Intravenous administration of IL-12 encoding self-replicating RNA-lipid nanoparticle complex leads to safe and effective antitumor responses.

Interleukin 12 (IL-12) is a potent immunostimulatory cytokine mainly produced by antigen-presenting cells (e.g., dendritic cells, macrophages) and plays an important role in innate and adaptive immunity against cancers. Therapies that can synergistically modulate innate immunity and stimulate adaptive anti-tumor responses are of great interest for cancer immunotherapy. Here we investigated the lipid nanoparticle-encapsulated self-replicating RNA (srRNA) encoding IL-12 (referred to as JCXH-211) for the treatment of cancers. Both local (intratumoral) and systemic (intravenous) administration of JCXH-211 in tumor-bearing mice induced a high-level expression of IL-12 in tumor tissues, leading to modulation of tumor microenvironment and systemic activation of antitumor immunity. Particularly, JCXH-211 can inhibit the tumor-infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). When combined with anti-PD1 antibody, it was able to enhance the recruitment of T cells and NK cells into tumors. In multiple mouse solid tumor models, intravenous injection of JCXH-211 not only eradicated large preestablished tumors, but also induced protective immune memory that prevented the growth of rechallenged tumors. Finally, intravenous injection of JCXH-211 did not cause noticeable systemic toxicity in tumor-bearing mice and non-human primates. Thus, our study demonstrated the feasibility of intravenous administration of JCXH-211 for the treatment of advanced cancers.

NIR Plasmonic Nanozymes: Synergistic Enhancement Mechanism and Multi-Modal Anti-Infection Applications of MXene/MOFs.

Nanozymes are considered as the promising antimicrobial agents due to the enzyme-like activity for chemo-dynamic therapy (CDT). However, it remains a challenge to develop novel nanozyme systems for achieving stimuli-responsive, and efficient nanozyme catalysis with multimodal synergistic enhancement. In this work, a near-infrared (NIR) plasmonic-enhanced nanozyme catalysis and photothermal performance for effective antimicrobial applications are proposed. A Ti3 C2 MXene/Fe-MOFs composite (MXM) with NIR plasmonic-enhanced CDT combined with photothermal properties is successfully developed by loading metal-organic framework (MOF) nanozymes onto Ti3 C2 MXene. The mechanism of NIR induced localized surface plasmon resonance (LSPR)-enhanced CDT and photothermal therapy (PTT) is well explained through activation energy (Ea ), electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS), fluorescence analysis experiments, and finite element simulation. It reveals that MXene nanosheets exhibit NIR plasmon exciters and generate hot electrons that can transfer to the surface of Fe-MOFs, promoting the Fenton reaction and enhances CDT. While the photothermal heating of MXene produced by LSPR can also boost the CDT of Fe-MOFs under NIR irradiation. Both in vitro and in vivo experimental results demonstrate that LSPR-induced MXM system has outstanding antimicrobial properties, can promote angiogenesis and collagen deposition, leading to the accelerated wound healing.

Polyphosphazene-derived P/S/N-doping and carbon-coating of yolk-shelled CoMoO4 nanospheres towards enhanced pseudocapacitive lithium storage.

Transition metal oxides as potentialanodes of lithium-ion batteries (LIBs) possess high theoretical capacity but suffer from large volume expansion and poor conductivity. To overcome these drawbacks, we designed and fabricated polyphosphazene-coated yolk-shelled CoMoO4 nanospheres, in which polyphosphazene with abundant C/P/S/N species was readily converted into carbon shells and provided P/S/N dopants. This resulted in the formation of P/S/N co-doped carbon-coated yolk-shelled CoMoO4 nanospheres (PSN-C@CoMoO4). The PSN-C@CoMoO4 electrode exhibits superior cycle stability of 439.2 mA h g-1at 1000 mA g-1after 500 cycles and rate capability of 470.1 mA h g-1at 2000 mA g-1. The electrochemical and structural analyses reveal that PSN-C@CoMoO4 with yolk-shell structure, coated with carbon and doped with heteroatom not only greatly enhances the charge transfer rate and reaction kinetics, but also efficiently buffers the volume variation upon lithiation/delithiation cycling. Importantly, the use of polyphosphazene as coating/doping agent can be a general strategy for developing advanced electrode materials.

