Objective responses in patients with malignant melanoma or renal cell cancer in early clinical studies do not predict regulatory approval.

PURPOSE: Tumor responses in early-phase trials are used to determine whether new agents warrant further study. Given that spontaneous regressions are observed in melanoma and renal cell carcinoma, this study assessed whether tumor responses, particularly in these two tumor types, predict for future regulatory drug approval. EXPERIMENTAL DESIGN: The literature was reviewed to assess tumor response rates to cytotoxic agents in phase I and II trials in the following solid tumors: melanoma, renal cell carcinoma, non-small-cell lung cancer, breast cancer, ovarian cancer, colorectal cancer, and other solid tumors. Response rates were categorized and the relationship of these categories to the end point of regulatory drug approval was determined. RESULTS: Fifty-eight drugs were assessed in 100 phase I trials, and 46 of these drugs were also studied in 499 phase II trials. Higher overall response rates in both phase I trials (P = 0.03) and phase II trials (P < 0.0001) were predictive of regulatory approval. However, response in melanoma or renal cell carcinoma was not predictive for either phase I or phase II studies. CONCLUSIONS: For cytotoxic agents, although overall objective response rates reliably predict subsequent marketing approval, isolated responses in melanoma and renal cell carcinoma are not predictive.     

P-fimbriae vaccines

To test for cross-protective capacity of two different P-fimbriae vaccines we vaccinated baboons with fimbriae purified from either Escherichia coli strain ER2 or strain JR1. The vaccinated animals showed elevated antibody titers to P-fimbriae from each of the E. coli strains used, suggesting cross-reactivity as was expected from the results of immunoprecipitation of the fimbriae. Enzyme-linked immunosorbent assay inhibition by heterologous P-fimbriae proved this to be true immunologic cross-reactivity.     

The phylogeny of howler monkeys (Alouatta, Platyrrhini): Reconstruction by multicolor cross-species chromosome painting

We performed multidirectional chromosome painting in a comparative cytogenetic study of the three howler monkey species Alouatta fusca, A. caraya and A. seniculus macconnelli (Atelinae, Platyrrhini) in order to reconstruct phylogenetic relationships within this genus. Comparative genome maps between these species were established by multicolor fluorescence in-situ hybridization (FISH) employing human, Saguinus oedipus and Lagothrix lagothricha chromosome-specific probes. The three species included in this study and previously analyzed howler monkey species were subjected to a phylogenetic analysis on the basis of a data matrix comprised of 98 discrete molecular cytogenetic characters. The results revealed that howler monkeys represent the genus with the most extensive karyotype diversity within Platyrrhini so far analyzed with high levels of intraspecific chromosomal variability. Two different multiple sex chromosome systems were identified. The phylogenetic analysis indicated that Alouatta is a monophyletic clade which can be derived from a proposed ancestral Atelinae karyotype of 2n=62 chromosomes by a chromosome fusion, a fission, a Y-autosomal translocation and a pericentric inversion. Following these suggestions, the genus Alouatta can be divided into two distinct species groups: the first includes A. caraya and A. belzebul, the second A. s. macconnelli, A. sara, A. s. arctoidea and A. fusca.     

Treatment of a juvenile patient with a maxillary all-ceramic resin-bonded fixed partial denture: a case report.

Treatment of juvenile patients with a missing maxillary incisor is difficult, because an implant cannot be placed until growth is completed. The other minimally invasive alternatives are also problematic: Removable dentures are rarely accepted by juvenile patients, and the conventional resin-bonded fixed partial denture often provides a poor esthetic result because the metal retainer causes the abutment teeth to lose their natural translucency and to become grayish. Moreover, the alveolar ridge defect makes it easy to identify the prosthesis in the pontic area. The present case report describes the prosthetic treatment of a juvenile patient who had lost a maxillary incisor to trauma. To avoid the disadvantages of conventional therapies, subepithelial connective tissue was grafted to reshape the alveolar ridge. The space was closed with an all-ceramic resin-bonded fixed partial denture.     

Syntactic language processing: ERP lesion data on the role of the basal ganglia.

The role of the basal ganglia in syntactic language processing was investigated with event-related brain potentials in fourteen neurologically impaired patients. Seven of these patients had basal ganglia lesions while 7 other patients primarily had lesions of the left temporo-parietal region excluding the basal ganglia. All patients listened to sentences that were either correct or included a verb argument structure violation. In previous experiments this type of violation elicited a biphasic pattern of an N400-P600 complex in young healthy participants. While the N400 may result from incorrect semantic-thematic role assignment, the P600 reflects the fact that verb information does not license the syntactic structure at present. Results of the patient experiment revealed a double dissociation: patients with left temporo-parietal lesions only show a P600, whereas patients with lesions of the basal ganglia showed no P600, but a negativity with extended duration that resembled an N400. The latter pattern not only confirms previous reports that the basal ganglia modulate the P600 but extends these results by showing that the N400 as a late semantic-thematic integration process appears partially modulated by the basal ganglia.     

Transferrin Phenotype and Level of Carbohydrate-deficient Transferrin in Healthy Individuals

Elevated concentrations of carbohydrate-deficient components of transferrin (CDT) in serum may be used as a sensitive and specific marker of regular, high alcohol consumption. When determined by a new, simplified assay, CDT values are nearly normally distributed in low- or non-alcohol-consuming control populations. The importance of transferrin phenotype for this normal variation was analyzed in 100 healthy, European men and women with no or negligible alcohol intake. No significant relation was found between phenotype and CDT value in this population. The three rare B-variants found had low CDT levels, and one subject, examined outside the study, with a rare D-variant indicated that D-variants may result in false-positive CDT values. Moreover, women tended to have somewhat higher values than men, in whom CDT levels were weakly correlated with age. Other as yet undefined biological factors are clearly responsible for the major part of the normal variation of CDT values in nonalcoholic individuals.     

A new immune-competent animal model of mucosally derived squamous cell carcinoma.

OBJECTIVES: To develop an immune-competent animal model for mucosally derived squamous cell carcinoma (SCCA). STUDY DESIGN: Fifteen Fischer 344 rats were inoculated with 1, 2, 5, 10, or 20 x 10(6) FAT7 cells in their flanks. The animals were observed for tumor growth and metastasis. RESULTS: All animals developed tumors that grew exponentially. Pulmonary metastases developed in all animals and 13% developed lymph node metastases. CONCLUSION: The FAT7 flank tumor in Fischer 344 rats is a new animal model that closely resembles the behavior of human mucosal head and neck cancer. SIGNIFICANCE: The existence of an immune-competent, mucosally derived, and reliable animal model of SCCA that somewhat resembles human head and neck SCCA gives the opportunity to perform immune-modulating experiments on head and neck cancer in these animals. EBM rating: B-3.