Certified causes of death in patients with mesothelioma in South East England

Background  

Mesothelioma is a highly fatal cancer that is caused by exposure to asbestos fibres. In many populations, the occurrence of mesothelioma is monitored with the use of mortality data from death certification. We examine certified causes of death of patients who have been diagnosed with mesothelioma, and assess the validity of death certification data as a proxy for mesothelioma incidence.     

Dual targeting of Src and ER prevents acquired antihormone resistance in breast cancer cells

Acquired resistance to endocrine therapies presents a major obstacle to the successful treatment of breast cancer patients. Previously, we have shown that acquisition of resistance to tamoxifen in breast cancer cells is accompanied by an elevation in Src kinase activity which promotes an aggressive, invasive phenotype in vitro. Here, we have explored the potential therapeutic effects of combining Src inhibition with anti-oestrogen treatment on the development of endocrine insensitivity in breast cancer cells. Treatment of MCF7 and T47D cells with tamoxifen alone resulted in an initial growth inhibitory phase followed by the eventual development of tamoxifen resistance together with an elevation of Src kinase activity, which was central to their increased invasive capacity. Chronic exposure of both cell types to the Src inhibitor, AZD0530, as a monotherapy resulted in outgrowth of AZD0530-resistant cells, in which Src kinase activity remained suppressed as did their in vitro invasive nature. Treatment of both MCF7 and T47D cells with AZD0530 in combination with tamoxifen resulted in a reduction of Src activity together with inhibition of focal adhesion kinase phosphorylation and a complete abrogation of their in vitro invasive behaviour. Furthermore, combination therapy significantly suppressed expression of cyclinD1 and c-myc and prevented cell proliferation and the subsequent emergence of a resistant phenotype, with total cell loss occurring by 12 weeks. These data demonstrate that pharmacological targeting of Src kinase, in conjunction with antihormone therapies, effectively prevents antihormone resistance in breast cancer cells in vitro and suggests a potential novel therapeutic benefit of Src kinase inhibitors clinically.     

Derivation of a subtype-specific biochemical signature of endometrial carcinoma using synchrotron-based Fourier-transform infrared microspectroscopy

Endometrial carcinoma consists of endometrioid (type I) and serous papillary (SP; type II) subtypes; a rarer form is malignant mixed müllerian tumours (MMMT; type II/mixed). We set out to determine whether one might be able to biochemically signature these subtypes using Fourier-transform infrared (FTIR) microspectroscopy and distinguish non-tamoxifen associated from tamoxifen-associated cases. Paraffin-embedded blocks were obtained from non-tamoxifen associated cases reported as endometrioid (n=7), SP (n=4) or MMMT (n=4). From tamoxifen-associated cases, endometrioid (n=1), SP (n=3) and MMMT (n=4) blocks were retrieved; benign tissues (n=3) were also analysed. Exploiting synchrotron-based radiation, sections (10-microm thick) on BaF(2) windows were interrogated through a 10 microm x 10 microm aperture. Point spectra were derived from >or=10 locations in each of six glandular elements per tissue; a further 20 stromal spectra were obtained. Following normalisation to Amide I, average spectra (1800-900 cm(-1)) per gland or stroma were analysed for variance using principal component analysis (PCA) and linear discriminant analysis (LDA). In scores plots, segregation of spectra from different subtypes or benign tissues was noted and it proved possible to distinguish tamoxifen-associated cases. In the PCA-LDA loadings plots, the wavenumbers that highlighted variance for benign or endometrioid carcinoma tissues were in the protein region (1800-1480 cm(-1)) whereas those contributing most to SP or MMMT segregation were primarily in the DNA/RNA region (1425-900 cm(-1)) of the vibrational spectrum. Our results suggest that the application of FTIR microspectroscopy is a powerful new approach in disease diagnosis and characterisation.     

Predicting breast cancer risk: implications of a “weak” family history

Published guidelines adopted in many countries recommend that women whose family history of breast cancer places them at a risk ≥1.7 times that of the age-matched general population, should be considered for inclusion in special surveillance programmes. However validation of risk assessment models has been called for as a matter of urgency. The databases of the four Scottish Familial Breast Cancer clinics and the Scottish Cancer Registry have been searched to identify breast cancers occurring among 1,125 women aged 40–56, with family histories placing them below the “moderate” level of genetic risk. The observed incidence over 6 years was compared with age-specific data for the Scottish population. Our findings confirm that when there are two affected relatives (one first degree) the relative risk (RR) exceeds 1.7 regardless of their ages at diagnosis. When only one (first degree) relative was affected at any age from 40 to 55, the RR does not reach 1.7 if that relative was a mother but exceeds it if the relative was a sister. The probable explanation is that sisters are more likely than mother/daughter pairs to share homozygosity for a risk allele. Surveillance programmes might therefore accommodate sisters of women affected before age 55. Evidence that “low penetrance” alleles contributing to breast cancer risk may be recessive should be taken into account in strategies for identifying them. All the authors are from the Scottish Cancer Family Clinical Centres.     

