Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.      

Composite carcinoma-carcinoid tumors of the gastrointestinal tract. A morphologic, histochemical, and immunocytochemical study

A morphologic, histochemical, and immunocytochemical study of 20 cases of pure gastrointestinal carcinoids, adenocarcinomas, and mixed neoplasms composed of both elements, so-called composite carcinoma-carcinoid tumors (CCC), was undertaken in order to correlate the morphologic patterns with the immunocytochemical localization of carcinoembryonic antigen (CEA), serotonin, and a battery of polypeptide hormones (calcitonin, glucagon, insulin, gastrin, somatostatin, and adrenocorticotropin [ACTH]). Paraffin sections from five pure carcinoids, seven pure adenocarcinomas, and eight CCC from the stomach, small bowel, appendix, and colon were studied with mucicarmine, silver impregnation stains, and a peroxidase-anti-peroxidase technic. Of the eight CCC, all were mucin positive, four were argyrophilic, and three were argentaffin positive. CEA was present in all eight, serotonin in seven, and calcitonin in one. No other neurohormonal peptides were demonstrated. The distribution of serotonin and CEA generally corresponded to the morphologic pattern, but discordance was observed in two cases, i.e., serotonin was not always localized to areas of carcinoid and CEA not always confined to areas of carcinoma. All five pure carcinoids demonstrated intracytoplasmic localization of serotonin, whereas none contained intracytoplasmic CEA. In two cases, CEA was present within acinar lumens only. The seven colonic adenocarcinomas were argyrophil and argentaffin negative. All contained CEA within the cytoplasm and in gland lumens. None contained serotonin. None of the neurohormonal peptides was localized in either pure adenocarcinomas or carcinoids. This study reveals that among gastrointestinal neoplasms displaying morphologic patterns of adenocarcinoma and carcinoid, immunocytochemical localization of CEA and serotonin confirms their bidirectional differentiation and justifies the designation "composite carcinoma-carcinoid."     

Hypospadias trends in two US surveillance systems

OBJECTIVE: Hypospadias is a common congenital anomaly, the cause of which is unknown. Unexplained increases in the rates of hypospadias occurred in five European countries in the 1970s and 1980s. We examined data from two birth defects surveillance systems in the United States for evidence of similar trends. METHODOLOGY: The Metropolitan Atlanta Congenital Defects Program (MACDP) provided birth prevalence rates from 1968 to 1993. The nationwide Birth Defects Monitoring Program (BDMP) provided rates from 1970 to 1993. MACDP data are population-based and could be categorized by the severity of the hypospadias. BDMP data allowed analysis of rate trends for the four census regions of the United States. RESULTS: Data from both surveillance systems showed an approximate doubling of hypospadias rates in the 1970s and 1980s. MACDP data showed that the rate of severe cases increased while the ratio of mild to severe cases decreased. BDMP data showed that hypospadias rates increased markedly in all four regions of the United States. CONCLUSIONS: The observed increases are unlikely to be attributable to increased sensitivity of the surveillance systems or the identification of more mild cases by physicians over time, because either trend would have increased rather than decreased the ratio of mild to severe cases. If real, these trends represent the largest number of cases and the first report of an increase in hypospadias rates outside of Europe. Additional investigation of a possible increase in hypospadias rates is warranted.     

Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancer types exhibiting microsatellite instability. Using intron primers previously reported for examination of the entire coding region of the TGFbetaRII gene, 29 sporadic gastric cancers were screened with non-radioactive single strand conformation polymorphism and subsequent DNA sequencing analysis. Mutations of the TGFbetaRII gene were detected in three out of 29 tumors (10%). Two cases showed deletions in a polyadenine tract in both alleles and was positively associated with replication error. One case had an insertion of GA dinucleotide sequence in one allele. Mutations of the TGFbetaRII gene were restricted to exon 3 and other coding regions were not affected. Loss of heterozygosity was detected by analyzing a polymorphic site in intron 2. Three out of nine (33%) informative cases, which were all of intestinal type and advanced cases, showed loss of heterozygosity but neither TGFbetaRII mutation nor replication error was found in these cases. Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different extent in the gastric cancer with genetically abnormal transforming growth factor. Although the numbers studied are small, homozygous (A)10 deletion or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and progression of at least some part of sporadic gastric cancer.      

Intracranial chondroma of the occipital lobe

A case report of an intracranial chondroma is discussed with emphasis on magnetic resonance imaging.     

The 2001 Bethesda System: terminology for reporting results of cervical cytology

Diane Solomon, MD; Diane Davey, MD; Robert Kurman, MD; Ann Moriarty, MD; Dennis O'Connor, MD; Marianne Prey, MD; Stephen Raab, MD; Mark Sherman, MD; David Wilbur, MD; Thomas Wright, Jr, MD; Nancy Young, MD; for the Forum Group Members and the Bethesda 2001 Workshop

JAMA. 2002;287:2114-2119.

Objectives  The Bethesda 2001 Workshop was convened to evaluate and update the 1991 Bethesda System terminology for reporting the results of cervical cytology. A primary objective was to develop a new approach to broaden participation in the consensus process.

Participants  Forum groups composed of 6 to 10 individuals were responsible for developing recommendations for discussion at the workshop. Each forum group included at least 1 cytopathologist, cytotechnologist, clinician, and international representative to ensure a broad range of views and interests. More than 400 cytopathologists, cytotechnologists, histopathologists, family practitioners, gynecologists, public health physicians, epidemiologists, patient advocates, and attorneys participated in the workshop, which was convened by the National Cancer Institute and cosponsored by 44 professional societies. More than 20 countries were represented.

Evidence  Literature review, expert opinion, and input from an Internet bulletin board were all considered in developing recommendations. The strength of evidence of the scientific data was considered of paramount importance.

Consensus Process  Bethesda 2001 was a year-long iterative review process. An Internet bulletin board was used for discussion of issues and drafts of recommendations. More than 1000 comments were posted to the bulletin board over the course of 6 months. The Bethesda Workshop, held April 30-May 2, 2001, was open to the public. Postworkshop recommendations were posted on the bulletin board for a last round of critical review prior to finalizing the terminology.

Conclusions  Bethesda 2001 was developed with broad participation in the consensus process. The 2001 Bethesda System terminology reflects important advances in biological understanding of cervical neoplasia and cervical screening technology.