CD98hc (SLC3A2), a novel marker in renal cell cancer.

BACKGROUND: In a variety of malignant diseases, molecular targeting represents a therapeutic option, whereby, when compared with chemotherapy, fewer side effects are thought to be expected. Especially in renal cell cancer (RCC), tyrosine kinase-inhibitors have been established as useful and highly effective therapy. However, tyrosine kinase-inhibitors currently approved for RCC treatment lack single molecule specificity and bear a variety of side effects of the gastro-intestinal tract, skin, heart and haematopoietic system. Therefore, the identification of novel cell surface markers is sought, which might lead to novel diagnostic and therapeutic strategies in cancer. MATERIAL AND METHODS: Paraffin-embedded RCCs from a well characterized tissue bank were immunohistochemically quantified for embryonic transmembrane antigen CD98hc (SLC3A2) expression and semi-quantitative analyses were correlated with subtype or grade of differentiation. RESULTS: We found increased CD98hc expression in different types of malign RCCs, among them clear cell (cc)RCC, papillary (p)RCC and chromophobe (ch)RCC, but lack of expression in the benign renal oncocytoma. Thereby, the extent of CD98hc expression directly complies with grade of malignancy. Furthermore, the more malignant type II pRCC significantly higher expressed CD98hc than the less malignant and more differentiated type I pRCC (type II 83.34%, type I 4.76% CD98hc positive, P < 0.00001; n = 51). The established marker for type I pRCC, Cytokreatin 7, showed 95.24% expression in type I and 26.67% expression in type II pRCC (P < 0.00001, n = 51). CONCLUSIONS: From these data, we conclude that CD98hc is expressed in RCCs, whereby the extent of expression is likely to correlate directly with grade of malignancy. In pRCCs, CD98hc might represent a novel and reliable marker for type II pRCC.

Cultured human epithelium: human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions.

BACKGROUND: Stem cells have the capacity to renew or to give rise to a specialized cell types. Human umbilical cord blood (HUCB) has been explored as an alternative source of stem cells. However, its potential to differentiate into cells of other tissues is still under discussion. The aim of our study was to evaluate if HUCB stem cells could differentiate into epithelial cells under in vitro conditions. METHODS: Human keratinocytes derived from adult female skin donors, were isolated and cultured on fibrin glue/fibroblast gels-control group. In the umbilical cord blood cell group, male umbilical cord blood cells were added at a 1:10 ratio to keratinocytes and co-cultured on the fibrin glue/fibroblasts gel. After 15 days of culture, the sheets were analyzed by use of histochemistry and FISH. DNA was extracted and evaluated by use of polymerase chain reaction (PCR) for detection of Y-chromosome-specific sequences. RESULTS: In both groups a regular epithelial sheet consisting of three to four layers of cells was formed. Using PCR and FISH, in the umbilical cord blood cell group the presence of Y-chromosome-specific sequences in the cultured keratinocytes could be detected. In the control group, no Y-chromosome-specific sequences could be detected. CONCLUSION: Our findings indicate that umbilical cord blood stem cells differentiate into epithelial cells under in vitro conditions and thereby, might serve as a starting material for isolation and expansion of cells for transplantation in patients with large skin defects.

Neurolysis: is it beneficial or harmful?

The term internal neurolysis means removal of fibrotic tissue inside a nerve trunk. Unfortunately the term was used for procedures with complete isolation of fascicles with all consequences like damage of links between the fascicle and impairment of blood supply. The conclusion based on some negative experiences that all surgery within a nerve trunk has to be avoided cannot be accepted. Neurolysis within a nerve trunk, id est within the epineurium, is a step-wise procedure to decompress fascicles from a constricting fibrosis. It stops immediately if this aim is achieved or continues with resection and reconstruction if an irreparable damage is present. It is better to use terms that describe exactly what was done and abandon the ill-defined term "internal neurolysis". Fibrosis of the paraneurium remains outside the epineurium but causes the same consequences as fibrosis of the epineurium.

Epidural metastasis of a glioblastoma after stereotactic biopsy: case report.

Tumor seeding along the biopsy tract is a rare complication in stereotactic biopsy. We present the unique case of a 42-year-old male with epidural tumor seeding along the needle tract after computer tomography-guided stereotactic biopsy of a glioblastoma in the right basal ganglia. Three months after the biopsy and one week following fractionated radiation therapy, the patient died of brain edema and cardiac dilatation. Besides further tumor growth at the primary site, autopsy revealed a right frontal epidural, nodular metastatic tumor at the site of dura incision of the stereotactic biopsy. Histological examination showed a glioblastoma that spread epidurally along the needle tract. This is the first report of an epidural intracranial implantation metastasis of a glioblastoma after stereotactic biopsy.