Test-retest reliability of in situ unaided thresholds in adults

PURPOSE: The purpose of this study was to examine test-retest reliability of in situ unaided thresholds measured using a handheld hearing aid programmer coupled to a hearing aid transducer in adults with normal hearing. METHOD: Randomized in situ thresholds at 4 octave frequencies were established in 1 ear of 43 adults twice using the Widex Diva SP3 device with the stimulus generated by and transduced through a Widex Diva SD-9 behind-the-ear hearing aid. Insert earphone tips were used in each of the measures to couple the hearing aid/transducer to the ear canal. RESULTS: Mean decibel differences between the test and retest thresholds were less than 1 dB at each frequency. Using an 80% statistical test criterion, results revealed test-retest reliability within 5 dB for all frequencies: 98% at 500 Hz, 100% at 1000 and 2000 Hz, and 93% at 4000 Hz. CONCLUSIONS: Test-retest reliability of in situ unaided thresholds using the SP3/SD-9 device is equivalent to that of currently accepted audiometric procedures.     

Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome

PURPOSE: To determine if rituximab, an anti-CD20 monoclonal antibody, reduces cerebrospinal fluid (CSF) B-cell expansion in opsoclonus-myoclonus syndrome (OMS) and results in clinical improvement. METHODS: Sixteen children with OMS and increased % CD20 B-cells in CSF received 4 rituximab infusions (375 mg/m IV) as add-on therapy to corticotropin (ACTH), intravenous immunoglobulins, or both, and were reevaluated 6 months later. Outcome measures were clinical (motor function, behavior, sleep) and immunologic (CSF and blood immunophenotype and Ig levels). Controls were 16 age-matched and sex-matched children, who did not have OMS. RESULTS: After rituximab, 81% of OMS had a lower motor severity score, and 44% improved one severity category. Mean total score decreased by 44% (P = 0.0005). Rituximab reduced rage score, nighttime awakenings, and the number of children with opsoclonus, action myoclonus, drooling, gait ataxia, and rage. Despite a 51% reduction in ACTH dose, 9 of 11 children on ACTH did not relapse. The percentage of CSF CD19 (and CD20) B-cells was lowered in all children (undetectable in 6), with a 90% reduction in the group mean (P = 0.00003). CSF B-cells were no longer expanded compared with controls. In blood, CD19 B-cells decreased (-90%, P = 0.0003), as did the CSF:blood CD19 B-cell ratio (P = 0.00003). Serum IgM fell by 69% (below reference range), with no statistically significant change in IgG or IgA. CONCLUSIONS: Rituximab seems efficacious and safe as adjunctive therapy for OMS. Selective targeting of CSF B lymphocytes represents a novel and valuable paradigm shift in the therapy for centrally mediated paraneoplastic disorders.     

Cerebral abscess associated with meningococcal meningitis

Purulent fluid collections, including brain abscess and subdural empyema, are exceedingly rare in association with meningococcal meningitis. We present a 5-month-old infant with meningococcal meningitis and sepsis complicated by an intracerebral abscess.     

Kawasaki disease in New Zealand

AIM: To determine the epidemiology, management and outcome of Kawasaki disease (KD) in New Zealand. DESIGN: Prospective audit using New Zealand Paediatric Surveillance Unit (NZPSU) Reports. SETTING: Single country 2-year epidemiological study. Patients: All patients diagnosed with KD in New Zealand reported to the NZPSU from January 2001 to December 2002. MAIN OUTCOME MEASURES: Incidence of KD; time to diagnosis; use of intravenous immunoglobulin; cardiac features and outcome. RESULTS: Forty-nine new cases were identified. The annual incidence was 8.0 cases/100,000 children aged less than 5 years. Age at onset was less than 5 years in 86% of cases. Incidence was 4.6/100,000 for children of European origin, 9.6 for Maori, 12.2 for Pacific Islanders and 32.2 for children of East Asian origin. KD was diagnosed at a median of 6 days from onset of illness. 89% had fever and four or more diagnostic features. All patients had at least one echocardiogram: There was one small (2%) coronary artery aneurysm only; 13 (26%) had mild coronary artery dilatation. Thirty-five per cent did not have an echocardiogram performed four or more weeks from illness onset. 45 (92%) cases received intravenous immunoglobulin at median day six. There was one death due to occlusive coronary artery disease in a 3-month-old boy with atypical symptoms in whom KD was diagnosed at post-mortem. CONCLUSIONS: The incidence of KD in New Zealand is defined with significantly variable risk according to ethnicity. Most patients received appropriate rapid diagnosis and treatment but there was considerable variation in practice in regard to number and timing of echocardiograms. There was a low coronary artery aneurysm rate (2%). Accelerated vaso-occlusive disease was responsible for the single fatality in an atypical case.