Cowden syndrome and Lhermitte-Duclos disease.

BACKGROUND. Cowden syndrome (CS) is a rare but underdiagnosed autosomal dominant condition also known as "multiple hamartoma-neoplasia syndrome." Patients have multiple tricholemmomas (a type of benign skin appendage tumor) and oral papillomatosis and cutaneous keratoses. They often have goiter, gastrointestinal polyps, and hamartomatous soft tissue lesions. Breast cancer affects approximately one third of women with CS. Lhermitte-Duclos disease (LDD) is a peculiar proliferation of abnormal neuronal elements of the cerebellum that has features of a hamartoma and of a neoplasm. METHODS. The authors described two patients who have both CS and LDD. Also reviewed were 50 of approximately 62 previously described cases of LDD (identified through literature searches) in an effort to find patients with LDD who had other associated lesions. RESULTS. Only one other patient in whom both LDD and CS were recognized has been reported. In addition, a number of patients with LDD who had other neoplasms and/or thyroid lesions have been described. CONCLUSIONS. Given the rarity of these two entities, we believe that their association is not fortuitous. LDD fits into the concept of CS as a hamartoma-neoplasia syndrome. In addition, a number of patients with LDD who had other neoplasms or thyroid lesions have been reported, raising the possibility that CS and LDD are more closely linked than is generally appreciated. We suspect that there are more patients with LDD who have unrecognized CS. Patients with either of the two diseases should be examined and followed up for evidence of the other.     

Chemoelectronic mobilization of chemical species in low-conductivity fluids: new electrokinetic effect.

An electrokinetic phenomenon is reported here which differs from its classical counterparts most distinctively by nonlinear conductivity and mobility. Neither purely electrolytic nor electrostatic in nature, this phenomenon is presumed to involve subtle charge transfer effects and association reactions permitting a controlled "chemoelectric" mobilization. In its electrokinetic manifestation, this phenomenon can be used to mobilize chemical species commonly with migration rates orders of magnitude greater than can be achieved electrophoretically and is shown to induce the movement of nonpolar molecules, such as aromatic hydrocarbons, at rates exceeding several centimeters per minute in easily achievable voltage gradients. The operational technique, developed as a separations method used for demonstrating the effect, is called "electromolecular propulsion".     

Zeniplatin in advanced malignant melanoma and renal cancer: phase II studies with unexpected nephrotoxicity

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m² every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade ≥ 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade ≥ 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn. Received: 16 March 1996 / Accepted: 25 March 1997     

Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials.

PURPOSE: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype. CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.     

Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.     

Both HCV and HBV are Major Causes of Liver Cancer in Southeast Asians

The incidence of hepatocellular carcinoma (HCC) is higher in Asian Americans than in other ethnicities. While hepatitis B virus (HBV) is common, hepatitis C virus (HCV) is more prevalent in some subgroups. Our goal was to determine the etiology of liver disease associated with HCC in subgroups of Asian Americans. This was an analysis of 510 Asian HCC patients at a US medical center. Patients were identified using ICD9 diagnosis. Multivariate logistic regression was used to study predictors of HCV as the cause of HCC. Patients were Southeast Asian, Chinese, and Korean, with similar gender, age, and foreign-born status. Southeast Asians had a similar proportion of HBV- and HCV-related HCC, while Chinese and Korean patients had a higher proportion of HBV-related HCC. HCC was usually associated with HBV in Chinese and Korean patients, but both HCV and HBV were important associations in Southeast Asians.