Adjuvant sequential chemoradiation therapy in high-risk endometrial cancer: results of a prospective, multicenter phase-II study of the NOGGO (North-Eastern German Society of Gynaecological Oncology).

PURPOSE: The management of high-risk endometrial cancer (HREC) remains controversial. We conducted a prospective multicenter phase-II clinical trial to evaluate an adjuvant chemotherapy (CT) with sequential radiotherapy (RT) in patients with HREC. METHODS: Patients with HREC from 8 institutions in Germany were enrolled. After surgery, patients received four cycles of paclitaxel 175 mg/m² (P) and carboplatin AUC5 (C) (d1, q21d) and subsequent external pelvic radiation therapy (1.8 Gy/d, d1-5) at a total dose of 45 Gy with vaginal brachytherapy (3 × 5 Gy). Quality of life (QoL) was assessed using the EORTC-QLQ-C30 questionnaire. Primary endpoints were tolerability, toxicity and QoL. Progression-free survival (PFS) was defined as secondary endpoint. RESULTS: Thirty-five patients were enrolled from 2004 through 2008. Median follow-up was 24 months (range 3-24 months). All patients received 4 cycles of P and C and completed RT. Overall, grade 3/4 haematological toxicity was 25.6 %. Three cycles were delayed because of leukopenia. Grade 3/4 non-haematologic toxicities were rare (≤3 %). No overall change in QoL occurred during treatment. Two-year median PFS and OS rates were both 75.8 %. CONCLUSIONS: Adjuvant combination CT with P + C and sequential RT is well tolerated and a feasible regimen in patients with HREC. Subsequent phase-III trials are warranted.

A 45-year-old female with hypokalemic rhabdomyolysis due to VIP-producing composite pheochromocytoma.

The watery diarrhea, hypokalemia and achlorhydria (WHDA) syndrome due to vasoactive intestinal polypeptide (VIP)-producing extra-pancreatic tumors is rare. We report on a 45-year-old woman who suffered from persistent secretory diarrhea for six years and who was admitted to hospital with complaints of muscular weakness and myalgia. Biochemical testing revealed pronounced rhabdomyolysis due to severe hypokalemia. Gastrointestinal evaluation of long-standing diarrhea including endoscopy of the upper and lower gastrointestinal tract and the small intestine did not show any pathologies. An abdominal computed tomography scan revealed a mass of 4 × 5 cm in the left adrenal gland demonstrating a strong uptake in the 123I-labelled metaiodobenzylguanidine scintigraphy. Plasma levels of chromogranin A, calcitonin, parathormone, basal renin and most prominently VIP were increased in line with a increased 24 hour urinary secretion of noradrenaline, dopamine, normetanephrine and vanillymandelic acid. A WDHA (watery diarrhea, hypokalaemia, achlorhydria) syndrome with hypokalemic rhabdomyolysis due to a VIP-producing adrenal tumor was diagnosed that was removed surgically. The histological evaluation demonstrated a composite pheochromocytoma. Diarrhea stopped immediately after surgery together with a normalization of laboratory parameters. In conclusion, this case report focuses on the rare clinical presentation of secretory diarrhea and electrolyte disturbances in combination with hypokalemic rhabdomyolysis which was caused by a VIP-producing composite pheochromocytoma.

Anticoagulation in neurointerventions: basic pharmacology and pathophysiology, current status, practical advice.

This article gives an overview of anticoagulative medication accompanying neurointerventional procedures. The basic pharmacology of prevalent medication is outlined and the thrombogenicity of standard procedures is described. A brief overview of the literature on risks and benefits of standard medications and their monitoring is provided. A customized regime of care is presented.

Characterization of direct and indirect cerebral revascularization for the treatment of European patients with moyamoya disease.