Development and Application of a Fast Gas Chromatographic Method Offer New Insights into l-theanine Production Regulation in Camellia sinensis L.

Tea is the most consumed beverage worldwide, and l-theanine in tea leaves significantly affects their flavor and market quality. We have developed and validated a fast and reliable gas chromatographic method with flame ionization detection (GC-FID) to quantify l-theanine after its extraction from Camellia sinensis (tea plant) and derivatization. The procedure was completed in 40 min, from extraction to chromatographic analysis, with a recovery rate of more than 93% and allowing a high sample throughput. The GC-FID intraday precision was within 0.57-2.28%, while the interday precision ranged from 1.57 to 13.48%. The intraday accuracy ranged from -6.84 to 5.26%, while the interday accuracy ranged from -1.08 to 3.12%. The limit of detection was 2.28 µg/mL, and the limit of quantification was 6.47 µg/mL. The GC-FID method was validated by high-performance liquid chromatography with UV detection (HPLC-UV) and was used to investigate the biosynthesis and regulation of l-theanine in tea plants. We found that plants fed with ethylamine significantly increased l-theanine concentrations in roots, while exogenous supplementation of glutamic acid, carbamide, and glutamine did not significantly affect the l-theanine level in roots. Our results also indicated that roots were not indispensable for the biosynthesis of l-theanine, which was detected in undifferentiated embryonic calluses in concentrations (g/100 g dry weight) as high as in leaves of whole plants (1.67 and 1.57%, respectively) and without any exogenous theanine precursor supplementation.

A Macromolecular Drug for Cancer Therapy via Extracellular Calcification.

Cancer chemotherapy typically relies on drug endocytosis and inhibits tumor cell proliferation via intracellular pathways; however, severe side effects may arise. In this study, we performed a first attempt to develop macromolecular-induced extracellular chemotherapy involving biomineralization by absorbing calcium from the blood through a new type of drug, polysialic acid conjugated with folate (folate-polySia), which selectively induces biogenic mineral formation on tumor cells and results in the pathological calcification of tumors. The macromolecule-initiated extracellular calcification causes cancer cell death mainly by intervening with the glycolysis process in cancer cells. Systemic administration of folate-polySia inhibited cervical and breast tumor growth and dramatically improved survival rates in mice. This study provides an extracellular therapeutic approach for malignant tumor diseases via calcification that is ready for clinical trials and offers new insights into macromolecular anticancer drug discovery.

Three new diterpenoids from Euphorbia peplus.

Three new diterpenoids (1-3) (two abietane type diterpenoids and a paralianone type diterpenoid), together with four known compounds (4-7) were isolated from the whole plants of Euphorbia peplus. Their structures were elucidated through spectroscopic analysis and physicochemical characteristics. The cytotoxic activities of compounds 1-7 against five human tumour cell lines were evaluated, however, they were inactive at the concentration of 40 µM. The compound 3 enhanced lysosomal biogenesis with Lyso Tracker staining intensity of 132.6%.

