Chylothorax in a child with rifampicin-resistant tuberculosis.

Chylothorax is rare in children. Only a few cases of tuberculosis (TB)-associated chylothorax have been reported. We present a child on standard four-drug TB treatment who presented with wheezing and a chylothorax. Bronchoscopy showed caseating lymph nodes, and rifampicin-resistant TB was identified from the bronchoalveolar lavage specimen. There was marked clinical and radiological improvement 1 month after starting multidrug-resistant (MDR) TB treatment and steroids. The association of chylothorax and MDR-TB has not been described in children. MDR-TB should be considered in children who fail adherent, empirically started drug-susceptible TB treatment.

A randomized phase II study comparing capecitabine alone with capecitabine and oral cyclophosphamide in patients with advanced breast cancer-cyclox II.

BACKGROUND: Capecitabine and cyclophosphamide are active in patients with advanced breast cancer, have non-overlapping toxic effects and synergy pre-clinically. We explored the efficacy and toxic effect of an all-oral combination of capecitabine with cyclophosphamide versus capecitabine alone in a multicentre, randomized, phase II study. PATIENTS AND METHODS: Patients with locally advanced or metastatic breast cancer were randomized to treatment with capecitabine given continuously (666 mg/m(2) b.i.d. days 1-28) alone (C) or with oral cyclophosphamide (100 mg/m(2) days 1-14 of a 28-day cycle) (CCy) for up to six cycles. RESULTS: Eighty-two patients were randomized. There was no complete response. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% [95% confidence interval (CI) -13.4 to 29.1]. Significant toxic effect was uncommon: grade ≥3 diarrhoea in 4 (10%) versus 1 (3%) patients; grade ≥3 fatigue in 2 (5%) versus 5 patients (13%) and grade ≥2 hand-foot syndrome in 7 (17%) versus 11 (28%) patients receiving C versus CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy, not significantly different statistically. There was no difference in overall survival. CONCLUSION: The difference in tumour response suggests a reasonable chance that CCy is superior to C alone.

Triple negative breast cancer in a male-to-female transsexual.

There is limited published literature on the risk of breast cancer in transgender patients. We report a case of an aggressive triple negative inflammatory breast cancer in a male-to-female transsexual. This patient had a complicated psychiatric history with significant antipsychotic use, and the case raises several questions about the pathogenesis of this breast cancer. The literature on breast cancer in transgender patients and in relation to hyperprolactinaemia is reviewed.

Expression and integrity of DNA topoisomerase II isoforms does not explain generic drug resistance in malignant mesothelioma.

PURPOSE: Malignant mesothelioma is a tumour that is highly resistant to a number of different chemotherapy agents, yet the mechanisms by which resistance occurs are poorly understood. The pattern of resistance is consistent with disruption of topoisomerase function or expression. Coupled with this, we have previously noted a common serological reaction to the beta isoform of topoisomerase II, suggesting that it may be aberrantly expressed in patients with mesothelioma. METHODS: We assessed the expression of topoisomerase II isoforms in sections of primary tumour. We tested a panel of five mesothelioma cell lines for sensitivity to the known topoisomerase-targeting drugs, doxorubicin and etoposide. We sequenced expressed segments of the topoisomerase genes from these cell lines that have previously been associated with drug resistance. We then investigated other potential resistance mechanisms. RESULTS: We found that the beta isoform of topoisomerase II was more frequently expressed in primary tumours. Only one of the five cell lines was highly resistant to etoposide and this cell line was found to have a point mutation in the gene for topoisomerase IIalpha. Protein levels of topoisomerase IIalpha and beta did not correlate with sensitivity to either doxorubicin nor to etoposide. Semiquantitative analysis suggested that there was marked variation in the levels of mRNA expression of MRP, gamma-GCS and MDR1. None of these findings could be associated with resistance to chemotherapy. CONCLUSION: We conclude that mutations in topoisomerase IIalpha can be associated with extreme resistance of mesothelioma to etoposide. The generic drug resistance of this tumour requires further investigation.

Carboplatin AUC8 in combination with etoposide and bleomycin in the treatment of intermediate and poor-risk metastatic germ cell tumours: a phase II study.

