Laryngeal dysplasia: a long-term follow-up study.

PURPOSE: To assess the progression of precancerous laryngeal lesions to squamous cell carcinoma (SCC), defined by specific histopathological criteria, in patients with longterm follow-up. METHODS: Patients with laryngeal dysplasia, followed/ treated between 1985 and 2008, were retrospectively evaluated and classified according to the World Health Organization classification system (WHO). The investigated outcome parameters were progression of dysplasia to SCC, time interval to malignant transformation and continuation of smoking as potential risk factors. RESULTS: Fifty-nine patients were studied. Progression of dysplasia to SCC between the first and the final histological examination was statistically significant (p<0.0001). Malignant transformation appeared in 29 patients (49.2%). Serious dysplasia was more likely to progress to SCC (64.8%) compared to mild (41.7%) or moderate (44.4%) (p<0.0001). However, the time interval needed in these 29 cases to progress to cancer was not statistically related to the initial histological diagnosis. Continuation of smoking did not affect the progression of disease. However, the mean time from dysplasia to laryngeal cancer was much longer in patients who quitted smoking (33.5 months) vs those who continued smoking (19.5 months), with a marginal statistical difference (p=0.057). CONCLUSION: All patients with laryngeal dysplasia should be followed up at regular intervals. The progression of dysplasia to SCC did not seem to be directly related to the continuation of smoking or not. However, large long-term follow- up studies taking into account the degree of exposure (e.g. time of exposure, number of cigarettes) are needed in order to clarify risk factors and proper management. Consensus guidelines in diagnosis, follow-up, and treatment would improve substantially the current clinical practice.

Hyperalgesia due to nerve damage: role of nerve growth factor.

The hypothesis that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contribute to hyperalgesia resulting from nerve damage was tested in rats in which the sciatic nerve was partially transected on one side. Administration of antisera raised against NGF and BDNF relieved mechanical and thermal hyperalgesia in these animals. It has been suggested that NGF may elicit hyperalgesia by inducing mast cells to release algesic agents such as serotonin (5-HT). We found that degranulation of mast cells with compound 48/80 relieved mechanical and thermal hyperalgesia produced by nerve damage. We also found that local injection of the 5-HT2A and 5-HT3 receptor antagonists ketanserin and ICS 205-930 into the affected hind paw relieved mechanical hyperalgesia in a dose-dependent fashion. These findings support the idea that in this rat model of hyperalgesia due to peripheral nerve damage, NGF acts on mast cells to induce release of 5-HT, which sensitizes nociceptors. Hyperalgesia due to nerve injury and hyperalgesia due to inflammation may share some common features.

Cell cycle regulation of the human DNA mismatch repair genes hMSH2, hMLH1, and hPMS2.

Hereditary nonpolyposis colorectal cancer is a cancer susceptibility syndrome that has been found to be caused by mutations in any of several genes involved in DNA mismatch repair, including hMSH2, hMLH1, or hPMS2. Recent reports have suggested that hMSH2 and hMLH1 have a role in the regulation of the cell cycle. To determine if these genes are cell cycle regulated, we examined their mRNA and protein levels throughout the cell cycle in IMR-90 normal human lung fibroblasts. We demonstrate that the levels of hMSH2 mRNA and protein do not change appreciably throughout the cell cycle. Although hMLH1 mRNA levels remained constant, there was a modest (approximately 50%) increase in its protein levels during late G1 and S phase. The levels of hPMS2 mRNA fluctuated (decreasing 50% in G1 and increasing 50% in S phase), whereas hPMS2 protein levels increased 50% in late G1 and S phase. Our data indicate that, at least in normal cells, the machinery responsible for the detection and repair of mismatched DNA bases is present throughout the cell cycle.