Factors for peripherally inserted central catheters care delay in cancer patients during the COVID-19 pandemic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has rapidly evolved into a global pandemic. The public health systems have consequently been placed under tremendous pressure. Peripherally inserted central catheters (PICCs) are widely used in patients with cancers. Little is known about the provision of PICCs care amongst cancer patients during this pandemic. METHODS: We studied 156 cancer patients with PICCs treated at the Cancer Center of the Fifth Affiliated Hospital of Sun Yat-sen University between January 2020 and March 2020. Their clinical characteristics, social features, psychological characteristics, and PICCs care situations were analyzed. The chi-squared (χ2) test or Fisher's exact test were used for univariate analyses. Multivariate logistic regression analyses were performed using stepwise variable selection. Differences were evaluated using a two-tailed test, and P<0.05 was considered statistically significant. RESULTS: Of 156 patients, 57 (36.5%) experienced delays of PICCs care, and 12 (21.1%) suffered from complications including infection, thrombosis, and mechanical failure. Univariate analysis detected that the increased risk of PICCs care delay was associated with older age (≥30), lower level of education (<9 years), working, taking public transport to the hospital, anxiety about COVID-19, lower social support rating scale (SSRS) score (<30). Multivariate analysis detected level of education, being employed or not, mode of transport, and SSRS score were independent predictive factors for the delay in PICCs care. CONCLUSIONS: Physical aspects, social factors, and psychological status commonly influenced patients' health care seeking behaviors such as PICCs maintenance. An increase in effort is required from patients' families and society to assure optimal care for cancer patients during this pandemic.

Research on the effect of health care integration on patients' negative emotions and satisfaction with lung cancer nursing activities.

BACKGROUND: Lung cancer is a clinical disease with multiple malignant tumors. Currently, it is difficult for patients to benefit from routine clinical nursing due to the lack of a pertinent and systematic approach. AIM: To investigate the effect of integrated nursing care on the negative emotions and satisfaction of lung cancer patients. METHODS: From January 2018 to December 2019, 92 patients with lung cancer were selected and divided into the study group and the control group; there were 46 patients in each group. The control group received routine nursing, and the study group received integrated medical care in addition to the care received by the control group. Negative emotions before and after the intervention, the self-management ability score after the intervention, family care burden after the intervention and nursing satisfaction after the intervention were measured in the two groups. RESULTS: After the intervention, the self-rating anxiety scale and self-rating depression scale scores in the study group were lower than those in the control group (P < 0.05); the scores for health knowledge, self-concept, self-responsibility and self-care skills in the study group were higher than those in the control group (P < 0.05); the scores for individual burden and responsibility burden in the study group were lower than those before the intervention (P < 0.05); and the nursing satisfaction in the study group (93.48%) was higher than that in the control group (78.26%, P < 0.05). CONCLUSION: An integrated nursing care approach for lung cancer patients can effectively relieve the patient's negative feelings, improve their self-management ability, help to reduce the burden of family care and improve patient satisfaction with nursing activities.

MIR17HG polymorphism (rs7318578) is associated with liver cancer risk in the Chinese Han population.

Numerous evidence has revealed that single-nucleotide polymorphisms (SNPs) are associated with liver cancer risk. To assess whether the MIR17HG polymorphisms are associated with the liver cancer risk in the Chinese Han population, we performed a case-control (432 liver cancer patients and 430 healthy controls) study. Genotyping of four variants of MIR17HG was performed with the Agena MassARRAY platform. We used χ2 test to compare the distribution of SNPs allele and genotypes frequencies of cases and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis to evaluate the association under genetic models. The results indicated that the rs7318578 was significantly associated with increased the risk of liver cancer in the allele (OR = 1.45, 95% CI: 1.18-1.77, P=3.04E-04), recessive (OR = 3.69, 95% CI: 2.45-5.56, P=4.52E-10) and additive model (OR = 1.35, 95% CI: 1.13-1.62, P=0.001). Moreover, we found that individuals with the genotype CC of rs7318578 presented with an increased risk of liver cancer (OR = 3.03, 95% CI: 1.98-4.65, P=3.83E-07); however, the CA genotype of rs7318578 significantly decreased the risk of liver cancer (OR = 0.61, 95% CI: 0.45-0.83, P=0.001, compared with those with the AA genotype. Our findings indicated that MIR17HG polymorphism (rs7318578) contributes to liver cancer susceptibility to the Chinese Han population. Further studies with larger samples are required to confirm the results, as well as functional studies to determine the role of this SNP in miRNA expression or molecular pathways.

Yes­associated protein protects and rescues SH­SY5Y cells from ketamine­induced apoptosis.

