Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway.

BACKGROUND: Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients. METHODS: We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva). RESULTS: A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p < 4.67e-8) related to sensory perception and detection of chemical stimuli, including smell perception (GO:0007606, GO:0007608, GO:0009593, GO:0050906, GO:0050907, and GO:0050911). The same six biological processes were significantly suppressed in the validation dataset (p < 9.02e-14). The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (ppaired-samples = 1.72e-9, psingle-timepoint-blood = 2.03e-15 and psingle-timepoint-saliva = 7.52e-56). CONCLUSION: The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell.

Negative and positive experiences of caregiving among family caregivers of older blunt trauma patients.

OBJECTIVES: Family caregivers play a fundamental role in the care of the older blunt trauma patient. We aim to identify risk factors for negative and positive experiences of caregiving among family caregivers. DESIGN: Prospective, nationwide, multi-center cohort study. SETTING AND PARTICIPANTS: 110 family caregivers of Singaporeans aged≥55 admitted for unintentional blunt trauma with an Injury Severity Score (ISS) or New Injury Severity Score (NISS)≥10 were assessed for caregiving-related negative (disturbed schedule and poor health, lack of family support, lack of finances) and positive (esteem) experiences using the modified-Caregiver Reaction Assessment (m-CRA) three months post-injury. METHODS: The association between caregiver and patient factors, and the four m-CRA domains were evaluated via linear regression. RESULTS: Caregivers of retired patients and caregivers of functionally dependent patients (post-injury Barthel score <80) reported a worse experience in terms of disturbed schedule and poor health (ß-coefficient 0.42 [95% Confidence Interval 0.10, 0.75], p = .01; 0.77 [0.33, 1.21], p = .001), while male caregivers and caregivers who had more people in the household reported a better experience (-0.39 [-0.73, -0.06], p = .02; -0.16 [-0.25, -0.07], p = .001). Caregivers of male patients, retired patients, and patients living in lower socioeconomic housing were more likely to experience lack of family support (0.28, [0.03, -0.53], p = .03; 0.26, [0.01, 0.52], p = .05; 0.34, [0.05, -0.66], p = .02). In the context of lack of finances, caregivers of male patients and caregivers of functionally dependent patients reported higher financial strain (0.74 [0.31, 1.17], p = .001; 0.84 [0.26, 1.43], p = .01). Finally, caregivers of male patients reported higher caregiver esteem (0.36 [0.15, 0.57], p = .001). CONCLUSIONS AND IMPLICATIONS: Negative and positive experiences of caregiving among caregivers of older blunt trauma patients are associated with pre-injury disability and certain patient and caregiver demographics. These factors should be considered when planning the post-discharge support of older blunt trauma patients.

BREAst screening Tailored for HEr (BREATHE)-A study protocol on personalised risk-based breast cancer screening programme.

Routine mammography screening is currently the standard tool for finding cancers at an early stage, when treatment is most successful. Current breast screening programmes are one-size-fits-all which all women above a certain age threshold are encouraged to participate. However, breast cancer risk varies by individual. The BREAst screening Tailored for HEr (BREATHE) study aims to assess acceptability of a comprehensive risk-based personalised breast screening in Singapore. Advancing beyond the current age-based screening paradigm, BREATHE integrates both genetic and non-genetic breast cancer risk prediction tools to personalise screening recommendations. BREATHE is a cohort study targeting to recruit ~3,500 women. The first recruitment visit will include questionnaires and a buccal cheek swab. After receiving a tailored breast cancer risk report, participants will attend an in-person risk review, followed by a final session assessing the acceptability of our risk stratification programme. Risk prediction is based on: a) Gail model (non-genetic), b) mammographic density and recall, c) BOADICEA predictions (breast cancer predisposition genes), and d) breast cancer polygenic risk score. For national implementation of personalised risk-based breast screening, exploration of the acceptability within the target populace is critical, in addition to validated predication tools. To our knowledge, this is the first study to implement a comprehensive risk-based mammography screening programme in Asia. The BREATHE study will provide essential data for policy implementation which will transform the health system to deliver a better health and healthcare outcomes.

Health Services Use and Functional Recovery Following Blunt Trauma in Older Persons - A National Multicentre Prospective Cohort Study.

OBJECTIVE: Frailty is associated with morbidity and mortality in older injured patients. However, for older blunt-trauma patients, increased frailty may not manifest in longer length of stay at index admission. We hypothesized that owing to time spent in hospital from readmissions, frailty would be associated with less total time at home in the 1-year postinjury period. DESIGN: Prospective, nationwide, multicenter cohort study. SETTING AND PARTICIPANTS: All Singaporean residents aged ≥55 years admitted for blunt trauma with an Injury Severity Score (ISS) or New Injury Severity Score (NISS) ≥10 from March 2016 to July 2018. METHODS: Frailty (by modified Fried criteria) was assessed at index admission, based on questions on preinjury weight loss, slowness, exhaustion, physical activity, and grip strength at the time of recruitment. Low time at home was defined as >14 hospitalized days within 1 year postinjury. The contribution of planned and unplanned readmission to time at home postinjury was explored. Functional trajectory (by Barthel Index) over 1 year was compared by frailty. RESULTS: Of the 218 patients recruited, 125 (57.3%) were male, median age was 72 years, and 48 (22.0%) were frail. On univariate analysis, frailty [relative to nonfrail: odds ratio (OR) 3.45, 95% confidence interval (CI) 1.33-8.97, P = .01] was associated with low time at home. On multivariable analysis, after inclusion of age, gender, ISS, intensive care unit admission, and surgery at index admission, frailty (OR 5.21, 95% CI 1.77-15.34, P < .01) remained significantly associated with low time at home in the 1-year postinjury period. Unplanned readmissions were the main reason for frail participants having low time at home. Frail participants had poorer function in the 1-year postinjury period. CONCLUSIONS AND IMPLICATIONS: In the year following blunt trauma, frail older patients experience lower time at home compared to patients who were not frail at baseline. Screening for frailty should be considered in all older blunt-trauma patients, with a view to being prioritized for postdischarge support.