BACKGROUND: The best revascularization strategy for moyamoya disease (MMD) remains unknown. Our aim was to characterize angiographic revascularization effects of a bilateral standardized revascularization approach, consisting of superficial temporal artery (STA)-middle cerebral artery (MCA) bypass and encephalomyosynangiosis (EMS) on one hemisphere and single EMS on the contralateral hemisphere of each patient, and to compare the effects of both revascularization strategies on cerebral hemodynamics. METHODS: In 30 patients (18 females/12 males, age 8-63 years), standardized revascularization was performed. Digital subtraction angiography was performed preoperatively and at 7 days, 6 months and 12 months postoperatively. STA-MCA and EMS functions were graded I (poor), II (medium) or III (extensive) according to angiographic aspects. In 20 patients, cerebrovascular reserve capacity (CVRC) was assessed pre- and postoperatively (at 12 months) using xenon CT. RESULTS: After 12 months, STA-MCA/EMS function was grade 1 in 40/40%, grade 2 in 27/26%, and grade 3 in 27/10% of hemispheres, respectively. Twelve months after surgery, single EMS showed grade I in 37%, grade II in 27%, and grade III in 20% of hemispheres. Combined revascularization improved CVRC significantly compared to preoperative measurement (preoperative: 16.5 ± 34.6% vs. postoperative: 60.8 ± 64.22%; p < 0.05). Single EMS did not improve CVRC significantly (preoperative: 21.8 ± 35.9% vs. postoperative: 34.8 ± 63.0%; p < 0.05). CONCLUSIONS: Combined and indirect revascularization may be successfully applied in a bilateral standardized approach. STA-MCA/EMS is superior to single EMS in restoring CVRC in adult MMD patients.

First evaluation of the Joint Clinical Registries of the Coordinating Tumor Center of Berlin.

In the present study, we report the first analysis of the clinical management [corrected] of patients with primary ovarian cancer following the summarized data of the Joint Clinical Registries of the Coordinating Tumor Center of Berlin (Dachverband Tumorzentrum Berlin e.V.). All data were summarized for the period of 2005 to 2008 regarding age, histopathology, time of surgical intervention, follow-up and survival, based on 1124 provided data sets of patients with suspected ovarian tumours. We identified 946 patients with a diagnosis of primary ovarian cancer, mostly of advanced T3 tumour stage (63.7%), FIGO III and IV stage (40.6%) or grade II and III (91%) histology. The median age at time of diagnosis was 61 years (range 15 to 94 years). Most patients (n=414, 69.8%) underwent cytoreductive surgery within one month of diagnosis. The median follow-up period was 26 months; 241 patients died in the analyzed period. The calculated 3-year survival rate was 63.3%, although the median overall survival has not yet been reached. We detected positive correlation of tumour stage (p<0.001) and of FIGO stage (p<0.001) with survival, and these were evaluated as being prognostically significant. The implementation of institutional based clinical registries as part of the modern clinical management of patients with ovarian cancer is feasible and well accepted inside the gynaecological departments of Berlin.

Effect of mouth opening on bypass function after combined revascularization for Moyamoya disease.

Moyamoya disease represents a rare steno-occlusive disease of the internal carotid artery (ICA) with a reactive and pathological basal network of collateral vessels. It may lead to ischemic stroke or intracerebral hemorrhage. Treatment options are either direct or indirect revascularization procedures or a combination thereof. Specialized centers report sufficient revascularization in most patients and low complication rates.Between 2005 and 2008, direct extra-intracranial bypass surgery in combination with encephalomyosynangiosis (EMS) was performed in 71 Moyamoya patients at the Mannheim University Medical Center.Following one case of reversible neurological deficits associated with mouth opening, we prospectively evaluated the effect of mouth opening on bypass function in this patient and four further consecutive patients by digital subtraction angiography.Three out of five patients showed alterations in bypass patency upon mouth opening. The obstruction was located at the junction of the bypass and the temporal muscle. Two temporary occlusions and one case of decreased flow were observed. One patient demonstrated reversible hemiparesis and aphasia.

Dual-energy CT after peri-interventional subarachnoid haemorrhage: a feasibility study.

PURPOSE: The aim was to assess the feasibility of dual-energy computed tomography (DE-CT) for detection of peri-interventional re-bleeding in patients with aneurysmal subarachnoid hemorrhage (re-SAH). METHODS: For in vitro-analyses DE-CT of partially clotted blood intermixed with fresh blood containing contrast agent was performed. In a clinical setting, 4 patients routinely underwent DE-CT after suspected peri-interventional re-SAH. DE-CT source data images, iodine maps and virtual non-contrast images (VNC) were analyzed and regions-of-interest (ROI) measurements of density values were performed. RESULTS: In vitro experiments demonstrated the feasibility of DE-CT to discriminate between blood with and without contrast agent. In all patients peri-interventional re-SAH was confirmed by detection of extravasated iodine within the subarachnoid spaces in post-interventional DE-CT. Dual-energy CT allowed the discrimination of old blood clots of the initial SAH and blood originating from peri-interventional re-SAH. After subtraction of the iodine-related high density signal, VNC images optimized the estimation of the true amount of subarachnoid blood. CONCLUSION: Dual-energy CT allows the discrimination and subtraction of blood and iodine mixed within the subarachnoid spaces in patients with peri-interventional re-SAH. It helps to avoid overestimation of SAH after peri-interventional re-bleeding and therefore is a potentially valuable tool in the assessment of peri-interventional re-SAH.

