Friedrich Kommoss

Adenovirus-Mediated Wild-Type p53 Gene Transfer in Patients Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer: Results of a Multicenter Phase II Study

PURPOSE To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.

Genetic Imbalances in Precursor Lesions of Endometrial Cancer Detected by Comparative Genomic Hybridization

Endometrial hyperplasia is regarded as a precursor lesion of endometrioid adenocarcinomas of the endometrium. The genetic events involved in the multistep process from normal endometrial glandular tissue to invasive endometrial carcinomas are primarily unknown. We chose endometrial hyperplasia as a model for identifying chromosomal aberrations occurring during carcinogenesis. Comparative genomic hybridization (CGH) was performed on 47 formalin-fixed, paraffin-embedded specimens of endometrial hyperplasia using the microdissection technique to increase the number of tumor cells in the samples and reduce contamination from normal cells. CGH analysis revealed that 24 out of 47 (51%) samples had detectable chromosomal imbalances, whereas 23 (49%) were in a genetically balanced state. The incidence of aberrant CGH profiles tended to parallel dysplasia grade, ranging from 22% aberrant profiles in simple hyperplasia to 67% in complex hyperplasia with atypia. The most frequent imbalances were 1p, 16p, and 20q underrepresentations and 4q overrepresentations. Copy number changes in 1p were more frequent in atypical complex hyperplasia than in complex lesions without atypical cells or simple lesions (42% versus 20% and 0%). Our results show that endometrial hyperplasia reveals recurrent chromosomal imbalances which tend to increase with the presence of atypical cells. The most frequent aberrations in endometrial cancer, 1q and 8q overrepresentations, are not present or are rare in its precursor lesions. This analysis provides evidence that tumorigenesis proceeds through the accumulation of a series of genetic alterations and suggests a stepwise mode of tumorigenesis.

Renal tubular dysgenesis (RTD) - an important cause of the oligohydramnion-sequence: Report of 3 cases and review of the literature

Renal tubular dysgenesis (RTD) is a disorder characterized by neonatal renal failure and regular gross renal architecture, although the histological features of immature and shortened proximal tubules lead to neonatal death. The pathogenesis of this condition includes a congenital familial condition, a twin-twin transfusion syndrome, and an angiotensin-converting enzyme inhibitor intake by the mother. The clinical picture shows an association with oligohydramnia, pulmonary hypoplasia, and skull ossification defects. In the present paper, we report the occurrence of RTD in three infants of a consanguinous couple and compared our data with those of the literature. Our data confirm that late second trimester demonstration of oligohydramnion, with structurally normal kidneys and with or without skull ossification defects, allows the diagnosis of renal tubular dysgenesis, which, however, has to be confirmed by histological and immunohistological examinations of the kidney.

Leptomeningeal Carcinomatosis and Cranial Nerve Palsy as Presenting Symptoms of a Clinically Inapparent Gallbladder Carcinoma

We present an occult metastatic signet-ring cell gallbladder carcinoma in a 78-year-old woman, who complained of recurrent headaches, dysarthria, and paresis of the tongue. Cranial imaging showed contrast enhancement of the basal leptomeninges, and the cerebrospinal fluid displayed clusters of adenocarcinoma cells proposed as leptomeningeal carcinomatosis of the breast, lung or gut. However, postmortem examination revealed the gallbladder as the site of the primary carcinoma with focal signet-ring cell differentiation. In patients with progressive neurologic deterioration due to leptomeningeal carcinomatosis, adenocarcinomas from the gastrointestinal and hepatic systems should be considered. It is likely that signet-ring cell carcinomas display an increased affinity to leptomeningeal spread.

Mature cystic teratoma of the ovary with struma and benign Brenner tumor: a case report with immunohistochemical characterization.

The association of mature cystic teratoma with struma ovarii and the association of Brenner tumour with mucinous cystadenoma is well known (1–3), and struma in conjunction with Brenner tumor has been reported sporadically (4–8). To our knowledge this is the first welldocumented case with immunohistochemical characterization of a mature cystic teratoma with struma mixed with a Brenner tumor. The literature is reviewed and implications for histogenesis are discussed.

Localization of cytokeratin 10 mRNA in human epidermis using nonradioactive in situ hybridization as a routine method

Among the 20 cytokeratins, which are composed of proteins related to alpha-keratin, cytokeratin 10 is an acidic (type I) cytokeratin. Its eight exons encode a glycine-rich polypeptide of 59.535 kDa, which is synthesized in the suprabasal cell layers of the human epidermis as well as in several epithelial tumours, squamous metaplasias and transformed keratinocytes (HaCaT). Cytokeratins 10 and 11 are closely related to and are mostly coexpressed with the basic cytokeratin 1. The cytokeratin 10 gene, which is similar to the bovine epidermal cytokeratin VIb gene and the murine cytokeratin M 59 gene, contains 6480 base pairs. Its expression in vivo and in vitro is positively influenced by the extracellular calcium concentration and is reduced by vitamin A or other retinoids [10]. In situ hybridization was first performed in 1969 by Pardue and Gall and by John et al. [4, 8] using radioactively labelled probes. Disadvantages of radioactive in situ hybridization are the radioactivity itself, the limited probe stability, the long exposure time and the inaccurate localization of the hybridization signal on the sections [2]. Therefore, a method of nonradioactive in situ hybridization was developed. The first hybridization results using the digoxigenin labelling and detection kit of Boehringer were reported in 1990 [5]. In situ hybridization of cytokeratin gene products with digoxigenin-labelled riboprobes has been described [3, 7, 12]. In order to investigate the expression of cytokeratin 10 in the human epidermis we developed an in situ hybridization protocol using the digoxigenin detection kit. To produce an antisense riboprobe complementary to exon 8 of the cytokeratin 10 gene the vector Bluescribe M 13 + was linearized with EcoR I. The 330 base pairs containing clone pKH 105-17 (identical with exon 8) was transcribed with T3 RNA polymerase. To obtain the sense riboprobe as a negative control, we linearized with Hind III and Ivo Meinhold-Heerlein · Thomas Brandstetter · Friedrich Kommoss · Herta Bettendorf · Manfred Hagedorn · Thomas Bauknecht