Cohort profile: The Singapore Breast Cancer Cohort (SGBCC), a multi-center breast cancer cohort for evaluation of phenotypic risk factors and genetic markers.

This article aims to provide a detailed description of the Singapore Breast Cancer Cohort (SGBCC), an ongoing multi-ethnic cohort established with the overarching goal to identify genetic markers for breast cancer risk, prognosis and treatment response, as well as to understand the ethnic differences in disease risk and outcome in an Asian setting. The cohort comprises of breast cancer patients aged 21 years and above from six public hospitals which diagnose and treat nearly 76% breast cancer cases in Singapore. Self-reported data on sociodemographic and lifestyle, reproductive risk factors, medical history and family history of breast or ovarian cancer is collected using a structured questionnaire. Clinical data on tumour characteristics, and treatment modalities are obtained through medical record. Bio-specimens (blood or saliva) is collected at recruitment. Follow-up on survival information is done through routine linkage with the Registry of Births and Deaths. As of 31 December 2016, 7,768 subjects have been recruited to the study with 76% subjects contributed bio-specimens. The SGBCC provides a valuable platform which offers a unique, large and rich resource for new research ideas on breast cancer related phenotypic risk factors and genetic markers.

Frailty and length of stay in older adults with blunt injury in a national multicentre prospective cohort study.

BACKGROUND: Patients suffering moderate or severe injury after low falls have higher readmission and long-term mortality rates compared to patients injured by high-velocity mechanisms such as motor vehicle accidents. We hypothesize that this is due to higher pre-injury frailty in low-fall patients, and present baseline patient and frailty demographics of a prospective cohort of moderate and severely injured older patients. Our second hypothesis was that frailty was associated with longer length of stay (LOS) at index admission. METHODS: This is a prospective, nation-wide, multi-center cohort study of Singaporean residents aged ≥55 years admitted for ≥48 hours after blunt injury with an injury severity score or new injury severity score ≥10, or an Organ Injury Scale ≥3, in public hospitals from 2016-2018. Demographics, mechanism of injury and frailty were recorded and analysed by Chi-square, or Kruskal-Wallis as appropriate. RESULTS: 218 participants met criteria and survived the index admission. Low fall patients had the highest proportion of frailty (44, 27.3%), followed by higher level fallers (3, 21.4%) and motor vehicle accidents (1, 2.3%) (p < .01). Injury severity, extreme age, and surgery were independently associated with longer LOS. Frail patients were paradoxically noted to have shorter LOS (p < .05). CONCLUSION: Patients sustaining moderate or severe injury after low falls are more likely to be frail compared to patients injured after higher-velocity mechanisms. However, this did not translate into longer adjusted LOS in hospital at index admission.

A rare case report of recurrent metastatic breast cancer mimicking primary pancreatic cancer.

INTRODUCTION: Secondary pancreatic tumors are rare, of which a breast cancer primary is extremely uncommon. To our knowledge, we present the 14th case reported worldwide and first from Singapore of lobular breast cancer metastasizing to the pancreas. PRESENTATION OF CASE: A 53-year-old woman presented with painless obstructive jaundice, weight loss over 1.5 months and a 2 cm right breast mass. She had left breast Invasive Lobular Carcinoma (ILC) treated 5 years prior with wide local excision, adjuvant radiotherapy and hormonal therapy. She had elevated bilirubin, liver enzymes and Cancer Antigen (CA) 19-9. Imaging found 3 right breast nodules, left axillary lymphadenopathy, biliary dilatation with an ampullary mass, and bone metastases. Breast nodule biopsies confirmed ILC but ampullary mass cytopathology was inconclusive. Frozen section of the mass during exploratory laparotomy showed metastatic ILC; a triple bypass surgery was done and chemo-endocrine therapy commenced. DISCUSSION: ILC is the commonest type of breast carcinoma in cases with pancreatic metastases, usually recurring after long disease-free intervals, and widely metastatic at presentation. Imaging characteristics help differentiate secondary from primary pancreatic tumors. Radiological features and history of an extra-pancreatic cancer suffice in suspecting pancreatic metastases. Despite limited surgical experience, it is well accepted that pancreatic metastasectomy offers reasonably good long-term survival rates, quality of life and can even be curative in highly selected cases. CONCLUSION: This case is an interesting case because it highlights the diagnostic dilemma involved in the rare entity of breast cancer metastatic to the pancreas, and summarizes its diagnosis and management.

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population.

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality.

CD16 regulates TRIF-dependent TLR4 response in human monocytes and their subsets.

Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16(+)) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R-associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16(+) monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis.