[The activating GNAS mutation : A survey of fibrous dysplasia, its associated syndromes, and other skeletal and extraskeletal lesions]. / Die aktivierende GNAS-Mutation : Eine Bestandsaufnahme bei der Fibrösen Dysplasie, der ihr assoziierten Syndrome sowie weiterer skelettaler und extraskelettaler Läsionen.

Fibrous dysplasia of bone is a connatal but not hereditary disease with monostotic or polyostotic manifestations and may be associated either with the extraskeletal disease McCune-Albright syndrome or with myxoma of the skeletal muscle, termed Mazabraud syndrome.The confirmation of recurrent chromosomal aberrations may lead to the conclusion that fibrous dysplasia is a neoplasia rather than a dysplastic skeletal disease.The primary cause of all forms of the described diseases is the activating GNAS mutation, which is detectable in almost all lesions. Research into the impact of this mutation has increased the understanding of these up to now solely descriptively defined diseases and also allowed easier discrimination of various fibro-osseous skeletal lesions. Current insights suggest that this mutation may also play a pivotal role in other extraskeletal neoplasias.

[Ewing's sarcoma, fibrogenic tumors, giant cell tumor, hemangioma of bone : Radiology and pathology]. / Ewing-Sarkom, fibrogene Tumoren, Riesenzelltumor, Hämangiom des Skeletts : Radiologie und Pathologie.

Radiological imaging only reflects the anatomy and its pathological abnormalities. Therefore, the radiologist should be able to recognize the basic features of the pathological anatomy of bone tumors. This can only be learned working closely with a pathologist who is experienced in this field. On the other hand, the pathologist needs from the radiologist their diagnostic assessment with information on size, location, aggressiveness and the existence of a bone tumor's matrix, of the whole lesion, because he usually only receives a small part for examination in the form of a biopsy. In this article, the features and fundamentals (standards) of radiological-pathological cooperation as the mainstay for a precise diagnosis in bone tumors are outlined. The radiological appearance and the histopathological features behind it are presented for Ewing's sarcoma, fibrogenic tumors, giant cell tumor, and hemangioma of the bone.

Immunohistochemical expression of receptor tyrosine kinase PDGFR-α, c-Met, and EGFR in skull base chordoma.

Chordomas are rare, locally aggressive malignancies that often exhibit an insidious natural history and are difficult to eradicate. Surgery and radiotherapy are the treatment mainstays of chordoma, but the chance of local recurrence remains high. Reports of receptor tyrosine kinase (RTK) expression in chordoma suggest that these tumors may respond to kinase inhibitor therapy. Currently, there are no effective chemotherapeutic protocols for chordoma. A tissue microarray containing 74 tumor specimens from primary chordoma patients and 71 from their recurrent tumors for a total of 145 tumor specimens was immunohistochemically analyzed for expression of a number of proteins involved in signal transduction from RTKs. Platelet-derived growth factor receptor-α (PDGFR-α), epidermal growth factor receptor (EGFR), c-Met, and CD-34 were detected in 100, 92, 100, and 59% of cases, respectively. PDGFR-α and c-Met staining was of moderate to strong intensity in all cases. In contrast, total EGFR staining was variable; weak staining was detected in 10 cases. Our results contribute to the understanding of the expression of RTKs in skull base chordomas and support the development of targeted therapies that inhibit RTKs, which may have a synergistic effect for chemotherapy in patients. There were statistically significant correlations between the expression of PDGFR-α, c-Met, and EGFR and disease-free survival. The results nonetheless suggest that chordomas may respond to RTK inhibitors or modulators of other downstream signaling.

Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in skull base chordoma: a series of 145 tumors.