PURPOSE: Carboplatin has demonstrated significantly poorer response rates in non-seminomatous germ cell tumours. A phase II study of higher than standard doses of carboplatin was conducted because of suspicion that the poorer response might have been due to suboptimal dosing. PATIENTS AND METHODS: A group of 19 patients with advanced germ cell tumours (International Germ Cell Cancer Collaborative Group intermediate and poor prognosis) were treated with carboplatin at an AUC of 8 mg/ml.min (using Calvert's formula) on day 1, etoposide 120 mg/m2 days 1-3 and bleomycin 60,000 U over 2 days (EBCa). Treatment was repeated every 3 weeks and a maximum of four courses was given. RESULTS: Of the 19 patients, 7 (37%) achieved complete remission, of whom 6 (32%) remained long-term progression-free. Post-chemotherapy surgery and further chemotherapy salvaged an additional 26%, leading to an overall disease-free survival rate of 58%. No relationship between outcome and degree of myelosuppression could be established. CONCLUSION: Dose-escalated carboplatin in combination, although feasible, did not improve the results and led to poorer results than those expected with cisplatin-based therapy. There is no evidence that the patients relapsing following this were easier to salvage. Further investigation of this regimen cannot be recommended.

p53 autoantibodies in patients with malignant mesothelioma: stability through disease progression.

Malignant mesothelioma (MM) generally occurs as a pleural tumour, related to the inhalation of asbestos fibres. It is highly aggressive and largely unresponsive to treatment. The incidence of MM is particularly high in Western Australia because of the extensive blue asbestos mining operations that occurred in the north of the state until 1966. MM is unusual in that mutations in the tumour suppressor gene p53 are rarely observed, whilst over-expression of p53 protein is common. As the level of antibodies directed against p53 is thought to be of prognostic value in some cancers and as MM is known to be immunogenic, we studied a cohort of Western Australian patients to determine the prevalence of anti-p53 antibodies and their value as diagnostic markers or prognostic indicators. 6/88 (7%) of patients had high titres (>2 SD above the mean of controls) of anti-p53 antibodies. There was no correlation between antibody titre and survival. Although 3/38 (8%) of sera obtained from patients exposed to asbestos but prior to a diagnosis of MM contained antibodies, the same proportion of sera obtained from patients exposed to asbestos but who remained disease free also contained antibodies (2/40; 8%). Sera collected sequentially demonstrated a profound temporal stability in the titre of anti-p53 antibodies in patients with MM throughout the course of their illness. These results show that anti-p53 antibodies are observed only at a low frequency in the sera of MM patients and where they do occur, their elicitation is an early event that may be unrelated to antigen load. The occurrence of anti-p53 antibodies does not serve as either a useful prognostic or diagnostic indicator in MM.

Response rates of Victorian general practitioners to a mailed survey on miscarriage: randomised trial of a prize and two forms of introduction to the research.

AIMS: To identify whether the form of introduction to a study and knowledge of a substantial prize influence the response rate of general practitioners (GPs) to a postal survey. METHODS: A postal survey of 700 randomly selected Victorian GPs concerning management of early pregnancy bleeding and miscarriage, incorporating two randomised-controlled trials of recruitment methods; analysis of response rates and costs at 4 weeks and 11 weeks. RESULTS: The response rate was 61.5% of eligible participants. Doctors made aware of a prize were more likely to respond in the first four weeks (difference in response rate 10.2%, 95% confidence interval (CI) 2.8%-17.6%). This difference diminished after the first four weeks. Doctors introduced to the survey by a telephone call were no more likely to respond than those introduced by a postcard. The use of a postcard saved 73% of the cost of introducing the survey by telephone. Female doctors were more likely than males to reply (difference 12.3%, 95% CI 4.7%-19.9%). Rural doctors were no more likely to reply than urban doctors. Very few doctors (16.2%) completed a Practice Assessment activity associated with the survey. CONCLUSIONS: A valuable prize will accelerate response to a survey by GPs, thereby reducing the costs of follow-up. The cost of telephoned introductions is not justified, when compared with a brief written introduction.

Simian virus (SV) 40 like sequences in cell lines and tumour biopsies from Australian malignant mesotheliomas.

