolytic Adenovirus Cytotoxicity in Ovarian Cancer.

Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses-the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)-to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.

RIPK3 promotes adenovirus type 5 activity.

Oncolytic adenoviral mutants infect human malignant cells and replicate selectively within them. This induces direct cytotoxicity that can also trigger profound innate and adaptive immune responses. However, the mechanism by which adenoviruses produce cell death remains uncertain. We previously suggested that type 5 adenoviruses, including the E1A CR2 deletion mutant dl922-947, might induce a novel form of programmed death resembling necroptosis. Here we have investigated the roles of core necrosis proteins RIPK1, RIPK3 and MLKL in the cytotoxicity of dl922-947 and other adenovirus serotypes. By electron microscopy, we show that dl922-947 induces similar necrotic morphology as TSZ treatment (TNF-α, Smac mimetic, zVAD.fmk). However, dl922-947-mediated death is independent of TNF-α signalling, does not require RIPK1 and does not rely upon the presence of MLKL. However, inhibition of caspases, specifically caspase-8, induces necroptosis that is RIPK3 dependent and significantly enhances dl922-947 cytotoxicity. Moreover, using CRISPR/Cas9 gene editing, we demonstrate that the increase in cytotoxicity seen upon caspase inhibition is also MLKL dependent. Even in the absence of caspase inhibition, RIPK3 expression promotes dl922-947 and wild-type adenovirus type 5 efficacy both in vitro and in vivo. Together, these results suggest that adenovirus induces a form of programmed necrosis that differs from classical TSZ necroptosis.

Patterns of sexual behaviors among unmarried adolescents and youth in three Asian cities.

We examined patterns of sexual behaviors of unmarried adolescents and youth (UAY) in three Asian cities (Shanghai, Taipei, and Hanoi) and identified factors related to the timing of initial sexual experience. From analysis of a sample of 16,554 UAY aged 15-24 years recruited from Shanghai, Taipei, and Hanoi plus data collected from face-to-face interviews complemented by computer-assisted self-interviews for intimate questions, we learned: UAY in Shanghai, Taipei, and Hanoi have different sexual behaviors. Affluent economic status increases the likelihood of early initial sexual experiences. Higher educational attainment may delay initial intercourse. Compared with Shanghai UAY, study participants from Taipei and Hanoi were 3.64 times and 0.33 times as likely to participate intercourse. These data can provide a basis for developing effective government policies and social interventions.

Paclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control.

Resistance to paclitaxel chemotherapy frequently develops in ovarian cancer. Oncolytic adenoviruses are a novel therapy for human malignancies that are being evaluated in early phase trials. However, there are no reliable predictive biomarkers for oncolytic adenovirus activity in ovarian cancer. We investigated the link between paclitaxel resistance and oncolytic adenovirus activity using established ovarian cancer cell line models, xenografts with de novo paclitaxel resistance and tumour samples from two separate trials. The activity of multiple Ad5 vectors, including dl922-947 (E1A CR2-deleted), dl1520 (E1B-55K deleted) and Ad5 WT, was significantly increased in paclitaxel resistant ovarian cancer in vitro and in vivo. This was associated with greater infectivity resulting from increased expression of the primary receptor for Ad5, CAR (coxsackie adenovirus receptor). This, in turn, resulted from increased CAR transcription secondary to histone modification in resistant cells. There was increased CAR expression in intraperitoneal tumours with de novo paclitaxel resistance and in tumours from patients with clinical resistance to paclitaxel. Increased CAR expression did not cause paclitaxel resistance, but did increase inflammatory cytokine expression. Finally, we identified dysregulated cell cycle control as a second mechanism of increased adenovirus efficacy in paclitaxel-resistant ovarian cancer. Ad11 and Ad35, both group B adenoviruses that utilise non-CAR receptors to infect cells, are also significantly more effective in paclitaxel-resistant ovarian cell models. Inhibition of CDK4/6 using PD-0332991 was able both to reverse paclitaxel resistance and reduce adenovirus efficacy. Thus, paclitaxel resistance increases oncolytic adenovirus efficacy via at least two separate mechanisms - if validated further, this information could have future clinical utility to aid patient selection for clinical trials.

The management of secondary lower limb lymphoedema in cancer patients: a systematic review.