Chordomas are locally invasive tumors that have a tendency to relapse despite optimal treatment. Specific biological markers might be used to describe their behavior. There is currently no agreement regarding the best way to manage intracranial chordomas. We studied the expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1P in 145 paraffin-embedded tumors. The purpose of our study was to determine: (a) the role of potent angiogenic factors VEGFR-2 and iNOS and their relationship to each other in skull base chordoma and (b) the role of monocytes/macrophages as a potential iNOS source in the angiogenic process. A series of 74 chordoma patients for a total of 145 lesions (including 71 recurrent lesions) and 10 specimens from embryonic notochord were investigated for the expression of iNOS, VEGFR-2, Ki-M1P, and CD-34 using immunohistochemistry. In the majority of the chordomas, correlations were found between iNOS and the immunoreactivity of Ki-M1P (r = 0.5303, P < 0.0001). Furthermore, the expressions of Ki-M1P was correlated with VEGFR-2 (r = 0.4181, P < 0.0001). Our results indicate that chordomas may respond to receptor tyrosine kinase inhibitors such as VEGFR-2 or modulators of other downstream signaling molecules. The future of VEGFR-2 and iNOS inhibitors as therapeutic agents in the treatment of chordoma will be clearer over the next years as results of the current clinical trials become available and as the factors regulating angiogenesis and the interactions between these factors are elucidated. However, appropriate functional experiments remain to be conducted to prove such a hypothesis.

Adenomatous tumors of the middle ear and temporal bone: clinical, morphological and tumor biological characteristics of challenging neoplastic lesions.

Adenomatous tumors of the middle ear and temporal bone are rare tumors. In this retrospective study, we examined nine patients who underwent surgery for an adenomatous tumor of the middle ear, mastoid cavity or eustachian tube. In seven patients, a middle ear adenoma (MEA) and in two patients an aggressive papillary tumor (APT) was diagnosed. We report the clinical, radiologic, morphologic, immunohistochemical and DNA image cytometrical characteristics that can help to correctly classify these tumors. Therapy consisted of surgical excision of the tumors in eight cases. In one elderly patient, only a large biopsy was taken, because this patient suffered from cardial and kidney disorders and was not suitable for an extended surgical approach. This patient received stereotactic radiotherapy. Seven patients underwent planned second look operation. Recurrences occurred in three patients (one with APT, two with MEA), whereas in two of these cases rather a residual tumor due to initial incomplete tumor resection occurred. By image analysis, DNA cytometry MEA were considered benign, whereas the appearance of aneuploid tumor cells in APT confirmed these tumors as low grade malignant lesions. The proliferation rates were equally low in both entities. APT and MEA are tumor entities which can only be correctly classified by a synopsis of histopathology, immunohistochemistry and DNA image cytometry. The recommended therapy is the complete tumor excision. In cases of APT, von Hippel-Lindau syndrome has to be excluded.

Brain abscess formation within an endodermal cyst of the frontal lobe: case report.

A 38-year-old man with a right frontal lobe cyst was treated by endoscopic cystoventriculostomy in 1998. Cyst capsule histology revealed surprisingly an endodermal cyst. The patient was reoperated for cyst expansion by endoscopic re-cystoventriculostomy in 2005. In 2007, the patient suffered from brain abscess formation within the cyst which was punctured. The history was positive for a dental infection. In 2008, a recurrent brain abscess in the cyst occurred. The cyst was completely resected. There was no history of trauma or sinusitis. In all, endodermal cysts may mimic a paraxial arachnoid cyst. It may predispose for recurrent brain abscess formation - especially due to bacteraemia. This report confirms earlier presentations that endodermal cysts should be resected, and endoscopic cyst opening is not sufficient.

Analysis of c-KIT expression and KIT gene mutation in human mucosal melanomas.

