A cancer geography paradox? Poorer cancer outcomes with longer travelling times to healthcare facilities despite prompter diagnosis and treatment: a data-linkage study.

BACKGROUND: Rurality and distance from cancer treatment centres have been shown to negatively impact cancer outcomes, but the mechanisms remain obscure. METHODS: We analysed the impact of travel time to key healthcare facilities and mainland/island residency on the cancer diagnostic pathway (treatment within 62 days of referral, and within 31 days of diagnosis) and 1-year mortality using a data-linkage study with 12 339 patients. RESULTS: After controlling for important confounders, mainland patients with more than 60 min of travelling time to their cancer treatment centre ((OR 1.42; 95% CI 1.25-1.61) and island dwellers (OR 1.32; 95% CI 1.09-1.59) were more likely to commence cancer treatment within 62 days of general practitioner (GP) referral and within 31 days of their cancer diagnosis compared with those living within 15 min. Island-dweller patients were more likely to have their diagnosis and treatment started on the same or next day (OR 1.72; 95% CI 1.31-2.25). Increased travelling time to a cancer treatment centre was associated with increased mortality to 1 year (30-59 min (HR 1.21; 95% CI 1.05-1.41), >60 min (HR 1.18; 95% CI 1.03-1.36), island dweller (HR 1.17; 95% CI 0.97-1.41). CONCLUSIONS: Island dwelling and greater mainland travel burden was associated with more rapid cancer diagnosis and treatment following GP referral even after adjustment for advanced disease; however, these patients also experienced a survival disadvantage compared with those living nearer. Cancer services may need to be better configured to suit the different needs of dispersed populations.

Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer.

BACKGROUND: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer. METHODS: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients. RESULTS: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines. CONCLUSION: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.

Uncontrolled Hypertension Is Common in Glaucoma Clinics.

BACKGROUND: To determine the magnitude of uncontrolled hypertension and smoking among patients visiting an eye clinic, and ascertain if referral to care providers is effective. METHODS: Information on smoking status and blood pressure (BP) was collected among patients ≥18 years visiting an eye clinic. Those with high BP (systolic: ≥140 mm Hg and/or diastolic: ≥90 mm Hg) received a pamphlet on harms of hypertension on vision and were referred to a primary care physician. Smokers received a pamphlet on negative effects of smoking on vision and were offered referral to a tobacco quitline. Patients were followed up for referral outcome within 10 weeks from screening. RESULTS: Screening: A total of participants screened included 140 (29.5%) with high BP and 31 (6.6%) current smokers. In the high BP group, 92 (66%) subjects were previously diagnosed with hypertension. Follow-up: Of the 140 participants with elevated BP, 84 (60%) responded to follow-up. Among these 84 participants, 57 (67.9%) had consulted primary care, of whom 5 (8.8%) reported being newly diagnosed with hypertension, and 11 (19.3%) reported a change in their antihypertensive prescription. Among the 31 smokers, 24 (77.4%) were willing for quitline referral. Sixteen (66.7%) of these patients responded to follow-up, 8 (50%) of whom reported participation in a smoking-cessation program with 1 patient (6.3%) successfully quitting smoking. CONCLUSIONS: Nearly one-third of patients attending an eye clinic had elevated BP, and a smaller, but substantial, number of patients were current smokers. Eye clinics may serve as point for identification and referral of these patients with unmet needs.

Performance of prediction models on survival outcomes of colorectal cancer with surgical resection: A systematic review and meta-analysis.

Prediction models allow accurate estimate of individualized prognosis. Increasing numbers of models on survival of CRC patients with surgical resection are being published. However, their performance and potential clinical utility have been unclear. A systematic search in MEDLINE and Embase databases (until 9th April 2018) was performed. Original model development studies and external validation studies predicting any survival outcomes from CRC (follow-up ≥1 year after surgery) were included. We conducted random-effects meta-analyses in external validation studies to estimate the performance of each model. A total of 83 original prediction models and 52 separate external validation studies were identified. We identified five models (Basingstoke score, Fong score, Nordinger score, Peritoneal Surface Disease Severity Score and Valentini nomogram) that were validated in at least two external datasets with a median summarized C-statistic of 0.67 (range: 0.57-0.74). These models can potentially assist clinical decision-making. Besides developing new models, future research should also focus on validating existing prediction models and investigating their real-word impact and cost-effectiveness for CRC prognosis in clinical practice.

Rural dwellers are less likely to survive cancer - An international review and meta-analysis.

BACKGROUND: Existing research from several countries has suggested that rural-dwellers may have poorer cancer survival than urban-dwellers. However, to date, the global literature has not been systematically reviewed to determine whether a rural cancer survival disadvantage is a global phenomenon. METHODS: Medline, CINAHL, and EMBASE were searched for studies comparing rural and urban cancer survival. At least two authors independently screened and selected studies. We included epidemiological studies comparing cancer survival between urban and rural residents (however defined) that also took socioeconomic status into account. A meta-analysis was conducted using 11 studies with binary rural:urban classifications to determine the magnitude and direction of the association between rurality and differences in cancer survival. The mechanisms for urban-rural cancer survival differences reported were narratively synthesised in all 39 studies. FINDINGS: 39 studies were included in this review. All were retrospective observational studies conducted in developed countries. Rural-dwellers were significantly more likely to die when they developed cancer compared to urban-dwellers (HR 1.05 (95% CI 1.02 - 1.07). Potential mechanisms were aggregated into an ecological model under the following themes: Patient Level Characteristics; Institutions; Community, Culture and Environment; Policy and Service Organization. INTERPRETATION: Rural residents were 5% less likely to survive cancer. This effect was consistently observed across studies conducted in various geographical regions and using multiple definitions of rurality. High quality mixed-methods research is required to comprehensively evaluate the underlying factors. We have proposed an ecological model to provide a coherent framework for future explanatory research. FUNDING: None.

The Singapore Liver Cancer Recurrence (SLICER) Score for relapse prediction in patients with surgically resected hepatocellular carcinoma.

BACKGROUND AND AIMS: Surgery is the primary curative option in patients with hepatocellular carcinoma (HCC). Current prognostic models for HCC are developed on datasets of primarily patients with advanced cancer, and may be less relevant to resectable HCC. We developed a postoperative nomogram, the Singapore Liver Cancer Recurrence (SLICER) Score, to predict outcomes of HCC patients who have undergone surgical resection. METHODS: Records for 544 consecutive patients undergoing first-line curative surgery for HCC in one institution from 1992-2007 were reviewed, with 405 local patients selected for analysis. Freedom from relapse (FFR) was the primary outcome measure. An outcome-blinded modeling strategy including clustering, data reduction and transformation was used. We compared the performance of SLICER in estimating FFR with other HCC prognostic models using concordance-indices and likelihood analysis. RESULTS: A nomogram predicting FFR was developed, incorporating non-neoplastic liver cirrhosis, multifocality, preoperative alpha-fetoprotein level, Child-Pugh score, vascular invasion, tumor size, surgical margin and symptoms at presentation. Our nomogram outperformed other HCC prognostic models in predicting FFR by means of log-likelihood ratio statistics with good calibration demonstrated at 3 and 5 years post-resection and a concordance index of 0.69. Using decision curve analysis, SLICER also demonstrated superior net benefit at higher threshold probabilities. CONCLUSION: The SLICER score enables well-calibrated individualized predictions of relapse following curative HCC resection, and may represent a novel tool for biomarker research and individual counseling.