Ketamine is a widely used intravenous anesthetic; however, basic and clinical studies have demonstrated that prolonged exposure can cause irreversible injury to the immature human brain. Yes­associated protein (YAP) is the main effector of the Hippo signaling pathway, which serves an important role in regulating tissue homeostasis and organ size during development. However, whether YAP mediates ketamine­induced apoptosis is not completely understood. Based on the functions of YAP during apoptosis resistance and cell self­renewal regulation, the present study hypothesized that YAP serves a role during ketamine­induced apoptosis. An in vitro model was utilized to investigate the effects of ketamine on neurotoxicity and to further investigate the role of YAP in ketamine­induced apoptosis using techniques including CCK­8 assay, flow cytometry and western blotting. The present study assessed the effects of YAP overexpression and knockdown on the expression of typical apoptotic markers in SH­SY5Y cells. Ketamine induced apoptosis in a dose­dependent manner, which was regulated by YAP. Following YAP overexpression, ketamine­treated SH­SY5Y cells displayed increased activity and viability, whereas expression levels of the apoptotic markers were decreased compared with the negative control group. By contrast, ketamine­induced apoptosis was enhanced following YAP knockdown. Collectively, the results of the present study indicated that YAP may serve an important role during ketamine­induced neurotoxicity, and alterations to YAP signaling may counteract ketamine­induced apoptosis. The neuroprotective effect of YAP activation may serve as a novel pharmacological target for the treatment of ketamine­induced neurotoxicity via neurogenesis normalization.

MiRNA155HG polymorphisms influenced the risk of liver cancer among the Han Chinese population.

BACKGROUND: Liver cancer is one of the most common cancers in the world. The primary aim of this research was to discover the correlation between single nucleotide polymorphisms (SNPs) of the MIR155HG and liver cancer risk. METHODS: The selected SNPs in MIR155HG were genotyped utilizing the Agena MassARRAY platform. We evaluated the correlation between MIR155HG polymorphisms and Liver cancer by genetic model analysis, stratification analysis and haplotype analysis. Relative risk of Liver cancer was shown based on odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Our results uncovered that rs12482371 and rs1893650 in the MIR155HG were associated with protection against Liver cancer. And the rs928883 was related to increase risk of Liver cancer. Furthermore, apart from rs77218221, other selected SNPs formed two LD blocks, and haplotype "GATAG" in block 2 elevated individual liver cancer risk. CONCLUSIONS: MIR155HG gene polymorphism may be correlated to Liver cancer susceptibility in Han Chinese population, particularly in males and aged ≤55 years.

Use of telephone intake for family history taking at a cancer genetics service in Asia.

Family history taking is a fundamental part of genetic counseling, and however, it is also a time-consuming process. To cope with the increasing demands at the Cancer Genetics Service in Singapore, alternative methods to collect patients' family history were implemented to reduce the duration of the initial consultation and increase the clinic's capacity. Two interventions were performed in this study, where a family history questionnaire and telephone intakes (telephone calls to collect patient family history) were implemented prior to a cancer genetics consultation. The primary outcome of this study is the duration of the initial consultation in relation to both interventions while the secondary outcome is the clinic attendance rate before and after implementing the telephone intake. The impact of interventions was evaluated with a Plan-Do-Study-Act (PDSA) methodology. The use of a family history questionnaire could not be evaluated due to poor patient response while the telephone intake was found to be feasible among the local population. Two improvements were observed after the implementation of telephone intake: (a) a significant reduction in the duration of the initial consultation from 60 to 45 min (p = .001) and (b) a significant increase of 29.7% in clinic attendance (p = .01). This study demonstrates that collecting family history information ahead of genetic counseling via telephone intake is a useful measure in improving clinic capacity, which potentially resulting in optimization of clinical resources.

Autologous adipose-derived stem cells for the treatment of Crohn's fistula-in-ano: an open-label, controlled trial.