Recent data suggested an increased frequency of KIT aberrations in mucosal melanomas, whereas c-KIT in most types of cutaneous melanomas does not appear to be of pathogenetic importance. However, studies investigating the status of the KIT gene in larger, well-characterised groups of patients with mucosal melanomas are lacking. We analysed 44 archival specimens of 39 well-characterised patients with mucosal melanomas of different locations. c-KIT protein expression was determined by immunhistochemistry, KIT gene mutations were analysed by PCR amplification and DNA sequencing of exons 9, 11, 13, 17 and 18. c-KIT protein expression could be shown in 40 out of 44 (91%) tumours in at least 10% of tumour cells. DNA sequence analysis of the KIT was successfully performed in 37 patients. In 6 out of 37 patients (16%) KIT mutations were found, five in exon 11 and one in exon 18. The presence of mutations in exon 11 correlated with a significant stronger immunohistochemical expression of c-KIT protein (P=0.015). Among the six patients with mutations, in two patients the primary tumour was located in the head/neck region, in three patients in the genitourinary tract and in one patient in the anal/rectal area. In conclusion, KIT mutations can be found in a subset of patients with mucosal melanomas irrespective of the location of the primary tumour. Our data encourage therapeutic attempts with tyrosine kinase inhibitors blocking c-KIT in these patients.

[Intratesticular metastasis of renal cancer]. / Intratestikuläre Metastasierung eines Nierenzellkarzinoms.

We report on a 66-year-old man after nephrectomy of the right kidney because of renal cell carcinoma. One year after diagnosis, an osseous metastasis of the right femur occurred and was resected. The following investigations, including positron emission tomography/computed tomography, showed no relapse. Three and a half years after diagnosis, the patient developed a testicular tumor of the right hemiscrotum, which was treated by testicular ablation. The histological investigation showed a testicular metastasis of renal cancer. This case represents one of the unusual forms of metastatic invasion of renal cell cancer.

Influence of vaccination with A/PR 8/34 (HO-N1) influenza virus on the oncogenic activity of polyoma virus in newborn Wistar rats.

Vaccination with the A/PR 8/34 (HO N1) strain of influenza virus can decrease significantly the oncogenic activity of polyomavirus in newborn Wistar rats. This effect was regularly observed when animals were vaccinated with 24 hr after birth, whereas vaccinations performed on Days 3 and 10 failed to influence the oncogenic potential of polyoma virus. In 3 series of experiments, influenza virus vaccination resulted in sigificantly decreased tumor rates, and, in a 4th series, in reduced tumor growth only. Heat inactivation of influenza virus failed to abolish its influence on the oncogenicity of polyoma virus. In most of the experiments, the antibody response to influenza virus was enhanced by inoculation of animals with polyoma virus. In contrast, polyoma virus antibody titers were, in some experiments, decreased, and, in others, not influenced by vaccination with influenza virus.

Increased thermal response to ultrasound in the Walker carcinosarcoma treated with vasoactive drugs.

In order to evaluate the potential of a highly selective Ca2+ entry blocker (nisoldipine) and of 5-hydroxytryptamine (5-HT) as adjuvant in hyperthermia treatment, we studied the differential flow response and time-course of tumor and normal tissue temperature following the administration of the two substances and during ultrasound heating. In 12 rats bearing Walker 256 carcinomas i.p. injection of 0.2-0.4 mg/kg nisoldipine caused a reduction in the tumor-to-muscle flow relationship of 4.4 +/- 1.9 (SD) to 1.74 +/- 0.86 as determined by intraarterial 133Xe injection; i.p. injection of 2-8 mg/kg 5-HT (N = 13) caused a respective reduction from 3.9 +/- 2.67 to 1.3 +/- 1.59. During a 20-min period of 41 degrees C normal tissue temperature-controlled ultrasound heating without drugs, tumor temperature attained 40.8 +/- 0.9 degrees C (N = 16). Nisoldipine or 5-HT injection at continuing 41 degrees C normal tissue temperature controlled energy delivery produced an instantaneous further increment of tumor temperature, eventually to 44.0 +/- 1.14 degrees C or 44.2 +/- 1.26 degrees C, respectively, after a period of 20 min. Injection of 0.9% NaCl (N = 4) solution caused only insignificant changes. Blood pressure and muscle perfusion were distinctly influenced by nisoldipine, but not by 5-HT. Since both drugs instantaneously increased the temperature differential between tumor and normal tissue, though by different vasoaction, they should be considered as adjuvants in hyperthermia.

