Progressive encephalopathy and myopathy in transgenic mice expressing human foamy virus genes.

Transgenic mice carrying the bel region of human foamy retrovirus (HFV) under transcriptional control of its own long terminal repeat expressed the transgene in their central nervous systems and in smooth and striated muscle tissues. The animals developed a progressive degenerative disease of the central nervous system and of the striated muscle. Because expression of the transgene was closely correlated with the appearance of structural damage and inflammatory reactions were scanty, the disease is likely to be caused directly by the HFV proteins. These unexpected findings call for a reevaluation of the pathogenic potential of HFV in humans.

[Sarcomatoid renal cell carcinoma. A rare and aggressive variation of primary renal cell carcinoma]. / Das sarkomatoide Nierenzellkarzinom. Eine seltene und aggressive Variante des primären Nierenzellkarzinoms.

Every year, renal cell carcinoma (RCC) is responsible for the highest proportion of cancer-associated deaths in relation to all other malignant urological diseases. Initially called carcinosarcoma, the sarcomatoid differentiation confers higher aggressiveness on any of the different subtypes of RCC, with a frequency of ca. 1%. The presence of a sarcomatoid component makes the disease locally aggressive, which typically presents an advanced grade that is associated with fast progression and fatal outcome in a vast proportion of cases, with median survival lower than 1 year. This is important for predicting the outcome for patients undergoing nephrectomy due to RCC, since chemotherapy in a certain group of patients with progressive disease can be a reasonable alternative to the failure of immunotherapy in sarcomatoid renal carcinoma. We report our experience with sarcomatoid RCC in four patients with extensive tumor progression in comparison to the literature.

[Mucinous adenocarcinoma of the Urachus: A Case Report]. / Muzinöses Adenokarzinom des Urachus--Ein Fallbericht.

Urachal carcinoma is a rare form of cancer. It often is diagnosed incidentally, like in our case report, because its cardinal symptom also occurs in a number of other urological diseases. We report the case of a 26-year-old man with a mucinous adenocarcinoma of the urachus. The carcinoma was removed via partial cystectomy with umbilical tumour excision.

[Long-term results of sentinel node biopsy diagnostics in penile carcinoma : Dynamic sentinel node biopsy in cases with nonpalpable lymph nodes in the groin]. / Langzeitergebnisse der Sentinel-Lymphknotendiagnostik beim Peniskarzinom : Dynamische Sentinel-Lymphknotenbiopsie bei nicht-palpablen Leistenlymphknoten.

OBJECTIVE: Dynamic sentinel node biopsy (DSNB) has been recommended in the EAU guidelines for several years as a minimally invasive method for lymph node staging in patients with penile carcinoma and nonpalpable lymph nodes. However, due to the high methodological demands and the primarily unreliable results, this method is rarely used in Germany. The aim of this study was to establish the reliability and morbidity of this method. MATERIAL AND METHODS: The frequency of lymph node recurrent disease and complications were prospectively recorded in patients with initially nonpalpable inguinal lymph nodes and histologically negative sentinel lymph nodes. Quality criteria were the false negative rate (percentage of lymph node recurrence in negative procedures) and the morbidity rate. Inguinal regions with palpable lymph nodes and/or evidence of metastases were not considered. RESULTS: The study included 37 patients with histologically negative sentinel lymph nodes in 63 groins with nonpalpable inguinal lymph nodes. There were 21 T1(a/b) stages, 10 T2, and 6 T3 stages. Tumor differentiation was good in 4, moderate in 26, and poor in 7 patients. During a median follow-up of 52 months (range 1-131 months), we observed a bilateral lymph node recurrence in 1 patient and a conservatively managed prolonged lymphorrhea in another patient. Per inguinal region the false-negative rate was 3.2 % and the morbidity rate was 1.6 %; seen per patient the rates were both 2.7 %. CONCLUSIONS: DSNB is a reliable method of lymph node staging in patients with penile carcinoma and nonpalpable inguinal lymph nodes. The high degree of reliability in combination with the low morbidity justifies the higher methodical complexity of this method.

[Salvage lymphadenectomy in patients with prostate cancer recurrence: A review]. / Salvagelymphadenektomie beim Rezidiv eines Prostatakarzinoms : Eine Übersicht.

BACKGROUND: Salvage extended pelvic lymph node dissection (salvage ePLND) in patients with prostate cancer (PCa) biochemical recurrence is an alternative to the commonly used androgen deprivation therapy (ADT) and/or chemotherapy. Small patient number, insufficient accuracy of contemporary imaging methods for lymph node relapse diagnostics, and the lack of prospective data present limiting factors for a wider application of salvage ePLND. The purpose of this publication is to review German and European data and studies on the subject of salvage ePLND and to discuss future perspectives. MATERIALS AND METHODS: We analyzed available studies up to October 2014 from Medline with the keywords "salvage lymph node dissection prostate cancer". RESULTS: A total of 51 publications since 1984 (up to October 2014) meeting the search criteria were found. Ten of these were studies that analyzed the results of salvage ePLND. Of these 10 studies, 6 originated from German clinics. Furthermore, among these 51 publications, there were 2 clinical case reports (1 from Germany) and 3 reviews (none from Germany). CONCLUSIONS: The available data show insufficient evidence-based validity. There have been no prospective studies and just one multicenter study. However, single-center retrospective studies have shown promising results. Salvage ePLND leads to biochemical remission, freedom from clinical recurrence, and probably also to renewed response to ADT in patients with castration-resistant PCa. Multicenter prospective studies should be conducted in Germany (where most of the available studies have been performed). The selection of patients should be analyzed in order to identify clear selection criteria for salvage ePLND.

