Antiglioma activity of GoPI-sugar, a novel gold(I)-phosphole inhibitor: chemical synthesis, mechanistic studies, and effectiveness in vivo.

Glioblastoma, an aggressive brain tumor, has a poor prognosis and a high risk of recurrence. An improved chemotherapeutic approach is required to complement radiation therapy. Gold(I) complexes bearing phosphole ligands are promising agents in the treatment of cancer and disturb the redox balance and proliferation of cancer cells by inhibiting disulfide reductases. Here, we report on the antitumor properties of the gold(I) complex 1-phenyl-bis(2-pyridyl)phosphole gold chloride thio-ß-d-glucose tetraacetate (GoPI-sugar), which exhibits antiproliferative effects on human (NCH82, NCH89) and rat (C6) glioma cell lines. Compared to carmustine (BCNU), an established nitrosourea compound for the treatment of glioblastomas that inhibits the proliferation of these glioma cell lines with an IC50 of 430µM, GoPI-sugar is more effective by two orders of magnitude. Moreover, GoPI-sugar inhibits malignant glioma growth in vivo in a C6 glioma rat model and significantly reduces tumor volume while being well tolerated. Both the gold(I) chloro- and thiosugar-substituted phospholes interact with DNA albeit more weakly for the latter. Furthermore, GoPI-sugar irreversibly and potently inhibits thioredoxin reductase (IC50 4.3nM) and human glutathione reductase (IC50 88.5nM). However, treatment with GoPI-sugar did not significantly alter redox parameters in the brain tissue of treated animals. This might be due to compensatory upregulation of redox-related enzymes but might also indicate that the antiproliferative effects of GoPI-sugar in vivo are rather based on DNA interaction and inhibition of topoisomerase I than on the disturbance of redox equilibrium. Since GoPI-sugar is highly effective against glioblastomas and well tolerated, it represents a most promising lead for drug development. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

[60-year old woman with round lesion of the right upper lobe of the lung after heart transplantation]. / 60-jährige Patientin mit Raumforderung im rechten Lungenoberlappen nach Herztransplantation.

We report on a woman presenting with fever and novel round lesion in the lung four months after heart transplantation. Microbiologic assessment of bronchial lavage and operative specimen revealed pulmonary nocardiosis. Furthermore, cerebral involvement has been observed. Antibiotic treatment according to the microbiological sensitivity test for eleven months resulted in complete remission of pulmonary and cerebral nocardiosis. Immunosuppressive treatment increases the risk for opportunistic infections early after transplantation as well as malignancies during the late course.

Interstitial leukocytes in right ventricular endomyocardial biopsies after heart transplantation in patients with complicated versus uneventful postoperative course.

BACKGROUND: Infections and rejections play key roles in morbidity and mortality in the early postoperative period after orthotopic heart transplantation (HTX). The aim of this study was to evaluate whether qualitative and quantitative analyses of various interstitial leukocytes in endomyocardial biopsies during the first 2 weeks after HTX provided early information on these complications. PATIENTS AND METHODS: During and after HTX, endomyocardial biopsies were obtained in 51 patients. By immunohistochemistry we determined the CD3-, CD4-, CD8-, CD15-, CD20-, CD57-, and CD68-positive cell numbers projected to planimetrically measured areas. To compare morbidity in the postoperative course, the patients were subdivided into complicated versus uncomplicated after 3 months. RESULTS: In the uncomplicated group, the cell counts of CD3-, CD8-, CD57-, and CD68-positive cells were significantly lower than in the complicated group. CD3-, CD4-, and CD8-positive cell numbers showed a significant decrease in the first week among the uncomplicated group. In the complicated group, the cell counts increased significantly in the second week. The numbers of CD57-positive cells were significantly lower during the first and second weeks among the uncomplicated group. CONCLUSIONS: Increased T lymphocytes, natural killer cells, and macrophages observed in the second week after HTX indicated increased morbidity. A reduction in CD3-positive cells in the first week indicated a low morbidity risk; an increase indicated a higher risk.