Multiple post-translational modifications of mouse insulin-like growth factor binding protein-6 expressed in epithelial Madin-Darby canine kidney cells.

Insulin-like growth factors (IGFs), IGF receptors and IGF binding proteins (IGFBPs) participate in the regulation of proliferation and differentiation of epithelial cells. Expression of the growth-inhibitory murine IGFBP-6 in epithelial Madin-Darby canine kidney (MDCK) cells followed by 2D analysis revealed the presence of multiple isoforms. Metabolic labelling experiments showed that several IGFBP-6 isoforms are modified by phosphate and sulfate groups. Expression analysis of mutant IGFBP-6 further demonstrated that serine residue 143 is O-glycosylated. Substitution of serine 143 by alanine did slightly reduce the preferential sorting of mIGFBP-6 to the apical site in MDCK cells grown on semipermeable filters. Both the presence of multiple and heterogeneously modified isoforms of murine IGFBP-6 in MDCK cells, and the preferential secretion of non-glycosylated IGFBP-6 mutants to the apical side suggest that the major apical sorting signal is the protein moiety.

Very early extubation after open-heart surgery in children does not influence cardiac function.

The objective of our study was to evaluate hemodynamic effects and the cardiac function after very early extubation within the first 6 hours after open-heart surgery in children. During a 12-month period, we performed a retrospective study of 50 children (ages 3 months to 7 years) admitted to the pediatric intensive care unit immediately after minor cardiac surgery. All children were extubated within the first 6 hours after their arrival. Arterial blood and central venous pressure were monitored, and arterial blood gas analysis was performed. Cardiac index, stroke volume index, systemic vascular resistance index, and extravascular lung water index were measured by thermodilution. Early extubation of children after minor open-heart surgery with cardiopulmonary bypass is safe and does not affect cardiac functions. A slight decrease of arterial oxygen tension not resulting in respiratory or metabolic acidosis or reintubation was noted. Very early extubation in children after open-heart surgery does not promote cardiodepressive effects. It is a safe procedure that helps to reduce the unnecessary and prolonged mechanical ventilation of children after cardiopulmonary bypass surgery.

[Molecular principles of alternative treatment approaches for hormone-refractory prostate cancer]. / Molekulare Grundlagen alternativer Therapieansätze für das hormonrefraktäre Prostatakarzinom.

Prostate cancer is more frequently diagnosed in men from Western countries than from Asian societies. Therefore, nutritional factors such as phyto-oestrogens from soya are considered to cause this prostate cancer prevention effect. As there is no curative therapy for hormone-refractory prostate cancer, new strategies are in demand which might include phyto-oestrogens or inhibitors of histone deacetylases. Both approaches have in common the potential to reduce the aberrant androgen receptor and IGF receptor signalling. Furthermore, invasiveness and acquired survival strategies of tumours can be diminished. Reduced tumour cell proliferation and PSA secretion coincide with altered gene expression in the aforementioned processes. In addition, selective knock-down of genes by RNA interference afforded functional analyses regarding impact and succession of expression events involved in the beneficial effects caused by phyto-oestrogens and histone deacetylase inhibitors.

[A 22 year old woman with fever, night sweats, weight loss and hepatomegaly]. / 22-jährige Frau mit Fieber, Nachtschweiss, Gewichtsverlust und Hepatomegalie.

A 22 year old female patient presented with fever, night sweats, weight loss and hepatomegaly associated with elevated inflammatory parameters and liver enzymes. Computer tomography revealed a mass located between the inferior vena cava and the psoas muscle as well as enlarged celiac, retroperitoneal and retrocaval lymph nodes. Biopsies of the retrocaval mass led to the diagnosis of retroperitoneal fibrosis. Within a few days of treatment with corticosteroids clinical presentation improved and imaging studies detected complete regression of the retrocaval mass after 6 months.

Oxygen: modulator of physiological and pathophysiological processes in the liver.

