There is a need for transplantable murine models of ovarian high-grade serous carcinoma (HGSC) with regard to mutations in the human disease to assist investigations of the relationships between tumor genotype, chemotherapy response, and immune microenvironment. In addressing this need, we performed whole-exome sequencing of ID8, the most widely used transplantable model of ovarian cancer, covering 194,000 exomes at a mean depth of 400× with 90% exons sequenced >50×. We found no functional mutations in genes characteristic of HGSC (Trp53, Brca1, Brca2, Nf1, and Rb1), and p53 remained transcriptionally active. Homologous recombination in ID8 remained intact in functional assays. Further, we found no mutations typical of clear cell carcinoma (Arid1a, Pik3ca), low-grade serous carcinoma (Braf), endometrioid (Ctnnb1), or mucinous (Kras) carcinomas. Using CRISPR/Cas9 gene editing, we modeled HGSC by generating novel ID8 derivatives that harbored single (Trp53–/–) or double (Trp53–/–;Brca2–/–) suppressor gene deletions. In these mutants, loss of p53 alone was sufficient to increase the growth rate of orthotopic tumors with significant effects observed on the immune microenvironment. Specifically, p53 loss increased expression of the myeloid attractant CCL2 and promoted the infiltration of immunosuppressive myeloid cell populations into primary tumors and their ascites. In Trp53–/–;Brca2–/– mutant cells, we documented a relative increase in sensitivity to the PARP inhibitor rucaparib and slower orthotopic tumor growth compared with Trp53–/– cells, with an appearance of intratumoral tertiary lymphoid structures rich in CD3+ T cells. This work validates new CRISPR-generated models of HGSC to investigate its biology and promote mechanism-based therapeutics discovery. Cancer Res; 76(20); 6118–29. ©2016 AACR.

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. 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. 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). 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.

The CovidSurg-Cancer Consortium aimed to explore the impact of COVID-19 in surgical patients and services for solid cancers at the start of the pandemic. The CovidSurg-Gynecologic Oncology Cancer subgroup was particularly concerned about the magnitude of adverse outcomes caused by the disrupted surgical gynecologic cancer care during the COVID-19 pandemic, which are currently unclear. This study aimed to evaluate the changes in care and short-term outcomes of surgical patients with gynecologic cancers during the COVID-19 pandemic. We hypothesized that the COVID-19 pandemic had led to a delay in surgical cancer care, especially in patients who required more extensive surgery, and such delay had an impact on cancer outcomes. This was a multicenter, international, prospective cohort study. Consecutive patients with gynecologic cancers who were initially planned for nonpalliative surgery, were recruited from the date of first COVID-19-related admission in each participating center for 3 months. The follow-up period was 3 months from the time of the multidisciplinary tumor board decision to operate. The primary outcome of this analysis is the incidence of pandemic-related changes in care. The secondary outcomes included 30-day perioperative mortality and morbidity and a composite outcome of unresectable disease or disease progression, emergency surgery, and death. We included 3973 patients (3784 operated and 189 nonoperated) from 227 centers in 52 countries and 7 world regions who were initially planned to have cancer surgery. In 20.7% (823/3973) of the patients, the standard of care was adjusted. A significant delay (>8 weeks) was observed in 11.2% (424/3784) of patients, particularly in those with ovarian cancer (213/1355; 15.7%; P<.0001). This delay was associated with a composite of adverse outcomes, including disease progression and death (95/424; 22.4% vs 601/3360; 17.9%; P=.024) compared with those who had operations within 8 weeks of tumor board decisions. One in 13 (189/2430; 7.9%) did not receive their planned operations, in whom 1 in 20 (5/189; 2.7%) died and 1 in 5 (34/189; 18%) experienced disease progression or death within 3 months of multidisciplinary team board decision for surgery. Only 22 of the 3778 surgical patients (0.6%) acquired perioperative SARS-CoV-2 infections; they had a longer postoperative stay (median 8.5 vs 4 days; P<.0001), higher predefined surgical morbidity (14/22; 63.6% vs 717/3762; 19.1%; P<.0001) and mortality (4/22; 18.2% vs 26/3762; 0.7%; P<.0001) rates than the uninfected cohort. One in 5 surgical patients with gynecologic cancer worldwide experienced management modifications during the COVID-19 pandemic. Significant adverse outcomes were observed in those with delayed or cancelled operations, and coordinated mitigating strategies are urgently needed.

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 α‐tocopherol (p < 0.001), lutein (p < 0.001), lycopene (p < 0.001), α‐carotene (p < 0.01) and β‐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 α‐ (p < 0.01) and β‐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), α‐tocopherol (p < 0.05) and α‐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.

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.

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.