BACKGROUND: Lower limb lymphoedema is a recognised complication of cancer commonly encountered in palliative care, associated with reduced mobility and poor quality of life. AIM: To evaluate the available evidence for the treatment of secondary lower limb lymphoedema in patients with malignancies. DESIGN: A systematic review of the literature. DATA SOURCES: The MEDLINE, Embase, LILACS, Science Citation Index, Cochrane Databases and conference proceedings for published data from date of inception to July 2014 were searched. Relevant unpublished studies via relevant databases, Internet searches and hand-searches of the bibliographies of relevant papers were performed. RESULTS: From 1617 citations, 32 papers were selected for full-text assessment. Two randomised trials and five observational studies were identified. The two randomised controlled trials evaluated graded compression stockings and Coumarin capsules, respectively. The five observational studies evaluated lymphovenous microsurgical shunts, pneumatic compression devices, compression bandages alone, manual lymphatic drainage with compression and a herbal remedy combining Coumarin, Ginkgo and Melitoto (with or without manual lymphatic drainage), respectively. The extracted studies showed substantial heterogeneity. Hence, a meta-analysis was inappropriate and not performed. CONCLUSION: Few studies have evaluated the clinical effectiveness and potential side effects of treatments for lower limb lymphoedema. Moreover, symptoms and quality-of-life assessments were inconsistently reported. All included studies report lower limb volume reduction after treatment, which includes complex decongestion therapy, graded compression stockings and lymphovenous microsurgical shunts. Adequately powered randomised controlled trials of these interventions are recommended. Effort should be made to establish standardised outcomes, to minimise bias and to improve reporting quality in future trials of treatment for lower limb lymphoedema.

The relationships between plasma and red cell vitamin B2 and B6 concentrations and the systemic and local inflammatory responses in patients with colorectal cancer.

B vitamins have been implicated in cancer pathogenesis. It is therefore of interest that plasma B6 falls as part of the systemic inflammatory response (SIR), whereas red cell concentrations do not. The modified Glasgow Prognostic Score (mGPS) is a validated inflammation-based prognostic score that consists of a combination of albumin and C-reactive protein concentrations. The aim of this study was to examine the relationships between the concentrations of plasma and red cell vitamin B concentrations, the local and systemic inflammatory response in patients with colorectal cancer. Preoperative venous blood of 108 patients with colorectal cancer were analyzed for C-reactive protein, albumin, flavin adenine dinucleotide (FAD), and pyridoxal phosphate (PLP), and lymphocyte counts. Pathological slides were retrieved for assessment of inflammatory cell infiltration. Increasing mGPS was associated with lower plasma PLP concentrations (P < 0.01) but not plasma and red cell FAD and red cell PLP concentrations. Increasing tumor stage was associated with the presence of venous invasion (P < 0.01) and low-grade inflammatory cell infiltrate (P < 0.05) but not the SIR, FAD, or PLP concentrations. A low-grade inflammatory cell infiltrate was not significantly associated with any other parameter. The presence of a SIR was associated with lower concentrations of plasma PLP but not red cell PLP concentrations in patients with colorectal cancer. Neither FAD and PLP were associated with the tumor inflammatory cell infiltrate.

Clinical utility of the pretreatment glasgow prognostic score in patients with advanced inoperable non-small cell lung cancer.