BACKGROUND: Simian virus (SV) 40 sequences have been found in some, but not all studies of mesotheliomas. This virus is known to cause tumours in rodents but its role in human oncogenesis remains controversial. AIMS: The aim of this study therefore was to determine whether SV40 is associated with the development of mesotheliomas in Australia. The absence of the virus or its gene products in tissue derived from mesotheliomas would detract from this possibility. METHODS: We used polymerase chain reaction from three pairs of primers to amplify different regions of the large T antigen from DNA from cell lines and cDNA from both cell lines and an independent set of tumour biopsies from patients with mesothelioma. RESULTS: We examined five human mesothelioma cell lines that were established in our laboratories. In addition, we examined several tumour biopsies from seven different patients. SV40 like sequences were present in all the cell lines and in at least one sample from each of the patients examined. CONCLUSIONS: The large T antigen of SV40 or an SV40 like virus is expressed in Australian mesotheliomas and therefore could be aetiologically-associated with tumourigenesis. Alternatively, these sequences could be expressed subsequent to the development of the disease.

New chemotherapeutics in malignant mesothelioma: effects on cell growth and IL-6 production.

PURPOSE: The benefits of chemotherapy can be assessed in terms of tumour shrinkage, prolongation of life or simply palliation of symptoms. In the study reported here, in vitro correlates of these parameters were sought as a rational guide to the choice of newer agents in the clinic. METHODS: The cytotoxicity and effects on IL-6 production of ten chemotherapy agents representing four different classes of drugs were tested against a panel of five mesothelioma cell lines. RESULTS: The mesothelioma cells were more sensitive to the action of irinotecan (and its active metabolite SN38) and gemcitabine than the control cell lines. Gemcitabine and to a lesser extent irinotecan inhibited the secretion of the proinflammatory cytokine IL-6 at concentrations of each drug that produced only small decreases in cell viability. This effect was not seen in cells treated with docetaxel or vindesine. Higher doses of gemcitabine and irinotecan caused a surge in IL-6 release and this was not due to release of intracellular stores of IL-6 through lysis of the cells. CONCLUSIONS: These results suggest that irinotecan and gemcitabine are not only more likely to be active against mesothelioma than other new chemotherapy agents but may also produce a palliative effect in nonresponders to these agents by decreasing the secretion of IL-6.

Systemic lupus erythematosus-associated lymphoproliferative disorder: report of a case and discussion in light of the literature.

A case of autoimmune disease-associated lymphadenopathy (ADAL) with histological, immunophenotypic, Epstein-Barr virus (EBV) in situ hybridization, and genotypic analyses is presented. The patient had a well-documented history of systemic lupus erythematosus (SLE) and was found at autopsy to have massive lymphadenopathy, thymic enlargement, pulmonary nodules, and polyclonal serum dysproteinemia. Histological examination revealed a polymorphous lymphoid infiltrate containing many plasma cells, rare immunoblasts, and a pronounced arborizing vasculature. No foci of necrosis were found and there was no evidence of lymphocyte depletion. The plasma cells were immunophenotypically polyclonal and no EBV mRNA (EBER-1) or gene rearrangements were identified. The unusual gross features, which resembled a malignant lymphoproliferative process, as well as the unusual histological features make this case a notable addition to the spectrum of atypical lymphoproliferative disorders associated with an autoimmune disorder. We conclude that although reminiscent of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), this case lacks the diagnostic features of AILD, and is, perhaps, best classified as an autoimmune disease-associated lymphadenopathy (ADAL).

Renal failure in Arnhem Land: missed opportunities for prevention and treatment.

This is a brief clinical description of a group of people from an Arnhem Land community with a population of about 1500. The community has five people on full-time dialysis in Darwin, about 400 km away, and another four people who are being actively prepared for dialysis. Of these nine people, three come from within two generations of one clan: that is, from a group of about 40. This apparent family tendency is one of many factors producing kidney disease in Northern Territory Aboriginal people, who suffer extreme rates of end-stage renal failure (ESRF). Our understanding of these causes is quite embryonic. Despite several years of lobbying by Aboriginal health organisations the Northern Territory government has no coherent plans for ongoing prevention and management of kidney problems, and no services outside the main urban centres. The issues involved are discussed from the perspective of our bush clinic, kilometres away from renal biopsies and formal clinical research.