BACKGROUND: Crohn's fistula-in-ano is a refractory disease in colorectal and anal surgery. Although autologous adipose-derived stem cell (ADSC) has been used in the treatment of Crohn's fistula-in-ano because of its convenience, non-incision of normal tissue, good tolerance, repeatability, quick recovery, less pain, less damage to anal function, and high quality of life during the perioperative period, there are no reports of its use in China. This is the first clinical trial in China on the treatment of Crohn's fistula-in-ano with ADSC to evaluate its efficacy and safety. METHODS: A total of 22 patients with Crohn's fistula-in-ano were enrolled in this study from January 2018 to October 2018 in the Colorectal Disease Center of Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine. Patients were divided (1:1) into an observation group (ADSC) and a control group (incision-thread-drawing procedure). Primary efficacy endpoint evaluated at months 3, 6, and 12 was the closure of fistulas (closure of all treated fistulas at baseline, confirmed by doctor's clinical assessment and magnetic resonance imaging or transrectal ultrasonography). The patients additionally completed some scoring scales at each follow-up including simplified Crohn's Disease Activity Index (CDAI), Perianal Disease Activity Index (PDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), pain scores with visual analog score (VAS), and Wexner score. The data of inflammatory indexes were also collected. RESULTS: The healing rates of the observation group and the control group at months 3, 6, and 12 were as follows: 10/11(90.9%) vs 5/11(45.5%), 8/11(72.7%) vs 6/11(54.5%), and 7/11(63.6%) vs 6/11(54.5%), respectively. There was no statistical difference between the two groups. In addition, the improvement in simplified CDAI, PDAI, IBDQ, VAS, and Wexner score of the observation group were better than that of the control group at each follow-up. The inflammatory indexes decreased in both the observation group and the control group at 3 months follow-up. And there were no significant differences in the changes of inflammatory indexes between two groups at month 3 compared with the baseline. Safety was maintained throughout month 12, and adverse events occurred in 63.6% of patients in the observation group and 100% patients in the control group. And no adverse event associated with ADSC injection was observed in the study. CONCLUSION: ADSC is a feasible and effective treatment for Crohn's fistula-in-ano, compared with traditional incision and thread-drawing. It can protect anal function of patients, relieve pain, allow quick recovery, be well-tolerated, and improve the quality of life during perioperative period. TRIAL REGISTRATION: China Clinical Trials Registry, No. ChiCTR1800014599. Registered 23 January 2018.

Evaluating empowerment in genetic counseling using patient-reported outcomes.

Data about patient reported outcomes from cancer genetics services (CGS) are lacking but are essential to guide service evaluation and improvements. We measured improvement in empowerment, following genetic counseling in Singapore using a culturally-adapted version of the Genetic Counseling Outcome Scale (GCOS-24); and sought to identify factors associated with change in empowerment. The GCOS-24 was administered to 155 patients of the CGS, at pre- and post-counseling or testing timepoints. Of which, 110 patients underwent genetic testing. Individual pre- and post-counseling responses were subjected to Rasch analysis; the scale was subsequently split into cognitive control (CC) and emotional control (EC) domains. Associations of baseline characteristics with changes in pre- and post-CC and EC scores were assessed using multiple regression analysis. Both CC and EC scores showed significant improvement following genetic counseling and testing. While all items in the CC domain of being showed increases at follow-up, aspects of EC related to alleviating negative emotions (P = .88) and hopelessness (P = .2) did not show significant improvement. Our study revealed significant improvement in empowerment in patients who have received cancer genetic counseling, while revealing a need to cultivate hope and facilitate the alleviation of negative emotions in patients during genetic counseling.

An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response.

Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8+ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8+ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy. SIGNIFICANCE: BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment.

Antibody-Functional Microsphere-Integrated Filter Chip with Inertial Microflow for Size-Immune-Capturing and Digital Detection of Circulating Tumor Cells.