Prognostic relevance of intracytoplasmic cytokeratin pattern, hormone expression profile, and cell proliferation in pituitary adenomas of akromegalic patients.

Seventy-six pituitary adenomas of akromegalic patients were investigated to find out the prognostic relevance of the intracytoplasmic distribution of cytokeratins (CK), immunohistochemically defined hormone production profile, proliferative activity and clinical presentation. CK distribution, growth fraction (MIB1 index) and hormone production profile were analyzed by means of immunohistochemistry. Apoptotic activity was investigated by the TUNEL method. Two different CK distribution patterns were seen: a dot-like pattern in 29 cases (type 1 adenomas), and a perinuclear fibrillary pattern in 47 cases (type 2 adenomas). Type 2 adenomas showed more prominent coexpression of prolactin (p < 0.0001), luteotrophic hormone (p < 0.002), follicle-stimulating hormone (p < 0.005), thyroid-stimulating hormone (p < 0.0001), and alpha-subunit (p < 0.005), as compared to type 1 adenomas. The mean MIB1 index was significantly higher in type 1 vs. type 2 tumors (4.23%, range: 1.93% - 9.83% vs. 2.07%, range: 0.67% - 4.87%, p < 0.0001). Apoptotic activity was too low in both examined groups to be used for balancing of tumor cell turnover. Clinical analysis of patients with type 1 adenomas revealed female predominance, younger age, larger tumor size, and more frequently aggressive growth with higher incidence of suprasellar extension (p < 0.0001) and cavernous sinus infiltration (p < 0.0001), as well as larger proportions of re-operations and incomplete resections (34.5% vs. 8.51%). Additionally, the interval until re-operation was shorter in type 1 adenomas (mean: 16 months, range: 9 - 21 months vs. mean: 57 months, range: 18- 158 months). We conclude that classification of adenomas of akromegalic patients based on intracytoplasmic CK distribution, combined with examination of proliferative activity, and immunohistochemically defined hormone production profile, provides important prognostic information for the management of akromegalic patients.

Spatial distribution of prostate cancers undetected on initial needle biopsies.

OBJECTIVES: The spatial distribution of cancer foci of prostate carcinomas with negative initial biopsies was compared to that of prostate carcinomas with positive initial biopsies to detect areas in which carcinomas were more frequently located when the initial biopsy was negative. METHODS: Twenty patients with prostate cancer and a negative initial biopsy trial were detected among 218 patients with preceding systematic biopsies (9.2%) in our hospital. Analysis of the prostatectomy specimens regarding cancer distribution, multifocality, tumour size, Gleason score, and stage was performed using pathohistological techniques and three-dimensional computer reconstruction. RESULTS: Prostatectomy specimens with negative initial biopsies showed more frequently cancer foci in apical (p<0.0001) and dorsal (p<0.02) prostatic compartments, higher incidence of multifocality (p<0.01), and smaller size of carcinoma foci (p<0.00003) compared to carcinomas in 81 stage-matched prostatectomy specimens with positive initial biopsies. Comparing both groups, no significant differences were noted in Gleason score of preoperative biopsies and prostatectomies, prostate weight, prostate-specific antigen (PSA) level, digital rectal examination, and patients age. CONCLUSIONS: Missing the cancer in clinically significant prostate carcinomas by current systematic biopsy techniques may also be due to an apico-dorsal cancer location, particularly in combination with multifocality and small size of carcinoma foci in large prostates. In case of reasonable clinical suspicion of prostate cancer and negative initial biopsy, an early repeat biopsy with special emphasis on the apico-dorsal peripheral zone should be envisaged.

Fibroblasts can express glial fibrillary acidic protein (GFAP) in vivo.

