Design, synthesis and initial characterisation of a radiolabelled [(18)F]pyrimidoindolone probe for detecting activated caspase-3/7.

Evasion of apoptosis is one of the six initially proposed hallmarks of cancer, and as such, a method to detect apoptosis in a tumour would be of considerable interest in both clinical trials of new cancer therapeutics, as well as for routine patient management. Activation of caspase-3/7 is a key biomarker of cellular apoptosis. Herein we describe the design, synthesis and initial characterisation of the first pyrimidoindolone compound for detection of caspase-3/7 activation using positron emission tomography.

A high-pressure interconnect for chemical microsystem applications.

A PEEK interface for use in microfluidic applications is designed, fabricated and tested. The interface allows for the facile, non-permanent coupling of standard capillary tubing to silicon/glass micromixer chips. Importantly, the interface provides for a secure connection between capillary lines and chip reservoirs without the need for any adhesive materials. Furthermore, when used in conjunction with silicon/glass micromixer chips fluidic transport is stable over a wide range of volumetric flow rates (1-1500 microL min(-1)), and the entire construct can be rapidly assembled and disassembled at any time during the course of experimentation.

Gliomatosis peritonei caused by ovarian teratoma.

A case of ovarian teratoma which produced glial peritoneal deposits is described. Twelve other cases in the literature are tabulated. The age at presentation ranges from 22 months to 22 years (mean age 14.6 years). The primary tumour may be solid or cystic. The prognosis does not appear to be improved by radical surgery as opposed to simple excision but depends mainly on the maturity of the tissues of the primary tumour and the peritoneal deposits. Although the period of follow up is generally short, a survival time up to 26 years is recorded. In the fatal cases, there is rapid recurrence and metastatic spread. The pathogenesis of the glial deposits is discussed.

Consistency in the observation of features used to classify duct carcinoma in situ (DCIS) of the breast.

AIM: To determine interobserver and intra-observer agreement in the assessment of cytological grade and intraduct necrosis in pure duct carcinoma in situ (DCIS) of the breast. METHODS: Sixty unselected cases with illustrated diagnostic criteria were circulated to 19 practising histopathologists. RESULTS: Overall agreement was moderate for cytological grade in three categories: 71% agreement; weighted kappa (kappa w), 0.36; intraduct necrosis in three categories (absent, present, extensive): 76% agreement; kappa w, 0.57; and the Van Nuys classification system: 73% agreement; kappa w, 0.48. Agreement was no better among observers participating in the National External Quality Assurance Programme. Intra-observer agreement for cytological assessment (69.6% agreement; kappa w, 0.52) and intraduct necrosis (68.3% agreement; kappa w, 0.48) was moderate, suggesting that individual variation rather than precision of criteria contributes to the lack of agreement. CONCLUSIONS: Moderate agreement on observations can be achieved by non-specialist pathologists, with better agreement on necrosis than cytological grade. There was evidence of consistent individual bias towards over or under scoring cytological grade, which could be corrected with adequate and prompt feedback.

Fibroadenolipoma of the breast.

Fibroadenolipoma is a well recognised but unusual benign tumour of the breast. It is a circumscribed lesion composed of fat and other breast tissues which may be normal or which may show various benign changes. The presence of smooth muscle has been recorded but was not found in our cases. A series of eight cases is described, occurring over a period of 10 years in a series of 20 000 mammograms. Radiological and pathological correlation is made and histological changes are described. Our findings are compared with other reviews in the literature. The lesions are usually diagnosed radiologically.

A solitary cardiac metastasis involving the tricuspid valve ring.

An unique case of solitary metastasis to the region of the tricuspid valve is described. The mechanisms of formation and symptomatology of cardiac neoplasms are discussed. Tumour spread in this case was probably embolic.

Preclinical assessment of carboplatin treatment efficacy in lung cancer by 18F-ICMT-11-positron emission tomography.