Circulating tumor cells (CTCs) in blood is the direct cause of tumor metastasis. The isolation and detection of CTCs in the whole blood is very important and of clinical value in early diagnosis, postoperative review, and personalized treatment. It is difficult to separate all types of CTCs that efficiently rely on a single path due to cancer cell heterogenicity. Here, we designed a new kind of "filter chip" for the retention of CTCs with very high efficiency by integrating the effects of cell size and specific antigens on the surface of tumor cells. The filter chip consists of a semicircle arc and arrays and can separate large-scale CTC microspheres, which combined with CTCs automatically. We synthesized interfacial zinc oxide coating with nanostructure on the surface of the microsphere to increase the specific surface area to enhance the capturing efficiency of CTCs. Microspheres, trapped in the arrays, would entrap CTCs, too. The combination of the three kinds of strategies resulted in more than 90% capture efficiency of different tumor cell lines. Furthermore, it is easy to find and isolate the circulating tumor cells from the chip as tumor cells would be fixed inside the structure of a filter chip. To avoid the high background contamination when a few CTCs are surrounded by millions of nontarget cells, a digital detection method was applied to improve the detection sensitivity. The CTCs in the whole blood were specifically labeled by the antibody-DNA conjugates and detected via the DNA of the conjugates with a signal amplification. The strategy of the antibody-functional microsphere-integrated microchip for cell sorting and detection of CTCs may find broad implications that favor the fundamental cancer biology research, the precise diagnosis, and monitoring of cancer in the clinics.

An evidence-based approach to assess the accuracy of diffusion kurtosis imaging in characterization of gliomas.

OBJECTIVE: Accurate and noninvasive pathologic grading of glioma patients before surgery was crucial to guiding clinicians to select appropriate treatment and improve patient prognosis. This study was performed to investigate the potential diagnostic value of diffusion kurtosis imaging (DKI) to distinguish high-grade gliomas (HGGs) from low-grade gliomas (LGGs) based on an evidence-based approach. METHODS: Relevant articles that used DKI to distinguish HGG from LGG in Embase, PubMed, China Knowledge Resource Integrated database (CNKI), Web of Knowledge, and Cochrane Libraries databases were electronically searched to April 31, 2018 by 2 reviewers. All analysis was performed by using Meta-disc1.4 and Stata. Influence factors on the diagnostic accuracy were evaluated using meta-regression analysis. RESULTS: Five eligible studies were included in this meta-analysis. The pooled sensitivity (SEN) and specificity (SPE) was 91% (confidence interval [CI]: 0.78-0.96; P = .02) and 91% (CI: 0.80-0.97; P = .01). The pooled data showed that diagnostic odds ratio (DOR) of DKI was 79.75 (CI: 31.57-201.45). The area under the curve (AUC) of summary receiver operating characteristic curve was 0.96. There is no evidence that our research has a threshold effect (Spearman correlation coefficient: 0.300, P = .624) and publication bias. Meta regression analysis identified that country, language, field strength, and parameter of magnetic resonance imaging had no significant effect on diagnostic performance. CONCLUSION: The present meta-analysis shows that the mean kurtosis values derived from DKI may be useful in characterization of gliomas with high sensitivity and specificity. Taken into consideration the small sample of this study, we need to be cautious when interpreting the results of this study.

Predictors of next-generation sequencing panel selection using a shared decision-making approach.

The introduction of next-generation sequencing panels has transformed the approach for genetic testing in cancer patients, however, established guidelines for their use are lacking. A shared decision-making approach has been adopted by our service, where patients play an active role in panel selection and we sought to identify factors associated with panel selection and report testing outcomes. Demographic and clinical data were gathered for female breast and/or ovarian cancer patients aged 21 and over who underwent panel testing. Panel type was classified as 'breast cancer panel' (BCP) or 'multi-cancer panel' (MCP). Stepwise multiple logistic regression analysis was used to identify clinical factors most predictive of panel selection. Of the 265 included subjects, the vast majority selected a broader MCP (81.5%). Subjects who chose MCPs were significantly more likely to be ≥50 years of age (49 vs. 31%; p < 0.05), Chinese (76 vs. 47%; p < 0.001) and have a personal history of ovarian cancer (41 vs. 8%; p < 0.001) with the latter two identified as the best predictors of panel selection. Family history of cancer was not significantly associated with panel selection. There were no statistically significant differences in result outcomes between the two groups. In summary, our findings demonstrate that the majority of patients have a preference for interrogating a larger number of genes beyond those with established testing guidelines, despite the additional likelihood of uncertainty. Individual factors, including cancer history and ethnicity, are the best predictors of panel selection.