INTRODUCTION: Traditional tumor-based staging systems provide limited information on the best treatment option for individual patients with advanced inoperable non-small cell lung cancer (NSCLC). The Glasgow prognostic score (GPS) reflects the host systemic inflammatory response and is a validated independent prognostic factor in these patients. The aim of this study was to examine the clinical application of the pretreatment GPS in a mature cohort of patients with inoperable NSCLC. METHODS: The data of 261 patients with inoperable NSCLC were collected prospectively and before treatment. Information on patient demographics, body mass index, performance status (PS), the modified Glasgow prognostic score (mGPS), the prognostic index, and treatment received were included. RESULTS: The majority of patients were aged 65 years or older (68%), were men (59%), had a body mass index more than 20 (89%), and an Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 or 1 (54%). Most patients had a pretreatment mGPS = 1 (62%) and pretreatment prognostic index = 1 (56%). During the follow-up period, 248 (95%) patients died, 246 from their disease. The median survival was 8 months. On multivariate analysis, age (p = 0.001), ECOG-PS (p < 0.05), mGPS (p < 0.0001), and tumor stage (p < 0.0001) were independently associated with cancer-specific survival. Using 5-year cancer-specific mortality as an end point, the area under the receiver operator curve was 0.735 (95% confidence interval [CI], 0.566-0.903; p = 0.024) for the mGPS, 0.669 (95% CI, 0.489-0.848; p = 0.106) for ECOG-PS, and 0.622 (95% CI, 0.437-0.807; p = 0.240) for tumor, node, metastasis stage. Patients with an increased mGPS were more likely to have a poorer ECOG-PS (p < 0.05), an increased white cell count (p < 0.05), and received palliative treatment (p < 0.05). CONCLUSION: The pretreatment mGPS is a useful and important predictor of cancer-specific survival in patients with inoperable NSCLC. Basing clinical assessment on the mGPS has implications for the routine monitoring and treatment of the patients.

Combined resection and radiofrequency ablation for bilobar colorectal cancer liver metastases.

BACKGROUND/AIMS: Traditionally multiple bilobar colorectal liver metastases were not considered suitable for surgical resection. The use of novel adjuncts to hepatic resection to aid tumour clearance is increasing. These include radiofrequency ablation (RFA), which destroys tumour tissue with high local temperatures. The present study reports a series of patients who underwent RFA and resection for bilobar colorectal liver metastases. Comparisons are made with patients undergoing hepatic resection alone over the same time period. METHODOLOGY: 100 consecutive patients underwent curative hepatic resections for colorectal liver metastases (84--resection alone; 16--combined RFA and resection). Most were < 75 years (87%), male (57%), had metachronous disease (65%). RESULTS: Median follow-up was 37 months. 47/84 hepatic resection and 10/16 combined RFA and resection patients died from recurrent cancer. Median hospital stay, morbidity and mortality were similar in both groups. Actuarial 3-year cancer specific survival rates were 54% for resection alone and 38% for RFA plus resection although this difference was not significant. CONCLUSION: A combined approach with RFA and resection achieves comparable perioperative outcomes in comparison to liver resection alone. With encouraging oncological outcomes, a combined approach is a potentially curative treatment option for patients with multiple bilobar hepatic metastases.

Vitamin antioxidants, lipid peroxidation, tumour stage, the systemic inflammatory response and survival in patients with colorectal cancer.

Both the tumour growth and progression and the systemic inflammatory response have the potential to increase oxidative stress. We therefore examined the relationship between lipid-soluble antioxidant vitamins, lipid peroxidation, the systemic inflammatory response and survival in patients with primary operable (n = 53) and advanced inoperable (n = 53) colorectal cancer. Compared with those patients with primary operable colorectal cancer, patients with unresectable liver disease had significantly lower median concentrations of alpha-tocopherol (p < 0.001), lutein (p < 0.001), lycopene (p < 0.001), alpha-carotene (p < 0.01) and beta-carotene (p < 0.001) and higher malondialdehyde concentrations. An elevated systemic inflammatory response (Glasgow prognostic score, mGPS) was associated with a greater proportion of females (p < 0.05) and more advanced tumour stage (p < 0.05), lower circulating levels of retinol (p < 0.01), lutein (p < 0.01), lycopene (p < 0.01) and alpha- (p < 0.01) and beta-carotene but not MDA (p = 0.633). In the liver metastases group 41 patients died of their cancer and a further 1 patient died of intercurrent disease on follow-up. On univariate survival analysis, mGPS (p < 0.01), retinol (p < 0.001), alpha-tocopherol (p < 0.05) and alpha-carotene (p < 0.05) were associated significantly with cancer-specific survival. On multivariate survival analysis of these significant variables, only mGPS (p < 0.01) and retinol (p < 0.001) were independently associated with cancer-specific survival. The results of the present study showed that the systemic inflammatory response was associated with a reduction of lipid-soluble antioxidant vitamins, whereas advanced tumour stage was associated with increased lipid peroxidation in patients with colorectal cancer. Of the antioxidant vitamins measured, only retinol was independently associated with cancer-specific survival.