Surgical removal of primary central nervous system lymphomas (PCNSL) presenting as space occupying lesions: a series of 33 cases.

AIMS: In this study we present a series of 33 patients with primary CNS lymphomas (PCNSL), many presenting with acute signs of increased intracranial pressure due to large space occupying lesions. METHODS: A series of 32 PCNSL patients for a total of 33 tumours treated from 1986 to 2000 in the Neurosurgical Department were reviewed. RESULTS: Radiotherapy and chemotherapy improved survival. No benefit could be demonstrated for the role of surgery. CONCLUSIONS: Our data confirm previous reports about the role of radiation and chemotherapy in the treatment of PCNSL's. Surgery might have a role in a selected subset of patients presenting with large single space occupying lesions and deteriorating neurological status.

[A rare case of isolated prostate metastasis from primary pancreatic cancer]. / Seltener Fall der Metastase eines Pankreaskarzinoms in die Prostata.

An otherwise healthy 66 year old male presented with a suspicious intraprostatic lesion detected by digito-rectal examination. Serum PSA levels were normal. A CT scan of the abdomen revealed a nondistinctive mass within the pancreatic head. A transrectal biopsy confirmed the intraprostatic lesion as a metastatic lesion from pancreatic cancer. Therefore, we report this unusual case of a primary pancreatic carcinoma, clinical stage IV, which led to metastases in the liver and prostate.

Loss of NF1 alleles distinguish sporadic from NF1-associated pilocytic astrocytomas.

Pilocytic astrocytomas classified as WHO grade I typically arise in childhood and upon complete surgical removal carry a favorable prognosis. Children with neurofibromatosis 1 (NF1) have a vastly increased risk for pilocytic astrocytomas, especially for those of the optic nerve. Using 4 intragenic NF1 microsatellite markers, we examined losses of NF1 alleles on the long arm of chromosome 17 in 12 NF1-associated and 25 sporadic pilocytic astrocytomas. The TP53 gene region on the short arm of chromosome 17 was also examined in these tumors using 3 markers. Loss of 1 NF1 allele was detected in 11 of 12 (92%) informative NF1-associated pilocytic astrocytomas. In contrast, only 1 of 24 informative (4%) sporadic pilocytic astrocytomas exhibited allelic loss in the NF1 region. Among the 11 NF1-associated tumors with NF1 loss, 5 had also lost alleles on 17p. The high rate of NF1 allele loss in NF1-associated pilocytic astrocytomas suggests a tumor initiating or promoting action of the NF1 gene in these patients. On the other hand, the much lower rate of NF1-allele loss in sporadic pilocytic astrocytomas argues for only minor importance of NF1 in that patient group. The present data support different mechanisms in the formation of NF1-associated and sporadic pilocytic astrocytomas.

Selective drug-induced reduction of blood flow in tumor transplants.