Neuropathologists use anti-glial fibrillary acidic protein (GFAP) antibodies as specific markers for glial cells, and neurobiologists use GFAP for targeting transgenes to glial cells. Since GFAP has also been detected in non-glial cells, we systematically analyzed GFAP expression in human and murine non-CNS tissues using a panel of anti-GFAP antibodies. In human tissues we confirm previously observed GFAP expression in Schwann cells, myoepithelial cells, and chondrocytes, and show for the first time GFAP expression in fibroblasts of epiglottic and auricular perichondrium, ligamentum flavum, and cardiac valves. In mice we show GFAP expression in Schwann cells, bone marrow stromal cells, chondrocytes, and in fibroblasts of dura mater, skull and spinal perichondrium, and periosteum, connective stroma of oral cavity, dental pulp, and cardiac valves. Anti-GFAP immunoblotting of human non-CNS tissues reveals protein bands with a molecular mass ranging between approximately 35 and approximately 42 kDa. In GFAP-v-src transgenic mice, whose oncogenic v-src transgene transforms GFAP expressing cells, non-CNS tumors originate from fibroblasts. We conclude that human and murine fibroblasts can express GFAP in vivo. The somatic distribution of GFAP expressing fibroblasts indicates origin from the neural crest. Development of non-CNS tumors from fibroblasts in GFAP-v-src mice functionally confirms GFAP expression in these cells.

Pseudogliomatous growth pattern of anaplastic small cell carcinomas metastatic to the brain.

Carcinomas metastatic to the brain usually grow very well circumscribed, with sharp delineation. Radiosurgery takes advantage of this fact by using the gamma knife for definitive treatment of small metastases. We report a systematic study of the growth pattern of cerebral metastases, focusing on tumor delineation. In 26 cases of 66 metastatic anaplastic small cell carcinomas and in one case of adenocarcinoma, we observed poorly defined borders and a highly diffuse pattern of invasion. Infiltrating carcinoma cells changed to an elongated shape adapting to preexisting tissue structures. This pseudogliomatous growth pattern of some brain metastases--apparently most likely in neuroendocrine carcinomas--is of potential importance for therapeutic strategies in the treatment of brain metastases, especially when considering treatment with radiosurgery and gamma knife.

Kynurenic acid metabolism in the brain of HIV-1 infected patients.

Patients who are infected with human immunodeficiency virus type 1 (HIV-1) frequently present with neurological and psychiatric symptoms. Kynurenic acid (KYNA), an intermediate metabolite of L-kynurenine (L-KYN), is a neuroprotectant and a broad-spectrum antagonist at excitatory amino acid (EAA) receptors. The present study examines the biosynthetic machinery of KYNA in the frontal cortex and cerebellum of 25 HIV-1 and 16 control (CO) patients. We measured the contents of L-KYN and KYNA and the activity of enzymes synthesizing KYNA, kynurenine aminotransferases I and II (KAT I and KAT II). The KYNA level was significantly increased in the frontal cortex (209 +/- 38% of CO; p < 0.05) and moderately increased in the cerebellum (164 +/- 31% of CO) of HIV-1 brains as compared with controls. The bioprecursor of KYNA, L-KYN, was increased in frontal cortex (188 +/- 45% of CO) and cerebellum (151 +/- 16% of CO; p < 0.05). The elevated KYNA in frontal cortex correlated with significant increases of KAT I (341 +/- 95% of CO; p < 0.05) and KAT II (141 +/- 8% of CO; p < 0.05). In the cerebellum, a high KYNA content was in the line with increased KAT I (262 +/- 52% of CO; p < 0.05) activity, while KAT II was in a control range (85 +/- 12% of CO). This study demonstrates that HIV-1 infection associates with elevated KYNA synthesis in the brain. In contrast to KAT II, KAT I was prominently increased in both brain regions investigated. Differences in neurochemical parameters of KYNA metabolism between frontal cortex and cerebellum suggests selective tissue damage. Drugs which influence the synthesis of the endogenous neuroprotectant KYNA may become useful in the therapy of neuropsychiatric manifestations of HIV-1 infected patients.

Renal oncocytoma with prominent intracytoplasmic vacuoles of mitochondrial origin.

AIMS: We observed two oncocytomas with prominent intracytoplasmatic vacuoles. To investigate if this previously undescribed finding is a diagnostic feature and compatible with the diagnosis of oncocytoma, we characterized these vacuoles by electron microscopy and immunohistochemistry. METHODS AND RESULTS: The tumours were analysed by transmission electron microscopy. Immunohistochemistry was performed with antimitochondrial antibody, anti-Golgi-zone antibody, anti-lysozyme antibody and anti-human-trans-Golgi-network antibody. By electron microscopy, the vacuoles were found to be double-membrane-bounded, and some contained fragmented christae. Immunohistochemistry showed a positive reaction of the vacuoles with anti-mitochondrial antibody. Staining with anti-Golgi-zone antibody, anti-lysozyme antibody and anti-human-trans-Golgi-network antibody was negative. CONCLUSION: Both tumours are benign oncocytomas. The phenomena of cells with prominent intracytoplasmatic vacuoles is not inconsistent with the diagnosis of oncocytoma. The vacuoles are of mitochondrial origin and may develop, by balloon degeneration, as a mechanism of mitochondrial involution and elimination.