Tumour response to therapy is assessed primarily in the clinic by monitoring reductions in tumour size. However, this approach lacks sensitivity since in many cases several weeks may elapse before there is evidence of tumour shrinkage. There is therefore a need to develop non-invasive imaging techniques for monitoring tumour treatment response in the clinic. Here, we assessed the pre-clinical utility of (18)F-ICMT-11 positron emission tomography--a method for detecting caspase 3/7 activation--in non-small cell lung cancer (NSCLC). (18)F-ICMT-11 uptake was compared to molecular biochemical measures of cell death in PC9 and A549 NSCLC cells following treatment with carboplatin in vitro and in vivo. Carboplatin-induced apoptosis in the ERCC1 low/mutant EGFR PC9 cells was characterised by time and dose-related increased caspase-3/7 activation, poly-ADP-ribose polymerase cleavage and Annexin V staining. 18F-ICMT-11 uptake was consequently increased up to 14-fold at 200 µM carboplatin compared to vehicle treated cells (P<0.01). In contrast, necrosis was the predominant death mechanism in ERCC1 high/wt EGFR A549 cells and no change in (18)F-ICMT-11 uptake was detected. In vivo, histological analysis of PC9 tumour xenografts indicated high pre-therapy necrosis. A 4.6-fold increase in cleaved caspase-3/7 was measured in non-necrotic regions of PC9 tumours at 48 h post carboplatin therapy. Average PET-derived tumour (18)F-ICMT-11 uptake was insensitive to changes in apoptosis in the presence of substantial pre-existing necrosis. PET-based voxel intensity sorting however, identified intra-tumoural regions of high (18)F-ICMT-11 uptake, enabling accurate assessment of apoptosis and therefore therapy response. In A549 tumours that lacked high pre-therapy necrosis, carboplatin induced growth inhibition that was only minimally associated with apoptosis and thus not detectable by (18)F-ICMT-11 PET.

The identification of 'casein' in human breast cancer.

A retrospective study of ninety-six cases of breast cancer was carried out to determine the prognostic values of a casein immunolocalization technique. This was performed using an indirect immunofluorescence method with antisera raised in rabbits to pooled human casein. Fluorescence positivity was graded according to its intensity and distribution. The pathology of each tumour was studied and the tumour type, histological grade and tissue response assessed. The relationship between these observations and the casein content of the tumour was studied. In addition the correlation between casein content and age, menopausal state, clinical staging and survival was investigated. The incidence of casein positivity in our series was 50% with approximately half of the positive cases showing strong fluorescence. There was a relationship between casein content and the age of the patients, with casein being more frequently found in tumours from younger patients. Tumours with a high casein content, in general, show a poorer survival than the group as a whole. This difference in survival was most marked in the first eight years after operation and restricted to those tumours in clinical stage I and histological grade I. The presence of casein in the tumours did not appear to be related to the other factors examined.

Risk of breast cancer in women with history of benign disease of the breast.

A consecutive series of 791 women who had attended diagnostic breast clinics during 1967-70 and been found to be free of malignant disease were later traced to determine their subsequent incidence of breast cancer. Of the 770 (97%) successfully traced, 22 had developed breast cancer. Based on data from the Welsh Cancer Registry only eight cases of breast cancer had been expected, so that the excess risk for the group was 2.7. The increased risk occurred in all age groups and in women deemed "essentially normal" as well as in those who had had a pathological abnormality. The risk was increased when epithelial hyperplasia was present. No excess mortality from breast cancer was apparent, but follow up was short. More breast symptoms were experienced and more biopsies performed than expected in this group of women. Women with a past history of benign breast disease have a slightly increased risk of breast cancer. Selective screening of these women, however, may be uneconomic and a cause of groundless anxiety.

Importance of mastalgia in operable breast cancer.

The importance of pain as a presenting symptom of breast cancer has been assessed in a series of 240 patients with operable breast cancer over four years. From an analysis of the case histories of 36 patients the diagnosis proved difficult in one-quarter of the cancers. This is explained by the high incidence of subclinical and lobular carcinoma in the group. Cancer must be seriously considered as a diagnosis in patients presenting with well-localised breast pain of recent onset. These patients should be followed for at least one year after the onset of the pain before cancer is confidently excluded.