Does Follow-up of Osteoporotic Women Treated with Antiresorptive Therapies Improve Effectiveness?

The use of biochemical markers of bone turnover has been advocated to improve follow-up of women receiving antiresorptive therapies for osteoporosis, but this strategy is not yet supported by trials showing it improves effectiveness of treatments. To explore the potential value of markers of bone turnover to monitor antiresorptive treatments of osteoporosis, we conducted a decision analysis using a decision tree and Markov modeling. We have compared two strategies: treatment of a woman without specific monitoring; and treatment of this woman with measurement of a serum marker of bone resorption after 3 months of treatment, with change of treatment if response to treatment assessed by this marker was not satisfactory. The base case is the treatment of a 60-year-old osteoporotic woman with a total hip T-score of −3, using a second generation bisphosphonate during 5 years. We found that follow-up produced slightly greater quality adjusted life years (QALYs) than no follow-up (8.1560 vs 8.1532, i.e. a one day difference). In a two-way sensitivity analysis, the follow-up option produced higher QALYs so long as adherence rate with follow-up was equal or superior to the proportion of women who adhered without follow-up. For example, if the proportion of women adherent to treatment was increased from 50% to 60% by follow-up, then the expected value of the follow-up branch was increased from 8.1560 QALYs to 8.1800 QALYs (i.e. a difference of 9 days). In addition, the higher the non-response rate, the greater the benefit from monitoring with a biochemical marker. In conclusion, our decision analysis model suggests that follow-up of osteoporotic women treated with a second generation bisphosphonate during a 5-year period using an early measurement of a serum marker of bone resorption may increase effectiveness of the treatment on quality of life, but the effect is very small. So, the use of follow-up measures of bone turnover may be based on patient and physician preferences. Received: 6 July 2001 / Accepted: 1 April 2002     

20q13.2 Amplification in intraductal hyperplasia adjacent to in situ and invasive ductal carcinoma of the breast

The 20q13 region harboring recently described putative oncogenes is frequently amplified in invasive ductal carcinoma (IDC). The aim of this study was to examine the 20q13 copy number in intraduct hyperplasia (IH), atypical duct hyperplasia (ADH), and ductal carcinoma in situ (DCIS) adjacent to IDC. In 5 patients, comparative genomic hybridization (CGH) after laser microdissection revealed 20q13 amplification in four of five cases of IH, in all of three cases of IH with atypia, all five of DCIS, and all five of IDC. Fluorescence in situ hybridization (FISH) confirmed the amplification at 20q13.2 in IH in the two specimens analyzed. The amplification rate, however, was higher in DCIS and IDC. In phenotypically normal ductal epithelium normal values were found for 20q13 copy number by FISH (n=2) and CGH (n=5). Although the number of cases presented here is small, our results suggest that mutations in the 20q13.2 region in IH may be associated with accelerated proliferation and hyperplasia of the ductal epithelium. Progression to DCIS and ICD is accompanied by a further increase in the 20q13.2 copy number. Received: 17 March 1999 / Accepted: 22 June 1999     

Development of Duchenne-type cardiomyopathy. Morphologic studies in a canine model.

The development of cardiac lesions was studied in xmd dogs aged from 1 day to 6 years. Cardiac lesions were not present in dystrophic dogs up to 3 months of age. Foci of mineralization were first seen at 6.5 months. A 1-year-old dog had foci of myocyte hypercontraction. Linear and anastomosing fibrosis was present in all dogs 1 year of age or older, most prominently and most consistently within the subepicardial region of the left ventricular (LV) free wall, the LV papillary muscles, and the right ventricular (RV) aspect of the septum. Ultrastructurally, endomysial fibrosis, decreased myofibrillar density, and prominence of mitochondria were consistent features. Severe degenerative changes were present in two dogs and included prominent intracytoplasmic myelin figures, lipid droplets, and lipofuscin. Immunocytochemical studies of an affected dog confirmed the absence of dystrophin in LV myocardium. Characteristic late-onset cardiac lesions, similar to those occurring in Duchenne dystrophy, are a consistent feature of canine X-linked muscular dystrophy (CXMD).     

