An evaluation of methods used in health technology assessments produced for the Medical Services Advisory Committee.

OBJECTIVE: To examine the methods used in health technology assessments (HTAs) produced for the Medical Services Advisory Committee (MSAC) reviewing the effectiveness of a technology or procedure. DESIGN AND SETTING: Data were extracted from the effectiveness section of HTA application assessment reports published between 1 January 1998 and 17 July 2006 and available on the MSAC website. Only HTAs of effectiveness interventions were examined, as the methods used to undertake such reviews are well established. MAIN OUTCOME MEASURES: Variables reflecting methods used in the HTAs to evaluate the effectiveness of health technologies or procedures. RESULTS: Of 56 MSAC HTA reports available, 31 met the inclusion criteria. Considerable variability was shown to exist between the various indicators of quality and the methodology used within the HTAs. Reports did not describe potential conflicts of interest of participants. The majority of reports (19/31) did not formally state the research question that the assessment was attempting to answer. Just over half of the reports (18/31) provided details of validity assessment of the included studies. CONCLUSIONS: Minimum and consistent standards of methodology and reporting are required in Australian HTAs, using international recommendations of best practice to increase the transparency and applicability of these reports.

Mutation analysis of CDP, TP53, and KRAS in uterine leiomyomas.

Leiomyomas are the most common gynecologic tumors in women, but very little is known about their molecular pathology. We used single-stranded conformational polymorphism/heteroduplex analysis to analyze 42 unselected uterine leiomyomas for somatic mutations in all coding exons of the gene encoding CCAAT displacement protein (CDP), as well as exons 5-8 of TP53 and codons 1-36 and 38-80 of KRAS. No somatic mutations were identified in either TP53 or KRAS, indicating that disregulation of these genes is not required for leiomyomas development. Aberrant band shifts were identified in CDP, but these were all germline nonpathogenic variants that have been reported previously. There is good functional and genetic evidence indicating that CDP is a leiomyoma suppressor, but our data suggested that somatic mutations in this gene were rare in unselected uterine leiomyomas. It is possible that CDP belongs to a class of tumor suppressor in which loss of only one copy of the gene, either by genetic or epigenetic mechanisms, is sufficient to allow tumor growth.

Mutation analysis of EP300 in colon, breast and ovarian carcinomas.

The putative tumour suppressor gene EP300 is located on chromosome 22q13 which is a region showing frequent loss of heterozygosity (LOH) in colon, breast and ovarian cancers. We analysed 203 human breast, colon and ovarian primary tumours and cell lines for somatic mutations in EP300. LOH across the EP300 locus was detected in 38% of colon, 36% of breast, and 49% of ovarian primary tumours but no somatic mutations in EP300 were identified in any primary tumour. Analysis of 17 colon, 11 breast, and 11 ovarian cancer cell lines identified truncating mutations in 4 colon cancer cell lines (HCT116, HT29, LIM2405 and LIM2412). We confirmed the presence of a previously reported frameshift mutation in HCT116 at codon 1699 and identified a second frameshift mutation at codon 1468. Bi-allelic inactivation of EP300 was also detected in LIM2405 that harbours an insC mutation at codon 927 as well an insA mutation at codon 1468. An insA mutation at codon 1468 was identified in HT29 and a CGA>TGA mutation at codon 86 was identified in LIM2412. Both these lines were heterozygous across the EP300 locus and western blot analysis confirmed the presence of an apparently wild-type protein. Our study has established that genetic inactivation of EP300 is rare in primary colorectal, breast and ovarian cancers. In contrast, mutations are common among colorectal cancer cell lines with 4/17 harbouring homozygous or heterozygous mutations. The rarity of EP300 mutations among these tumour types that show a high frequency of LOH across 22q13 may indicate that another gene is the target of the loss. It is possible that bi-allelic inactivation of EP300 is not necessary and that haploinsufficiency is sufficient to promote tumorigenesis. Alternatively, silencing of EP300 may be achieved by epigenetic mechanisms such as promoter methylation.