No tissue damage by chronic deep brain stimulation in Parkinson's disease.

We report on the pathological findings in the brains of 8 Parkinson's disease patients treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (6 cases) and subthalamic nucleus (2 cases). DBS was performed continuously for up to 70 months. All brains showed well-preserved neural parenchyma and only mild gliosis around the lead track compatible with reactive changes due to surgical placement of the electrode. We conclude that chronic DBS does not cause damage to adjacent brain tissue.

Capillary haemangioma of the testis.

A case of testicular capillary haemangioma is reported and the importance of intraoperative examination of this very rare lesion emphasised. Capillary haemangioma of the testis can be similar to malignant testicular tumours on clinical presentation, as well as on ultrasonography and magnetic resonance imaging, and therefore should be included in the intraoperative differential diagnosis. Because of the benign nature of this lesion, conservative surgical treatment by means of tumour enucleation with preservation of the testis is possible, if intraoperative examination of frozen sections of representative tissue can be performed.

Exocrine pancreatic function in critically ill patients: septic shock versus non-septic patients.

OBJECTIVE: To determine the exocrine pancreatic function in critically ill patients. DESIGN: Prospective cohort study. SETTING: Medical intensive care unit. PATIENTS: A total of 18 critically ill patients (11 patients with septic shock according to the criteria of the American College of Chest Physicians/Society of Critical Care Medicine, 7 nonseptic patients). The results obtained in these subjects were compared with the data obtained in seven healthy volunteers. INTERVENTIONS: Examination of exocrine pancreatic function was done by means of a cholecystokinin-secretin test. Intravenous stimulation of the exocrine pancreas with cholecystokinin and secretin (1 unit/kg body weight/hr each) and aspiration of duodenal fluid by a gastroscopically inserted oroduodenal tube was done during a period of 1 hr. MEASUREMENTS AND MAIN RESULTS: The content of amylase, chymotrypsin, and trypsin in aspirated duodenal fluid was significantly reduced in patients with septic shock compared with nonseptic patients as well as healthy subjects (p < .01). The volume of aspirated fluid was significantly reduced in patients with septic shock compared with healthy controls (p = .03), but not in nonseptic patients. The content of bicarbonate was not statistically different in the three groups. No significant correlation was to find between variables of exocrine pancreatic function and Acute Physiology and Chronic Health Evaluation III score, sepsis-related organ failure assessment score, systolic arterial pressure and mean arterial pressure in septic shock patients. Positive end-expiratory pressure was significantly correlated with the content of trypsin (r2 = 0.52; p = .02). Postmortem examinations of five septic patients who died during the intensive care stay did not reveal gross morphologic alterations of pancreatic tissue. CONCLUSIONS: The study shows two pancreatic enzyme systems, namely, amylase as a carbohydrate splitting enzyme and the proteolytic enzymes trypsin and chymotrypsin, strongly affected in critically ill patients with septic shock.

Resection of a Langerhans cell histiocytosis granuloma of the hypothalamus: case report.

The natural course and optimal treatment for isolated hypothalamic Langerhans cell histiocytosis (LCH) are unknown. We describe an adult female in whom total resection of a hypothalamic LCH granuloma was performed 12 years after transphenoidal resection of a pituitary adenoma. A retrospective review of the histological specimen of the first operation revealed CD1a positive cells characteristic of LCH along with a plurihormonal adenoma 12 years earlier. No other manifestations of LCH were found and MRI of the brain at the last follow-up 4 years after surgery did not show any recurrent or additional lesion. The diagnosis of isolated hypothalamic LCH is only possible by biopsy and our case demonstrates the feasability of a gross total resection in certain cases.

Expression of the CD40 antigen on normal endothelial cells and in benign and malignant tumours of vascular origin.

