Ingo B. Runnebaum

p53 Mutations and expression in ovarian cancers : Correlation with overall survival

The p53 gene is altered in approximately 50% of all human malignancies. p53 overexpression, identified by immunohistochemistry, and p53 mutations, identified by single-strand conformational polymorphism (SSCP) and DNA sequencing, have been described in ovarian cancers. p53 overexpression has been correlated with poor outcome for women with ovarian cancer in some studies. With only limited data, the assumption has been made that p53 overexpression corresponds to p53 mutations. The purpose of this investigation was to assess p53 alterations in ovarian cancer to determine if p53 overexpression corresponds with mutations in the p53 gene, and to assess whether either predicts clinical outcome in ovarian carcinoma. Frozen ovarian carcinoma tumor specimens from 105 patients were analyzed by immunohistochemical staining for p53 expression. SSCP was used to screen for mutations and DNA sequencing was used to confirm the specific mutation in exons 2 to 11, encompassing the entire p53 open reading frame. Those ovarian carcinomas identified as wild-type p53 by SSCP were subjected to automated DNA sequence analysis of the entire open reading frame. Relative to DNA sequence analysis, the sensitivity of SSCP was 85% and the specificity was 98%. Immunohistochemical staining demonstrated that 72 of the 105 (69%) cases had positive immunostaining. SSCP and DNA sequencing identified and confirmed mutations in 60 of the 105 carcinomas (57%). Although there was a statistically significant association between p53 immunostaining and p53 mutations (p = 0.0002), false-negative and -positive results were identified. Tumor grade (p = 0.03), stage (p = 0.08), and overall survival (p = 0.15) were moderately associated with positive p53 immunostaining. Patients with p53 mutations and overexpression had shorter overall patient survival (p = 0.02). The findings demonstrated that, individually, p53 mutations and p53 overexpression were each related to shorter patient survival, but the strongest predictor of outcome was a combination of both mutations and overexpression. Comparisons of overall survival for women with mutations in loop 2, loop 3, and the loop-sheet-helix domains together showed a statistically significant difference in survival compared to survival of women whose ovarian cancers had other mutations (p = 0.046).

p53 mutant His175 identified in a newly established fallopian tube carcinoma cell line secreting interleukin 6

Fallopian tube carcinoma is a lethal gynecologic malignancy. Etiologic factors are unknown. No experimental data on molecular alterations exist so far. For an in vitro model, we established the permanent human tubal carcinoma cell line FT‐MZ‐1. The median doubling time was 14 days with 24.2% in S phase. A point missense mutation of the p53 tumor suppressor gene resulting in the His175 mutant was identified. Aberrant p53 protein accumulated in nucleus and cytoplasm. FT‐MZ‐1 substantially secreted interleukin 6 (Il‐6) coinciding with the inactivation of p53 as a transrepressor on the Il‐6 gene promoter.

Pregnancy outcome after repeated blunt abdominal trauma

During a four-year period, five of 49671 parturients were admitted on a prospective study protocol for repeated direct blunt abdominal trauma due to falls during pregnancy. Preterm contractions were noted in three patients one of which delivered preterm. No delayed abruptio placentae, intrauterine growth restriction or antepartum death were encountered. All patients delivered spontaneously. Repeated blunt abdominal trauma occurs rarely in pregnancy. Routine hospitalised surveillance in the absence of vaginal bleeding or uterine contractions may not be warranted.

Intrauterine resuscitation by rapid urinary bladder instillation in a case of occult prolapse of an excessively long umbilical cord.

Occult umbilical cord prolapse is a dramatic obstetrical emergency jeopardizing health and life of the fetus. Distending the maternal urinary bladder provides alleviation of pressure on the cord by reducing uterine contractions and by maintaining fetal structures elevated in order to protect the fetus from asphyxia until Cesarean delivery.

Multiplex PCR (MPCR) Screening Can Detect Small Intragenic p53 Deletion and Insertion Mutations

Mutations of the p53 tumor suppressor gene are the most common alterations associated with malignancy identified so far. Inactivation of the p53 gene contributes to loss of a cell-cycle check point at the G1-S boundary and to genetic instability of the cell eventually allowing cells to replicate in an uncontrolled fashion (1). Inactivating p53 mutations have frequently been identified in many different forms of cancer including more than 50% of ovarian cancers (2,3). The type and location of p53 mutations occurring in human tumors are nonrandom. In a compilation of more than 4200 p53 mutations in human cancers by Soussi et al., 50% of the mutations were missense mutations, 37% frameshift mutations, and 13% nonsense mutations (4). Small intragenic deletions and insertions have gained little attention in the analyses of the p53 gene in human tumors (5,6). However, a review that compiled 740 p53 mutations from a wide variety of cancers showed that 10% of the mutations were either deletions or insertions (7). Insertions were mostly flanked by short direct repeats of up to 14 basepairs (bp). Deletions of up to 37 bp often occurred in areas of sequence repeats. Such structural changes may be explained by a slipped mispairing mechanism during DNA replication (7).