Decreased periprosthetic bone loss in patients treated with clodronate: a 1-year randomized controlled study.

The efficacy of clodronate to reduce bone loss around uncemented stems after total hip arthroplasty(THA) was evaluated. Ninety-one patients operated with uncemented THA were randomized to receive either intramuscular clodronate at a dose of 100 mg weekly for 12 months or no treatment. Periprosthetic and contralateral bone mineral density (BMD) scans were performed and biochemical markers of bone turnover measured at baseline and at 3, 6, and 12 months. At month 12, with the exception of Gruen zones 4 and 5, patients treated with clodronate showed less bone loss at all zones, reaching statistical significance (P\0.05) in Gruen zones 2 and 6 (difference of 6.6 and 5.9%, respectively). Analysis of data according to gender revealed sex-related differences in bone loss and efficacy of treatment. After 12 months, the difference in bone loss between treated and untreated women in five out of seven Gruen zones ranged from 6.2 to 13.3% (SS at zones 2 and 6), whereas comparison between treated and untreated men showed no BMD differences in all zones(P[0.05). Median percent changes in serum levels of markers of bone metabolism by gender were consistent with BMD changes. A 1-year treatment with intramuscular clodronate determined a significant reduction of bone loss after THA. This was mainly attributed to its greater efficacy in the female population, which is at higher risk for bone loss. This observation suggests the need for the characterization of high-risk subjects as potential candidates for prevention strategies.

Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas.

The high-affinity folate-binding protein (FBP) is primarily involved in the uptake of the 5-methyltetrahydrofolate, and its expression may be physiologically regulated by the intracellular folate content. The overexpression of FBP on the cell surface of ovarian carcinoma cells may be responsible for an increased folate uptake. We tested the hypothesis of the existence of a defect in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) in ovarian tumours that could cause reduced intracellular regeneration of the 5-methyltetrahydrofolate and induce increased FBP expression. No sequence mutations were found in the MTHFR gene, but allelic deletions of this gene were frequently detected in ovarian tumours (59%). Chromosomal losses appeared to be confined to the 1p36.3 region to which the MTHFR gene maps. Although it cannot be stated that MTHFR is the target gene of the chromosomal loss involving the 1p36.3 region, a correlation between loss of heterozygosity at this locus and decrease in MTHFR activity was shown, suggesting a role of these allelic deletions in generating a biochemical defect in folate metabolism. Further studies are needed to assess further the relationship between MTHFR and FBP overexpression, but the demonstration of the alteration of a key metabolic enzyme of the folate cycle in a subset of human ovarian tumours is in accordance with the hypothesis of an altered folate metabolism in these neoplasias and might be exploited for therapeutic purposes.

Diagnostic and biological determinants in undifferentiated and poorly differentiated ovarian carcinomas.

Six ovarian undifferentiated carcinomas (UCs) and 19 poorly differentiated serous (14 cases) and endometrioid (5 cases) carcinomas with areas of solid diffuse carcinomas have been considered for the study. Pathological findings were analyzed in conjunction with molecular analysis concerning the structure and expression of nm23-H1 gene. Differences in the frequency of loss of heterozigosity (LOH) of this gene have been observed between the two groups, UCs displaying lower percentage of LOH (1/5) as compared to poorly differentiated tumors (17/17). The remaining 3 cases (1 UC and 2 poorly differentiated carcinomas) were homozygotes, i.e., noninformative. UCs might occur as a consequence of cellular dedifferentiation, being at the end of the differentiation spectrum of epithelial ovarian tumors. Nevertheless, this study suggests that, in a fraction of cases, UCs could represent a distinct entity not involved in the malignant progression, associated with peculiar DNA anomalies, one possibly being that of the nm23-H1 deletion. In other words, a noticeable subset of UCs, not harboring nm23-H1 alterations, may be histologically uncommitted "ab initio". Moreover, nm23-H1 LOHs could be considered early events in the ovarian carcinogenesis, because similar molecular patterns were found both in primary and metastatic sites of the same tumor.

Suppressive role of the metastasis-related nm23-H1 gene in human ovarian carcinomas: association of high messenger RNA expression with lack of lymph node metastasis.

The nm23-H1 gene has been proposed as a metastasis suppressor gene. It is located on the long arm of chromosome 17, which is frequently deleted in ovarian cancer, and shows altered expression and structure in some advanced neoplasms. To evaluate the role of nm23-H1 in ovarian carcinogenesis, we have analyzed this gene in 66 primary human ovarian carcinomas at both the DNA and RNA levels. Despite the high frequency (76%) of nm23-H1 loss of heterozygosity (LOH), the complete absence of gene mutations in the coding portions of the retained allele clearly indicated that, in ovarian carcinomas, this gene does not function in the same way as do classic oncosuppressor genes. The relationship of clinicopathological parameters with nm23-H1 gene deletions and expression levels was also investigated. LOHs were more common in the serous and endometrioid histotypes (85 and 93%, respectively), and the highest LOH frequency was detected in poorly differentiated tumors (89%). A significant relationship between nm23-H1 mRNA expression and lymph node metastasis was observed in high-grade tumors, which are intrinsically more invasive than are low-grade tumors. In particular, among the poorly differentiated tumors showing areas of undifferentiated solid carcinoma (classified as G3/G4), lymph node-negative tumors displayed expression levels that were significantly higher than those of lymph node-positive tumors (P < 0.001). In conclusion, our data suggest that the nm23-H1 gene product may exert an inhibitory effect on the lymphatic dissemination of human ovarian tumors. However, several other factors, biological or time and patient dependent, influence the complex metastatic progression of ovarian tumors and may cooperate with nm23-H1 in the promotion or inhibition of this process.