CD40, a member of the nerve growth factor/tumour necrosis factor-receptor family, is expressed on endothelial cells in situ and in tissue culture. It is functionally involved in the regulation of the expression of adhesion molecules in these cells. In the current study we investigated the expression of CD40 on the endothelia of normal fetal and adult human tissues, as well as in the stroma of various neoplasms and in different inflammatory tissue reactions. By immunohistochemistry, endothelia were negative or only weakly positive for CD40 in all normal adult and most fetal organs studied. In contrast, endothelial cells of fetal and embryonic lungs, kidneys and larger vessels consistently expressed the CD40 antigen. Strong expression of CD40 on endothelial cells of blood vessels but not of lymphatic vessels was found in inflammatory reactions. In 65 tumours of vascular origin we found moderate to strong expression of CD40 in all of four juvenile proliferating capillary haemangiomas and 11 lobular capillary haemangiomas of adults. Senile and cavernous haemangiomas as well as lymphangiomas were negative or exhibited only weak CD40 reactivity. Weak to moderate CD40 expression was found in five of eight malignant neoplasms of endothelial origin. Our finding that the CD40 antigen is present on only a minority of normal endothelial cells, whereas strong staining can be detected on the majority of endothelial cells in inflammatory processes, complements previous reports which suggest that this surface receptor plays an important role in tissue inflammation. The heterogeneous pattern of expression in malignant endothelial neoplasms argues against a major role for CD40 in the pathogenesis of these tumours. Its consistent presence in juvenile and lobular capillary haemangiomas suggests rather the involvement of CD40 in the development and/or progression of these benign vascular proliferations.

Repermeation of partially embolized cerebral arteriovenous malformations: a clinical, radiologic, and histologic study.

PURPOSE: To describe the pattern and time course of embolization-related tissue lesions and repermeation of the intranidal cast after endovascular embolization of cerebral arteriovenous malformations (AVMs) with N-butyl cyanoacrylate (NBCA). METHODS: We retrospectively reviewed the records of 26 patients who were treated by endovascular embolization with NBCA and subsequent surgical extirpation to look for embolization-related tissue lesions and repermeation of the cast. A residual flow through the malformation was identified on preoperative angiograms in every case. RESULTS: Pattern and time course of embolization-related tissue lesions were typical. Until 3 months after embolization, repermeation of embolized structures did not occur. In contrast, repermeation was found in every patient who had surgery later than 3 months after the first embolization (n = 13; 50%). In these cases, histologic examination of the resected nidus disclosed capillary structures inside the lumen of embolized vessels. Capillaries were traced immunohistochemically with antibodies against membrane-bound factor VIII. No parameter other than the interval between the first embolization and surgery was found to relate to the repermeation of the cast. CONCLUSION: Intranidal recapillarization can occur later than 3 months after the first embolization with NBCA if total and solid casting of the nidus was not accomplished.

Langerhans cell histiocytosis of the hypothalamus: diagnostic value of immunohistochemistry.

The immunophenotype of 6 cases of Langerhans cell histiocytosis (LCH) of the hypothalamus and 3 cases of cranial bone manifestation of LCH was investigated by means of immunohistochemistry on paraffin sections. Antibodies against S 100 protein, lysozyme, CD68 (PG-M1), CD68 (KP1), HLA-DR, beta 2 microglobulin, placental alkaline phosphatase (PLAP), the monoclonal antibody MAC 387, and a monoclonal antibody against CD1a were used. All examined cases showed positive staining of lesional cells for S 100 protein, HLA-DR, beta 2 microglobulin, macrophage associated markers and CD1a. According to the "confidence levels" of the Writing Group of the Histiocyte Society [Chu et al. 1987], a "definite diagnosis" of LCH requires the demonstration either of Birbeck granules in lesional cells by electron microscopy, or of CD1a antigenic determinants on the surface of lesional cells. Since electron microscopy of these rare CNS lesions is not possible in many cases, we are now able to give a definite diagnosis of LCH of the hypothalamus by means of immunohistochemistry for CD1 a on routinely fixed and processed tissue.

Trilobar holoprosencephaly ("triprosencephaly"): a unique type of cerebral malformation.

Little is known about the neuropathology of the median facial cleft syndrome, which presents as a combination of a wide range of teratological manifestations. We report a unique type of cerebral malformation combined with the median facial cleft syndrome in a 7-day-old female infant with malformations of toes and fingers, hypertelorism and a median cleft nose, as well as a frontally protruding, dorsomedian hornlike cele. At autopsy, the cranium presented facial clefts and bony defects, resulting in partitioning of the anterior cranial fossa into three compartments. The brain had malformative features of lobar holoprosencephaly combined with tripartition of frontal lobes, including an encephalomeningocystocele originating from a right accessory frontal lobe.