Human foamy virus: an underestimated neuropathogen?

Human foamy virus (HFV) is a recently characterized retrovirus which was originally isolated from patients with various neoplastic and degenerative diseases. However, until today it has not been possible to identify HFV as the causative agent of any disease and little is known about its prevalence in human populations. Like HTLV and HIV, HFV encodes the three structural retroviral genes, gag, pol and env, and an additional region containing three open reading frames, bel-1 to bel-3. Bel-1 activates transcription of the long terminal repeat of HFV and HIV. In order to study the consequences of expressing HFV regulatory genes and to investigate a possible pathogenic potential of HFV, we have introduced parts of the HFV genome into the germ line of mice. Our studies with transgenic mice demonstrate that HFV transgenes encompassing the bel region are transiently transcribed between midgestation and birth at moderate levels in various tissues. Expression is then suppressed, but resumes after a latency of several weeks in a restricted range of tissues and leads to extensive accumulation of HFV transcripts in single cells. This is associated with a progressive degenerative disease of the central nervous system and of striated muscle. These findings provide the first evidence of a disease induced by HFV and suggest that HFV might also act as a human pathogen in neurological diseases. Moreover, the transgenic mouse model will be useful for studying the molecular basis of HFV-induced neurotoxicity, the role of individual disease-associated HFV genes and the regulation of retroviral latency.

[Pain as an indication for functional TMJ surgery]. / Der Schmerz als Indikation fur die funktionelle Kiefergelenkchirurgie.

In 113 patients presenting with painful impediment of jaw function, which did not respond to non-surgical treatment, several kinds of functional surgery of the temporomandibular joint were applied. Comparison of the pre- and postoperative pain profiles of these patients show that good results from the surgery methods used could generally be expected when the patient, preoperatively, had pain restricted to the TMJ area with function. More unfavorable results were shown in patients with pain already present for years, muscular or bilateral pain as well as pain not related to function or pain at night. Continuous pain should only be seen as an indication for surgery with rheumatoid arthritis of the TMJ.

[Selection of the approach to the TMJ under esthetic aspects]. / Zur Wahl des Zugangsweges zum Kiefergelenk aus ästhetischer Sicht.

The esthetic results of 128 TMJ surgeries are reported. 81 TMJs were treated via the preauricular, 47 via the retroauricular approach. The preauricular approach with a curved or modified line of incision is characterized by an almost unnoticeable scar, particularly if the incision is placed into a preauricular crease or pit. Leaving the scar in an invisible area, the retroauricular approach is esthetically superior to all other procedures. Both approaches involve a minimum risk for complications, if the correct technique avoiding traumatization of the marginal branch of the facial nerve is used. Considerations related to the choice of the different approaches are discussed with respect to their characteristic features.

Human foamy virus proteins accumulate in neurons and induce multinucleated giant cells in the brain of transgenic mice.

Human foamy virus (HFV) is a retrovirus encoding structural genes and, like human immunodeficiency virus and human T cell leukemia virus I, several ancillary reading frames collectively termed the be1 genes. We have previously shown that HFV transgenic mice develop an encephalopathy with neuronal loss in hippocampus and cerebral cortex. We have now raised and characterized rabbit antisera to various recombinant portions of gag, pol, env, and bel-1, the viral trans-activator. Immunoreactivity for gag and bel-1 was observed in nuclei and processes of hippocampal and cortical neurons before the onset of morphological lesions and correlated with the appearance of HFV mRNA. Astrocyte-derived multinucleated giant cells containing HFV proteins were present in the brain of transgenic mice coexpressing full-length HFV genes but not in mice expressing truncated gag and env, suggesting that these genes contain a fusogenic domain. Expression of full-length structural genes decreased the life expectancy of transgenic mice, implying an adjuvant role for these proteins in HFV-induced brain damage.

Expression of human foamy virus is differentially regulated during development in transgenic mice.

The human foamy virus (HFV) is a recently characterized member of the spumavirus family. Although no diseases have been unequivocally associated with HFV infection, expression of HFV regulatory genes in transgenic mice induces a characteristic acute neurodegenerative disease and a myopathy. To better characterize the sequence of events leading to disease, and to gain a better understanding of the underlying pathogenetic mechanisms, we have analyzed in detail the transgene expression pattern during development. Transcription of a construct containing all regulatory elements and ancillary genes of HFV was analyzed by in situ hybridization and was shown to occur in two distinct phases. At midgestation, low but widespread expression was first detected in cells of extraembryonic tissues. Later, various tissues originating from embryonic mesoderm, neuroectoderm, and neural crest transcribed the transgene at moderate levels. However, expression decreased dramatically during late gestation and was suppressed shortly after birth. After a latency period of up to 5 weeks, transcription of the transgene resumed in single cells distributed irregularly in the central nervous system and in the skeletal muscle. By the age of 8 weeks, an increasing number of cells displayed much higher expression levels than in embryonic life and eventually underwent severe degenerative changes. These findings demonstrate that HFV transgene expression is differentially regulated in development and that HFV cytotoxicity may be dose-dependent. Such biphasic pattern of expression differs from that of murine retroviruses and may be explained by the specificity of HFV regulatory elements in combination with cellular factors. Future studies of this model system should, therefore, provide novel insights in the mechanisms controlling retroviral latency.