Characterisation of a subtype of colorectal cancer combining features of the suppressor and mild mutator pathways

BACKGROUND: 10% of sporadic colorectal cancers are characterised by a low level of microsatellite instability (MSI-L). These are not thought to differ substantially from microsatelite-stable (MSS) cancers, but MSI-L and MSS cancers are distinguished clinicopathologically and in their spectrum of genetic alterations from cancers showing high level microsatellite instability (MSI-H). AIMS: To study the distribution of molecular alterations in a series of colorectal cancers stratified by DNA microsatellite instability. METHODS: A subset of an unselected series of colorectal cancers was grouped by the finding of DNA MSI at 0 loci (MSS) (n = 51), 1-2 loci (MSI-L) (n = 38) and 3-6 loci (MSI-H) (n = 25). The frequency of K-ras mutation, loss of heterozygosity (LOH) at 5q, 17p and 18q, and patterns of p53 and beta catenin immunohistochemistry was determined in the three groups. RESULTS: MSI-H cancers had a low frequency of K-ras mutation (7%), LOH on chromosomes 5q (0%), 17p (0%) and 18q (12.5%), and a normal pattern of immunostaining for p53 and beta catenin. MSI-L cancers differed from MSS cancers in terms of a higher frequency of K-ras mutation (54% v 27%) (p = 0.01) and lower frequency of 5q LOH (23% v 48%) (p = 0.047). Whereas aberrant beta catenin expression and 5q LOH were concordant (both present or both absent) in 57% of MSS cancers, concordance was observed in only 20% of MSI-L cancers (p = 0.01). CONCLUSIONS: MSI-L colorectal cancers are distinct from both MSI-H and MSS cancers. This subset combines features of the suppressor and mutator pathways, may be more dependent on K-ras than on the APC gene in the early stages of neoplastic evolution, and a proportion may be related histogenetically to the serrated (hyperplastic) polyp.     

Processing of radical prostatectomy specimens for correlation of data from histopathological, molecular biological, and radiological studies: a new whole organ technique

AIMS: To develop a method of processing non-formalin fixed prostate specimens removed at radical prostatectomy to obtain fresh tissue for research and for correlating diagnostic and molecular results with preoperative imaging. METHODS/RESULTS: The method involves a prostate slicing apparatus comprising a tissue slicer with a series of juxtaposed planar stainless steel blades linked to a support, and a cradle adapted to grip the tissue sample and receive the blades. The fresh prostate gland is held in the cradle and the blades are moved through the cradle slits to produce multiple 4 mm slices of the gland in a plane perpendicular to its posterior surface. One of the resulting slices is preserved in RNAlater. The areas comprising tumour and normal glands within this preserved slice can be identified by matching it to the haematoxylin and eosin stained sections of the adjacent slices that are formalin fixed and paraffin wax embedded. Intact RNA can be extracted from the identified tumour and normal glands within the RNAlater preserved slice. Preoperative imaging studies are acquired with the angulation of axial images chosen to be similar to the slicing axis, such that stained sections from the formalin fixed, paraffin wax embedded slices match their counterparts on imaging. CONCLUSIONS: A novel method of sampling fresh prostate removed at radical prostatectomy that allows tissue samples to be used both for diagnosis and molecular analysis is described. This method also allows the integration of preoperative imaging data with histopathological and molecular data obtained from the prostate tissue slices.     

Basic isoferritin and hypercalcaemia in renal cell carcinoma

A 63-year-old man with iron loss anaemia and hypercalcaemia was found to have a renal cell carcinoma. Despite the iron-deficient blood and bone marrow picture, the serum ferritin concentration was markedly raised. This was mainly due to a “basic isoferritin”. The serum parathormone concentration was normal. The serum ferritin and calcium concentrations returned to normal after the tumour was removed. We propose that the renal cell carcinoma cells in this patient secreted the basic isoferritin as well as humoral factor(s) responsible for hypercalcaemia.