Oxygen has important functions as substrate for biochemical reactions and as modulator of gene expression. In the liver, the physiologically occurring oxygen gradient is a major effector of metabolic zonation. In addition, cross-talks between the O2 signaling and nutrient signaling chains initiate a dynamic zonation pattern. Under pathological situations, hypoxia appears to be a major determinant for liver diseases and cancer. Thereby transcription factors of the HIF family are activated whereas USF proteins have the potential to counteract HIFs. In addition, feedback mechanisms between hypoxia, HIF and the IGF axes appear to exist. Thus, the knowledge of these mechanisms may help to initiate new therapies in diseases with disturbed O2 availability.

Thyrohyoid approach to cidofovir injection: a case study.

Various techniques for injection into the larynx have been well described, including transoral injection with indirect laryngoscopy or direct laryngoscopy and transcutaneous injection through the thyroid cartilage or cricothyroid membrane. We describe a case not amenable to these techniques, in which entry through the thyrohyoid membrane for injection of cidofovir was successfully performed with a thyrohyoid approach. This technique is described, and comparisons are made with currently available techniques.

The role of the IGF axis in hepatocarcinogenesis.

Primary hepatocellular carcinoma (HCC) is one of the most common forms of malignant cancer with the fourth highest mortality rate worldwide. Major risk factors for the development of HCC include chronic infections with the hepatitis B or C virus, alcohol consumption, exposure to dietary aflatoxin B1, hereditary liver disease or liver cirrhosis of any etiology. Recent studies have discovered changes in the insulin-like growth factor (IGF) axis that affect the molecular pathogenesis of HCC, including the autocrine production of IGFs, IGF binding proteins (IGFBPs), IGFBP proteases, and IGF receptor expression. Characteristic alterations detected in HCC and hepatoma cell lines comprise the overexpression of IGF-II and the IGF-I receptor emerging as critical events in malignant transformation and growth of tumors. Simultaneous reduction of IGFBP expression and the increase in proteolytic cleavage of IGFBPs result in an excess of bioactive IGFs. Finally, defective functions of the IGF-II/mannose 6-phosphate receptor involved in degradation of IGF II, the activation of the growth inhibitor TGF-beta1, and the lysosomal targeting of cathepsin proteases capable to degrade extracellular matrix proteins may contribute to the development of HCC.

Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators.

The genesis of hepatocellular carcinoma is promoted by changes in the regulatory MDM2-P14ARF system. The incidence of such changes has to date not been analysed in non-tumourous livers showing regenerative proliferation. In the present study, 24 cirrhotic livers of alcohol-, autoimmue disorder- or HCV-caused genesis were screened for MDM2-P14ARF alterations at the level of protein, DNA and mRNA. Using confocal laser scanning microscopy, the absence of MDM2 and P14ARF expression was detected in all samples except three HCV-infected livers (four livers) which contained hepatocytes overexpressing MDM2 (P14ARF) protein. In two of the samples lacking P14ARF expression, laser microdissection and PCR demonstrated deletion of the P14ARF gene. The P14ARF gene amplified from other specimens did not carry mutations. MDM2 splicing variants were present in tissues from alcohol- and autoimmune disorder-induced cirrhoses. Sequencing of full-size mRNA revealed a MDM2 mis-sense mutation in an alcohol-induced cirrhosis. One sample contained regenerative nodules with genetic instability occurring at MDM2 locus D12S83 according to the data of automatic PCR fragment analysis. In summary, this study gives first evidence for different types of MDM2 and P14ARF alterations in cirrhotic livers. We suggest that the changes impair the regulatory MDM2-P14ARF system, thus possibly favouring regenerative proliferation and transformation.

Regulation of insulin-like growth factor-I and of insulin-like growth factor binding protein-1, -3 and -4 in cocultures of rat hepatocytes and Kupffer cells by interleukin-6.

