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.

Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer.

BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin. METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy. RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013). CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04467411.

Not all small HER2 positive breast cancers have the same clinical outcome in the North-East of Scotland.

HER2-positive breast cancers, representing up to 20% of all breast cancers, are more aggressive and have poorer outcomes. Systemic therapy has been proven to prevent disease recurrence and improve survival. Existing literature provides only limited evidence to support this in smaller HER2-positive tumors. The study aimed to evaluate HER-2 positive breast cancer management and treatment of all T1N0 tumors in the North of Scotland, diagnosed 2012-2019. Clinical-pathological details, comorbidities, treatments and clinical events were retrieved from the Scottish North Cancer Alliance audit database and analyzed using univariate and multivariate analysis including cox-regression and log-rank testing (SPSSv23).Overall, 299 patients (41% screen detected/ 56.9% symptomatic /2.1% other), median age 63 years and median tumor size 13 mm, were included. Most cancers were grade 2/3 (43.1%/ 55.5%). Most patients (59.5%) received treatment with trastuzumab (tT); 40.8% concurrent with chemotherapy and endocrine therapy. 7.7% of patients received neo adjuvant chemotherapy. Median follow-up time was 2.6 years, with recurrence on average occurring 2.9 years after diagnosis. Patients receiving trastuzumab were younger, had a higher grade and larger size tumor. 78.5% of patients in the untreated group (non-tT) were ER positive compared to 65.2% in the treated group (tT). Trastuzumab significantly lowered breast cancer recurrence (Tt=3.4% versus non-Tt=8.3%, p = 0.022 HR= 0.096, 95% CI 0.025-0.361). In conclusion, receiving anti-HER2 treatment significantly improved clinical outcome in this T1N0 patient group. Consideration, at the very least informed discussions with patients, should be undertaken to treat these early stage HER2-positive breast cancers.

Does the gut microbiome environment influence response to systemic breast cancer treatment?

The gut microbiome is a novel player in the pathogenesis and treatment of breast cancer. The term "microbiome" is used to describe the diverse community of micro-organisms existing within the gastrointestinal tract. The gut microbiome plays an important role in oestrogen metabolism through its ability to deconjugate oestrogens within the gut resulting in their reabsorption. Therefore, it is not unsurprising that "dysbiosis", the disruption of normal gut microbiota composition, is now thought to play a role in the development of the disease, as women with breast cancer have been shown to have altered gut microbiota and this has been correlated with tumour characteristics. There is emerging evidence to suggest that the gut microbiota may also impact on breast cancer treatment, by mediating both drug efficacy and toxicity. The present review will discuss the influence of the gut microbiota on systemic treatments for breast cancer, including chemotherapy, anti-human epidermal growth factor receptor 2 (HER2) therapy, endocrine therapy and immunotherapy as well as other targeted treatments.

Serpin b3 is associated with poor survival after chemotherapy and is a potential novel predictive biomarker in advanced non-small-cell lung cancer.

INTRODUCTION: In a previous biomarker discovery project using gene-expression profiling we identified Serpin B3 (SB3) as a predictor of resistance to platinum doublet chemotherapy (PtC) in non-small-cell lung cancer (NSCLC). This independent prospective study was designed to confirm the predictive utility of SB3. METHODS: SB3 immunohistochemistry was scored by previously validated criteria (score 0 = negative, score 1 = 1%-10% tumor cells positive, score 2 = 11%-50% tumor cells positive, and score 3 = >50% tumor cell positive) in 197 patients with stage IV NSCLC treated with PtC. This provided 80% power to detect a median survival increase from 150 days in patients with an SB3 immunohistochemistry score of 2 or more to 300 days in those with an SB3 score of 0 or 1. RESULTS: Thirty-six percent of NSCLCs stained positive for SB3. Median survival for SB3 negative/score 0 was 332 days, SB3 positive/score 1 was 268 days, and SB3 positive/score 2 or 3 was 120 days (p = 0.004). Cox proportional hazards analysis demonstrated that SB3 positivity is an independent predictor of survival (hazard ratio = 1.87; 95% confidence interval, 1.29-2.71; p = 0.001).The disease control rate in SB3 score 0, 1 = 65%, and score of 2 or more = 20 % (p = 0.002), with median survival 306 days (score 0, 1) versus 120 days (score ≥ 2, hazard ratio= 1.71; 95% confidence interval. 1.14-3.10; p = 0.002). CONCLUSIONS: SB3-positive immunohistochemistry score of 2 or more (>10% tumor cells positive) identifies a subgroup of patients with stage IV NSCLC who have a poor survival (median 120 days) when treated with PtC, similar to that estimated for untreated or chemo-refractory stage IV NSCLC. Further prospective qualification using biospecimens from randomized studies is needed, but SB3 seems to be a useful biomarker that identifies a highly resistant subgroup in whom PtC should be avoided.

The use of non-prescription medicines by general practitioner attendees.

PURPOSE: Against a background of increasing availability and use of non-prescription medicines, this study set out to explore: use of such medicines by patients seeing their general practitioner (GP); frequency of GP enquiry about such use; and frequency of recommendations to use a non-prescription medicine. METHOD: Patients attending four general practices in Aberdeen, Scotland, completed separate questionnaires (before and after seeing their GP). RESULTS: Some 461 individuals waiting to see their GP were invited to participate: 427 (93%) completed the pre-consultation questionnaire and 305 (71% of questionnaires issued) completed the post-consultation questionnaire. Almost half (45%) of all participants reported using non-prescription medicines in the 7 days prior to visiting their doctor; with 20% of the medicines purchased from non-pharmacy retail outlets. Thirteen per cent of participants were asked about their use of non-prescribed medicines by their GP. Eight per cent of participants were recommended to use a non-prescription medicine by their GP. CONCLUSION: Although there was a high level of recent use of non-prescribed medicines by the general practice attenders, relatively few reported being asked about such use, or were recommended to use such medicines by their GP.