Bone scintigraphy in the evaluation of bone grafts used for mandibular reconstruction.

Bone scintigraphy was applied in the follow-up of 24 patients who received bone grafts for reconstruction of the mandible after partial resection. Semiquantitative assessment of the grafts was done with a six-grade scoring system, based on comparison of tracer uptake in the graft and in the calvarium (as an internal control). Sixty-nine bone scans were evaluated. Late planar imaging was carried out in all cases, and single-photon emission tomography (SPET) was performed additionally in 34 of these cases. Complications were observed in four grafts. They occurred less frequently in revascularized grafts than in non-revascularized grafts. Planar scintigrams performed within 14 days after reconstruction showed a significantly higher tracer uptake in grafts with an uncomplicated further course than in those which developed complications. Follow-up scintigrams after 1 and 3 months revealed a significant increase in tracer uptake in grafts with an uncomplicated course. This was not apparent in grafts which developed complications. The tracer uptake was estimated to be higher on the basis of the SPET scans as compared with the planar scintigrams. It is concluded that bone scintigraphy is of prognostic value in the evaluation of bone grafts used for mandibular reconstruction. SPET seems to be more sensitive than planar imaging for the assessment of graft viability.

[Growth disorders following fractures of the midface in children]. / Wachstumsstörungen nach Frakturen des Mittelgesichtes im Kindesalter.

12 patients who had suffered mid face fractures during their childhood were examined for skeletal deformities of the facial skull. The cephalometric data showed that neither the position nor the inclination of the maxilla were significantly different from normal anatomy. No correlation was found between the age, the severity of injuries and surgical treatment and resulting deformities.

Use of sequential bone scintigraphy for monitoring onlay grafts to grossly atrophic jaws.

OBJECTIVES: To evaluate the capability of sequential bone scintigraphy for assessing the viability of avascular onlay grafts in combination with primary or secondary implant placement. METHODS: Forty-six patients with severe alveolar ridge atrophy received full-arch onlay grafts from the iliac crest. Twenty patients received primary insertion of endosseous implants, while secondary implant placement was performed in 26 patients after an average interval of 95 days. In cases of primary implant placement, bone scintigraphy was performed after grafting and before abutment connection. In patients with secondary insertion, bone scans were performed after grafting, before and after implant placement and before abutment connection. For bone scintigraphy, 8 MBq 99mTc-MDP/kg body weight were administered intravenously and anterior views of the skull were obtained 3 h later. Regions of interest were drawn over the grafted area and over the calvarium as a reference area. Ratios of count densities between jaw and calvarium were calculated as a measure of tracer uptake. RESULTS: Bone grafts with primary insertion of implants showed a significant decrease (P = 0.0001) in ratios calculated for the whole graft from a mean of 3.53 after grafting to 2.35 before abutment connection. In cases of secondary implant placement, ratios decreased significantly after grafting from 4.04 to 2.78 before implant placement (P = 0.0001). After implant placement, there was a significant increase to 3.28 (P = 0.0062), which was followed again by a significant decrease to a mean ratio of 2.58 (P = 0.0437). CONCLUSIONS: Sequential bone scintigrams can provide information about the viability of the graft at the time of implant insertion and may thus indicate the ability of the grafted bone to accomplish osseointegration.

Analysis of the determinants of neurotropism and neurotoxicity of HFV in transgenic mice.

The Bel-1 protein of human foamy virus (HFV) is a transactivator acting on the U3 region of the long terminal repeat and on an internal promoter (IP) immediately upstream of the bel genes. An HFV transgene called delta gpe, containing both promoters and all bel genes, is expressed in the central nervous system and induces neurodegeneration in mice. To dissect the role of individual promoters and bel genes on transgene expression and neurotoxicity we generated transgenic mice with a construct termed pL-bel1, which lacks the IP and the ancillary genes except bel-1. L-bel1 mice transcribed the HFV transgene in more tissues than delta gpe mice, suggesting that CNS specificity is dictated by cis-acting elements not present in the pLbel-1 construct. Unlike delta gpe mice, L-bel1 mice did not develop neurodegenerative changes and did not show induction of nitric oxide synthase expression, although both strains expressed Bel-1 in the brain. Therefore, Bel-1 expression is not sufficient for neurotoxicity. Our results suggest that Bet, a fusion protein between bel-1 and bel-2 which is highly expressed in delta gpe but not in L-bel1 mice, is a candidate for neurotoxicity.