The effect of a calcium antagonist and a physiologic amine on tumor and muscle perfusion was investigated with the aim of improving the preconditions for external hyperthermia treatment of cancer. Nisoldipine (0.04-4.0 mg/kg) and 5-hydroxy tryptamine (5-HT) (0.2-8.0 mg/kg) were administered i.p. in Sprague-Dawley rats bearing Walker 256 carcinoma, Yoshida sarcoma, or a homologous tumor transplant derived from a spontaneous leiomyosarcoma of the uterus. At the maximum dosage used, nisoldipine injection caused a decrease of the regional washout rate of Xenon-133 of 63 +/- 8% (SEM) in the Walker carcinoma and an increase of 80 +/- 41% in the muscle of the hind leg. 5-HT (8 mg/kg) caused a drop of 79 +/- 29% in the Walker carcinoma and only a slight fall of the washout rate in muscle of 14 +/- 4.8%. Tumor-to-muscle uptake ratios of 11C-butanol fell from 5.63 +/- 1.98 to 3.32 +/- 1.21, and from 5.3 +/- 0.56 to 2.98 +/- 0.30, after injection of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT, respectively. Similar reaction patterns and percentage changes were observed in different tumor lines at constant doses of 0.2 mg/kg nisoldipine and 4 mg/kg 5-HT. Both drugs representing two different rationales of vasomotor action were able to reduce blood flow specifically in transplanted tumors; nisoldipine increased muscle blood flow and decreased arterial blood pressure, whereas 5-HT acted without substantial systemic effects.

Radioisotope therapy of cystic craniopharyngomas.

Eighteen patients suffering from cystic craniopharyngeoma were treated with intracavitary irradiation. The beta-emitting radioisotope 90y (2.25 MeV) was instilled into the cyst following stereotactic puncture of the space-occupying lesion. The surgical approach was planned using angiograms and reconstructed transmission computer tomography (TCT) coronal and saggital sections. Therapy was devised to deliver 20,000 rad to the cyst's wall. Eleven patients received follow-up TCT examinations after four months. Eight of 11 patients had a significant volume decrease in the craniopharyngeoma cyst. In two patients, the cystic volume remained unchanged; one had progression of disease. It is concluded that the intracavitary treatment of cystic craniopharyngeoma will result in a reduction of the size of the space-occupying lesion.

[131I] Hippuran renography in the detection of orthostatic hypertension.

Scintigrams in prone and standing positions were done in 11 hypertensive women. All had nephroptosis with ventral rotation. On the basis of the renograms, seven patients were identified as suffering from orthostatic hypertension. Nephropexy resulted in normalization of blood pressure in six of the seven patients and normalization of the renograms of all seven. We believe that sequence scintigrams in prone and standing positions offer a simple method of identifying patients with orthostatic hypertension.

Nitrogen-13 glutamate uptake and perfusion in Walker 256 carcinosarcoma before and after single-dose irradiation.

Nitrogen-13 (13N) glutamate uptake was recorded in 18 anesthetized rats, both before and at least once after intervention. Each investigation was immediately followed by imaging of blood flow distribution using [11C]butanol. All animals had Walker 256 carcinosarcoma implants in one hind leg. Tumors were locally irradiated with a dose of 800 rad in 14 rats; in four rats, the vasoactive substance 5-hydroxytryptamine (5-HT) was administered. Prior to interventions, the [13N]glutamate tumor-to-muscle uptake showed a linear correlation with blood flow close to identity (y = 0.117 + 0.915x, r = 0.97). After irradiation, a discordant pattern was observed: blood flow tended to increase, while [13N]glutamate tumor-to-muscle uptake dropped from 4.30 +/- 0.66 (s.e.m.) to 3.06 +/- 0.36 (p less than 0.005) during 30 min and attained 4.04 +/- 0.67 2 days later. If [13N]glutamate tumor-to-muscle uptake was related to that of [11C] butanol in each individual animal, this index dropped from 0.93 +/- 0.03 (s.e.m.) to 0.62 +/- 0.04 (p less than 0.001) 30 min after irradiation and attained 0.90 +/- 0.09 after 2 days. In animals treated with 5-HT, [13N]glutamate and [11C]butanol showed a parallel drop from 6.60 +/- 0.84 to 2.10 +/- 0.60 (p less than 0.05) and from 6.8 +/- 0.78 to 2.08 +/- 0.74 (p less than 0.05), respectively. Thus, single-dose irradiation causes [13N]glutamate uptake to be uncoupled with respect to flow, while [13N]glutamate uptake in untreated tumors is flow-limited and responds together with flow on vasomotion.