BACKGROUND/AIMS: Catabolism is associated with decreased serum concentrations of insulin-like growth factor (IGF)-I and insulin-like growth factor binding protein (IGFBP)-3 associated with elevated IGFBP-3 protease activity and increased concentrations of IGFBP-1 and -4. The effects of the acute phase mediators interleukin (IL)-6, IL-1beta and tumor necrosis factor alpha (TNFalpha) on the biosynthesis of IGF-I and IGFBPs were studied in primary rat liver cells. METHODS: mRNA levels of IGF-I and of IGFBPs were analyzed by Northern blotting, secretion of IGFBPs by [(125)I]IGF-I ligand blotting. Proteolytic activity was measured using iodinated recombinant IGFBP-3 as the substrate. RESULTS: In hepatocytes, Kupffer cells (KC) and cocultures of hepatocytes with KC, IL-6 reduced IGF-I biosynthesis dose-dependently. IL-6 stimulated mRNA expression and protein secretion of IGFBP-1 and -4 in hepatocytes and that of IGFBP-3 in KC, respectively. In cocultures, biosynthesis of IGFBP-1, -3 and -4 was increased dose-dependently by IL-6, while the effects of IL-1beta or TNFalpha were less prominent. At neutral pH, proteolytic activity against IGFBP-3 was not detected in media of cocultures treated with IL-6. CONCLUSIONS: The alterations of IGF-I, IGFBP-1 and -4 observed in catabolism correlate with the effects of IL-6 on the biosynthesis of these components in primary rat liver cells, while a neutral IGFBP-3 protease was not detectable.

Fragments of human oncoprotein MDM2 reveal variable distribution within and on cultivated human hepatoma cells.

Human oncoprotein MDM2 reveals a MHC class I binding motif HMDM441 characterizing MDM2 as a potential tumor antigen. To analyze the distribution of MDM2 proteins containing this motif in liver cancer cells we produced rabbit anti-HMDM441 serum. The novel antibodies bound to an MDM2 fragment of approximately 55 kDa which lacked the N-terminal region and was present in lysate and supernatant of a human hepatoma cell line overexpressing normal 90-kDa MDM2. The 55-kDa fragment was detected in the cytoplasm and nucleoli and at the nuclear envelope of hepatoma cells, whereas normal hepatocytes were negative. Double-fluorescence labeling indicated that the MDM2 fragments and MHC class I molecules were coexpressed on the surface of the hepatoma cells. Further studies must clarify whether MDM2 fragments containing motif HMDM441 are novel targets of immunotherapy and immunochemical tumor diagnosis.

The IGF axis and hepatocarcinogenesis.

Deregulation of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs), IGFBP proteases, and the expression of the IGF receptors, has been identified in the development of hepatocellular carcinoma (HCC). Characteristic alterations detected in HCC and hepatoma cell lines comprise the increased expression of IGF-II and the IGF-I receptor (IGF-IR), which have emerged as crucial events in malignant transformation and the growth of tumours. Alterations of IGFBP production and the proteolytic degradation of IGFBPs resulting in an excess of bioactive IGFs, as well as the defective function of the IGF degrading IGF-II/mannose 6-phosphate receptor (IGF-II/M6PR), may further potentiate the mitogenic effects of IGFs in the development of HCC.

Regulation of the components of the 150 kDa IGF binding protein complex in cocultures of rat hepatocytes and Kupffer cells by 3',5'-cyclic adenosine monophosphate.

In the circulation, most of IGFs are bound to a high molecular mass complex of 150 kDa that consists of IGF-I (or IGF-II), IGFBP-3 and the acid-labile subunit (ALS). Within rat liver, biosynthesis of these components has been localized to different cell populations with hepatocytes as source of ALS and nonparenchymal cells (endothelial and Kupffer cells (KC)) as source of IGFBP-3. In the present study, the regulatory effects of the cAMP analogs dibutyryl-cAMP (db-cAMP) and 8-bromo-cAMP (8-br-cAMP) on IGF-I, ALS, and IGFBP expression were evaluated in primary cultures of rat hepatocytes, KC as well as in cocultures of hepatocytes and KC. In cocultures, biosynthesis of IGFBP-3 and ALS was inhibited dose-dependently by db-cAMP and 8-br-cAMP while that of IGF-I, IGFBP-1, and -4 was stimulated as demonstrated by ligand and Northern blotting. IGFBP-3 expression in primary cultures of pure KC did not respond to cAMP treatment indicating the importance of a cellular interaction between KC and hepatocytes for the decreased IGFBP-3 synthesis. The inhibition of IGFBP-3 in db-cAMP-treated cocultures was due to a decrease of IGFBP-3 mRNA level accompanied by a reduced cellular degradation of IGFBP-3. We conclude that cAMP stimulate the biosynthesis of IGF-I, IGFBP-1, and -4 in cocultures of hepatocytes and KC thereby enabling the formation of binary IGF/IGFBP complexes while the formation of the 150 kDa complex is impaired through downregulation of IGFBP-3 and ALS. This complex regulation may be a prerequisite for the effects of cAMP-dependent hormones on the transfer of IGFs from circulation to peripheral tissues.