Respiratory Deleted in Malignant Brain Tumours 1 (DMBT1) levels increase during lung maturation and infection.

Deleted in Malignant Brain Tumours 1 (DMBT1) is a secreted scavenger receptor cysteine-rich protein that binds and aggregates various bacteria and viruses in vitro. Studies in adults have shown that DMBT1 is expressed mainly by mucosal epithelia and glands, in particular within the respiratory tract, and plays a role in innate immune defence. We hypothesized that respiratory DMBT1 levels may be influenced by various developmental and clinical factors such as maturity, age and bacterial infection. DMBT1 levels were studied in 205 tracheal aspirate samples of 82 ventilated preterm and full-term infants by enzyme-linked immunosorbent assay. Possible effects of various clinical parameters were tested by multiple regression analysis. DMBT1 levels increased significantly with lung maturity (P < 0.0001 for both gestational and postnatal age) and in small-for-gestational-age infants (P = 0.0179). An increase of respiratory DMBT1 levels was detected in neonatal infections (P < 0.0001). These results were supported by Western blotting. Immunohistochemical analyses of archived newborn lung sections (n = 17) demonstrated high concentrations of DMBT1 in lungs of neonates with bacterial infections. Our data show that preterm infants are able to up-regulate DMBT1 in infection as an unspecific immune reaction.

[Subtotal cricoid resection as primary therapy for a highly differentiated chondrosarcoma]. / Subtotale Krikoidresektion als primäre Therapie eines hochdifferenzierten Chondrosarkoms des Ringknorpels.

Chondrosarcomas of the larynx are rare malignant tumors usually diagnosed with significant delay due to their nonspecific symptoms. We report a 50-year-old male presenting with progressive dyspnea. Indirect laryngoscopy revealed a subglottic stenosis. The cricoid cartilage was shown on CT to be massively damaged. Histologic differentiation between chondroma and highly differentiated chondrosarcoma was very difficult. Therefore, an organ-preserving treatment concept using partial cricoid resection and staged endoscopic arytenoidectomy was chosen. Total laryngectomy and permanent tracheostomy could be avoided. Due to the risk of recurrence, early follow-up with endoscopy and CT is mandatory.

Expression of acyl-CoA synthetase 5 in human endometrium and in endometrioid adenocarcinomas.

AIM: Fatty acid metabolism of the endometrium is important for tissue homeostasis in the proliferative and secretory phase of the menstrual cycle. The enzyme acyl-CoA synthetase 5 (ACS5) plays a crucial role in fatty acid metabolism, mainly through the generation of multifunctional long-chain-fatty-acid-CoA esters. The aim of the present study was to characterize expression and localization of ACS5 in the normal human endometrium and in endometrioid adenocarcinomas. METHODS AND RESULTS: Expression of ACS5 in the human endometrium was investigated by in situ techniques (immunohistochemistry, mRNA in situ hybridization) and a molecular approach (reverse transcriptase-polymerase chain reaction, Western blot). ACS5 protein and mRNA were localized to the epithelium of the human endometrium. Here, ACS5 expression was found throughout the menstrual cycle as well as in the postmenopausal endometrium. Notably, in endometrioid adenocarcinomas, the ACS5 molecule was found abundantly in well-differentiated tumours, but not in poorly differentiated adenocarcinomas. CONCLUSIONS: The abundance of ACS5 in the endometrial epithelium throughout the menstrual cycle provides support for its role in the regulation of tissue homeostasis. With regard to its value for histopathological diagnosis, immunohistochemical characterization of endometrioid adenocarcinomas shows that a decrease in ACS5 expression correlates with tumour dedifferentiation.

[Intraoperative endosonographic guided resection of tongue carcinoma]. / Intraoperative endosonographisch gesteuerte Resektion von Zungenkarzinomen.