Effect of methotrexate on perfusion and nitrogen-13 glutamate uptake in the Walker-256 carcinosarcoma.

The tissue uptake of [13N]glutamate (glu) was related to that of [11C]butanol (but), a highly diffusible perfusion tracer. In 25 rats bearing Walker-256 carcinomas tumor-to-muscle glu uptake averaged 6.34 +/- 2.84 (s.d.) prior to interventions and the respective uptake of but was 6.79 +/- 3.08 (y = 0.03 + 0.94x). One hour after selective intraarterial administration of methotrexate (mtx), glu uptake fell by 47%, whereas blood flow remained within the pretreatment range (N = 9). Four hours after mtx, perfusion was reduced by approximately 40%, and 2 days later both perfusion and glu uptake reached extremely low levels. No significant difference in the effect of 10 and 50 mg/kg mtx was observed. Regional tissue mtx uptake estimations using 77Br-labeled bromomethotrexate did not reveal any significant uptake in muscle. The relationship between tumor-to-muscle uptake of glu and but (13N/11C-index) was 0.94 +/- 0.015 (s.e.m., N = 25) before intervention. After methotrexate (1 hr, 4 hr, and 2 days) this index was 0.58 +/- 0.06 (N = 9), and 0.85 +/- 0.04 (N = 11) and 1.03 +/- 0.05 (N = 5), respectively. These values demonstrate an early mtx-induced uncoupling of glu uptake with respect to perfusion.

N-13 L-glutamate uptake in malignancy: its relationship to blood flow.

Studies on glutamate uptake, with special reference to perfusion, were carried out in 35 rats, each bearing one of five different tumor transplants; also in 15 rats after bone fracture, and in three rabbits. Single-pass extraction of N-13 glutamate was 85-93% in the VX2 tumor of the rabbit and in muscle. Bone fracture in rats caused a threefold increase of tracer uptake 2 days after the event. In tumor transplants, the tumor-to-muscle uptake ratio reached a maximum immediately following injection of the tracer. Comparing N-13 glutamate uptake with the retention of 1-121 microspheres, identical tumor-to-muscle ratios were found for three out of five tumor lines. Comparing the uptake with that of C-11 butanol (ten rats), a close correlation was observed throughout the range of tumor lines. The results suggested that glutamate uptake by malignant tumors is related to blood flow. In nine patients with malignant or benign lesions tumor-to-muscle uptake of N-13 glutamate and TI-201 showed a linear correlation close to identity.

Studies with positron emission tomography after systemic administration of fluorine-18-uracil in patients with liver metastases from colorectal carcinoma.

Fluorouracil (FU) is the most common cytostatic agent used for chemotherapy in patients with colorectal tumors. Fifty patients with 78 hepatic metastases from colorectal tumors were examined with positron emission tomography (PET) following intravenous infusion of 18F-FU. The uptake of the cytostatic agent was evaluated in normal liver parenchyma, liver metastases and the aorta. Tracer uptake was expressed with the standardized uptake value (SUV). The maximum liver activity was 11.3 SUV (mean value) with a standard deviation of 1.85 SUV. The highest activity concentrations were noted 30 min (mean value) postinjection. In comparison, the activity concentration of individual metastasis was low. Two hours after tracer injection, the mean activity in metastases was 1.3 SUV, but notable individual variation in uptake was seen. Fluorine-18 concentration values 2 hr after FU infusion were approximately 44% of the FU uptake 20 min postinfusion. Fifty-three metastases were also examined with 15O-labeled water. The examination was performed to compare the uptake of the nonmetabolized tracer with FU uptake. We noted a statistically significant correlation between 15O-water concentration, uptake of nonmetabolized FU 8 min after the end of the infusion and FU retention (120 min postinjection) in a subgroup of metastases. The results suggest that FU retention in different metastases is highly variable and mainly dependent on early FU uptake into tumor cells.