admission. This proportion could already be greater in some parts of the country and may increase if referrals of cases of self-poisoning increase faster than the facilities for their assessment and management. The provision of social work and psychiatric expertise in casualty departments may be one means of preventing unnecessary medical admissions without risk to the patients. Dr Blake's and Dr Bramble's figures do not demonstrate, however, that any advantage would attach to medical teams taking over assessment from psychiatrists except that, by implication, assessments would be completed sooner by staff working on the ward full time. What the figures actually suggest is that if assessment of overdoses were left to house doctors there would be an increase in admissions to psychiatric units (by 19°U), outpatients (by 5O°'), and referrals to social services (by 140o). So for house doctors to assess overdoses would provide no economy for the psychiatric or social services. The study does not tell us what the consequences would have been for the six patients who the psychiatrists would have admitted but to whom the house doctors would have offered outpatient appointments. E J SALTER

Vitamin D deficiency.

Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

4 CLINICAL PARTICULARS 4.1 Therapeutic Indications Trimetazidine is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled by or intolerant to first-line antianginal therapies. 4.2 Posology and method of administration Oral administration. Posology The dose is one tablet of 35mg of trimetazidine twice daily during meals. Special populations Renal impairment In patients with moderate renal impairment (creatinine clearance [30-60] ml/min) (see sections 4.4 and 5.2), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Elderly Elderly patients may have increased trimetazidine exposure due to age-related decrease in renal function (see section 5.2). In patients with moderate renal impairment (creatinine clearance [30-60] ml/min), the recommended dose is 1 tablet of 35mg in the morning during breakfast. Dose titration in elderly patients should be exercised with caution (see section 4.4). Health Products Regulatory Authority

Summary of product characteristics

PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.

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PARP inhibitors: Synthetic lethality in the clinic

Background/aim Activins are dimeric glycoproteins that play a significant role in reproduction and in endocrine-active tumors. The aim of this study was to evaluate the potential correlation between the concentration of activins (activin A, activin B, and activin AB) in patients receiving adjuvant chemotherapy for breast cancer. Patients and methods The serum concentration of activins in 30 patients receiving chemotherapy within the German SUCCESS A study was analyzed using different enzyme-linked immunosorbent assays at three time points: After primary surgery, but before chemotherapy; 4 weeks after the end of chemotherapy; and 2 years after chemotherapy during recurrence-free follow-up. Results The activin concentration decreased in all patients after chemotherapy. Premenopausal patients had significantly lower concentrations of activin AB during follow-up than postmenopausal women (p=0.037). Thirteen out of 16 premenopausal patients developed chemotherapy-related amenorrhea (CRA) but did not significantly differ in their activin concentrations compared to the other premenopausal women. A positive human epidermal growth factor receptor 2/neu status was associated with a significant reduction of activin AB concentration (p=0.02), and trastuzumab treatment correlated with significantly decreased activin A concentration (p=0.012). Conclusion Serial measurements of activin A concentration might be used for monitoring trastuzumab treatment. A sudden increase of activin concentration could be an early indicator of disease recurrence.

Expression of Activin During and After Chemotherapy in Peripheral Blood of Patients with Primary Breast Cancer.

Malignant Transformation of a Serous Borderline Tumor and Early Metastasis of Associated Low-Grade Serous Carcinoma Detected on Screening Mammography

Background: Phytoestrogens have controversial effects on hormone-dependent tumors. Herein we investigated the effects of parsley root extract (PCE) on DNA synthesis performance, metabolic activity and cytotoxicity in malignant and benign breast cells. Materials and Methods: The PCE was prepared and analyzed by mass spectrometry. MCF7 and MCF12A cells were incubated with various concentrations of PCE and analyzed for DNA synthesis performance, metabolic activity and cytotoxicity by BrdU proliferation, MTT and LDH assays, respectively. Results: PCE was found to contain a substantial ratio of lignans. At a concentration range of 0.01 mu g/ml-100 mu g/ml the LDH assay analysis showed no significant cytotoxicity of PCE in both cell lines. However, at 500 mu g/ml PCE's cytotoxicity was well over 70% of total cell population in both cell lines. According to the BrdU proliferation assay analysis, PCE demonstrated significant DNA synthesis inhibition of up to 80% at concentrations of 10, 50, 100 and 500 mu g/ml in both cell lines. Based on the MTT assay analysis, only at a concentration of 500 mu g/ml, PCE demonstrated a statistically significant inhibition of cellular metabolic activity of 63% in MCF7 and 75% in MCF12A of their respective normal capacity. Conclusion: PCE showed antiproliferative effects in MCF7 and MCF12A cells. Further investigation is required to determine whether this effect can be solely attributed to its phytoestrogens.

The Effects of Petroselinum Crispum on Estrogen Receptor-positive Benign and Malignant Mammary Cells (MCF12A/MCF7).

ENGOT-OV16/NOVA: Results of secondary efficacy endpoints of niraparib maintenance therapy in ovarian cancer

Several risk factors like obesity and hyperlipidemia were described for endometrial cancer. Here, the nuclear NAD-dependent histone-deacetylase Sirtuin1 (SIRT1) seems to be important. SIRT1 is also involved in cell regulatory mechanisms and can serve as tumor promotor or suppressor. Its role in tumor biology is not clear yet. In this study, we evaluated and correlated the SIRT1 expression with patients’ tumor characteristics in endometrioid and clear-cell cancer of the uterus. 65 paraffin-embedded samples of patients with endometrial and clear-cell cancer of the uterus were immunohistochemically stained and SIRT1 expression was evaluated by immunoreactive score. The results were correlated to clinical and pathological tumor characteristics as well as to the expression of ARID1A and β-Catenin. The staining was significantly more intensive in uterine endometrioid carcinoma compared to uterine clear-cell carcinoma (p = 0.007). The expression of SIRT1 correlated significantly with the membranous expression of β-Catenin (p = 0.028) and ARID1A (p = 0.021). Patients with positive Sirtuin1 expression had a significantly better progression-free survival (p = 0.042), the overall survival showed a trend towards a better prognosis (p = 0.070). SIRT1 expression seems to be associated with improved progression-free survival in uterine cancer (endometrioid and clear-cell) and is correlated to the tumor suppressors β-Catenin and ARID1A. Further studies are necessary to elucidate the role of SIRT1 in uterine and ovarian cancer and its potential as a therapeutic target.

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Sven Mahner

Papers

Expression of Activin During and After Chemotherapy in Peripheral Blood of Patients with Primary Breast Cancer.

Malignant Transformation of a Serous Borderline Tumor and Early Metastasis of Associated Low-Grade Serous Carcinoma Detected on Screening Mammography

The Effects of Petroselinum Crispum on Estrogen Receptor-positive Benign and Malignant Mammary Cells (MCF12A/MCF7).

ENGOT-OV16/NOVA: Results of secondary efficacy endpoints of niraparib maintenance therapy in ovarian cancer

Sirtuin1 expression and survival in endometrial and clear-cell uterine cancer.