Risk management adherence following genetic testing for hereditary cancer syndromes: a Singaporean experience.

Assessing adherence behavior among mutation carriers to cancer risk management guidelines is important for both service improvement and cost-effectiveness analyses, but such real-world data is often lacking. The present study aims to report adherence rates among mutation carriers in a recently established cancer genetics program in Singapore. We conducted a medical chart review of mutation carriers who had attended for genetic counseling and gathered data regarding risk management behavior, including cancer surveillance and/or risk-reducing surgery, and cancers subsequently detected. Of the 52 subjects included in the study, the majority were affected prior to genetic testing (78.8%) and had family history suggestive of a germline mutation (88.5%). The overall adherence rate was 96.2%, including 37 (74.0%) fully-adherent and 13 (26.0%) partially-adherent subjects, with five cancers subsequently detected. Among the 28 BRCA1/2 mutation carriers, adherence to breast cancer risk management was also high (89.3%), although uptake of risk-reducing bilateral salpingo-oophorectomy was not as common (60%). Whilst overall adherence in this cohort was high, BRCA1/2 mutation carriers may require targeted interventions to improve ovarian cancer risk management uptake. Additionally, further education among health professionals and the wider community regarding cancer genetics is needed to ensure the early identification of mutation carriers.

Evaluation of the relative effectiveness of the 2017 updated Manchester scoring system for predicting BRCA1/2 mutations in a Southeast Asian country.

BACKGROUND: Germline mutations in the BRCA1 and BRCA2 genes have significant clinical implications for both risk-reducing and early surveillance management. The third and most recent revision of the Manchester scoring system (MSS3) used to distinguish patients indicated for germline BRCA1/2 testing included further adjustments for triple negative breast cancer, high-grade serous ovarian cancer and human epidermal growth factor 2 (HER2) receptor status. This study aims to evaluate the relative effectiveness of MSS3 in a Southeast Asian population. METHODS: All patients in our centre were tested using next-generation sequencing (NGS) panels that included full gene sequencing as well as coverage for large deletions/duplications in BRCA1/2. We calculated MSS1-3 scores for index patients between 2014 and 2017 who had undergone BRCA1/2 genetic testing and recorded their genetic test results. MSS1-3 outcomes were compared using receiver operating characteristic analysis, while associations with predictors were investigated using Fisher's exact test and logistics regression. Calculations were performed using Medcalc17. RESULTS: Of the 330 included patients, 47 (14.2%) were found to have a germline mutation in BRCA1 or BRCA2. A positive HER2 receptor was associated with a lower likelihood of a BRCA1/2mutation (OR=0.125, 95% CI 0.016 to 0.955; P=0.007), while high-grade serous ovarian cancer was conversely associated with an increased likelihood of a BRCA1/2 mutation (OR=5.128, 95% CI 1.431 to 18.370; P=0.012). At the 10% threshold, 43.0% (142/330) of patients were indicated for testing under MSS3, compared with 35.8% (118/330) for MSS1% and 36.4% (120/330) for MSS2. At the 10% threshold, MSS3 sensitivity was 91.5% and specificity 65.0%, significantly better than the previous MSS1 (P=0.037) and MSS2 (P=0.032) models. CONCLUSION: Our results indicate that the updated MSS3 outperforms previous iterations and relative to the Manchester population, is just as effective in identifying patients with BRCA1/2 mutations in a Southeast Asian population.