BACKGROUND: Exact estimation of a tumor's size and the definition of adequate resection margins in carcinomas of the tongue are often difficult because of the tumor's extension and deep infiltration. METHODS: We have developed a method that allows intraoperative visualisation and marking of tumor margins. Intra-operative endosonography was performed on nine patients with carcinomas of the tongue using a 8-12 MHz linear array transducer. The oral cavity was flooded with normal saline solution and the transducer was immersed therein. This allowed scanning in a non-contact mode. The tumor margins were marked with a surgical suture under endosonographic monitoring. RESULTS: In the nine patients studied, the histological margins corresponded to the sonographic margins. The sonographic marking proved to be useful during the resection of the tumor and histological safety margins were respected in each case. CONCLUSIONS: This non-invasive procedure provides a quick and reliable orientation during the resection of tongue carcinoma, and a more precise and individual definition of resection margins is possible. Intraoperative non-contact use of endosonography is a promising method.

[Anorectal melanoma. A rare and highly malignant tumor entity of the anal canal]. / Das anorektale Melanom. Eine seltene und hochmaligne Tumorentität des Analkanals.

Anorectal melanomas represent a very small group of mucosal melanoma with unknown etiology and poor prognosis. In view of their location, a history of sun exposure is not likely to have had an impact on their development. Recent epidemiologic data indicate a bimodal age distribution. To date there is no information whether an infection with the human papilloma virus plays a role in the tumorigenesis of anorectal melanoma. The lesions can be misdiagnosed as hemorrhoids on clinical examination. On histological examination amelanotic types have been misdiagnosed as lymphoma, sarcoma,and undifferentiated carcinoma. Useful immunohistochemical markers are S 100 protein, HMB-45, Melan A, and MiTF (microphthalmia-transcription-factor). Therapy includes local excision or abdominoperineal resection followed by optional inguinal and parailiac lymph node dissection, and consecutive chemo- and immunotherapy. The poor long-term prognosis of anorectal melanomas correlates with their advanced tumor size and depth of infiltration at diagnosis. The overall 5-year survival rates range between <5 and 22% in different series.

[Secondary malignant melanoma of the gallbladder. A contribution to the differential diagnosis of pigmented lesions of the gallbladder]. / Sekundäres malignes Melanom der Gallenblase. Ein Beitrag zur Differenzialdiagnose pigmentierter Läsionen der Gallenblase.

The history of gallbladder involvement by a malignant melanoma in a 65-year-old woman is reported. The gallbladder, clinically resected for cholecystitis, harboured a polypoid dark pigmented tumour. The tumour was identified as a malignant melanoma immunohistochemically by positive reactions for gp100 (HMB45), melan A, and MiTF. Clinically, the patient was treated for cutaneous malignant melanoma by local excision 10 years earlier. The literature of pigmented lesions of the gallbladder is reviewed. In conclusion, the most important differential diagnosis of pigmented lesions of the gallbladder is the secondary gallbladder melanoma.

Anorectal melanomas do not harbour the Kaposi sarcoma-associated human herpesvirus type 8 DNA.

Anorectal melanomas are similar to cutaneous melanomas with regard to the mode of spread and to the immunophenotype. When compared with patients with cutaneous melanoma, those suffering from anorectal melanoma have a much worse outcome. The etiology of anorectal melanomas is as yet completely unknown. For anatomical reasons, ultra-violet (UV-B) radiation can not cause anorectal melanomas as in cutaneous tumours, that are associated with exposure of the skin to UV-B radiation. As the cytokine interleukin-6 (IL-6) is known to stimulate melanoma tumour cell proliferation and a functional homologue of human IL-6 has been identified recently in the HHV-8 genome, this tumorigenic virus might be involved in the pathogenesis of anorectal melanomas. Twelve formalin fixed and paraffin embedded primary anorectal melanomas from seven female and five male patients with a mean age at diagnosis of 71 years (range 38-88 years) were investigated for the presence of HHV-8 DNA. Using a specific and highly sensitive polymerase chain reaction protocol, this tumorigenic gamma-herpesvirus was not detectable in any tumour. This data indicates that HHV-8 is not involved in the development of anorectal melanomas.