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Recently, we identified the microRNA-99 family as unfavorable prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate its value as circulating biomarker for PDAC. Tissue and corresponding preoperative blood samples of 181 patients with PDAC UICC Stages I–IV (n = 90), intraductal papillary mucinous neoplasm (IPMN, n = 11), chronic pancreatitis (n = 40), pancreatic cystadenoma (n = 20), and age-matched healthy blood serum controls (n = 20) were collected between 2014 and 2017 prospectively. Expression of microRNA-21 as confirmatory marker and the microRNA-99 family, consisting of microRNA-99a, -99b, and -100, was analyzed by qRT-PCR. Target analysis of insulin-like growth factor 1 receptor (IGF1R) was performed using tissue array immunohistochemistry and Western blotting. Expression of microRNA-99 family members was significantly increased in macrodissected tumor tissue and corresponding blood serum samples (p

Purpose EWS-ETS fusion genes are the driving force in Ewing's sarcoma pathogenesis. Because of the variable breakpoint locations in the involved genes, there is heterogeneity in fusion RNA and protein architecture. Since previous retrospective studies suggested prognostic differences among patients expressing different EWS-FLI1 fusion types, the impact of fusion RNA architecture on disease progression and relapse was studied prospectively within the Euro-E.W.I.N.G. 99 clinical trial. Patients and Methods Among 1,957 patients who registered before January 1, 2007, 703 primary tumors were accessible for the molecular biology study. Fusion type was assessed by polymerase chain reaction on frozen (n = 578) or paraffin-embedded materials (n = 125). The primary end point was the time to disease progression or relapse. Results After exclusion of noninformative patients, 565 patients were entered into the prognostic factor analysis comparing type 1 (n = 296), type 2 (n = 133), nontype 1/nontype 2 EWS-FLI1 (n = 91) and EWS-ERG fusions (n = 45). Median follow-up time was 4.5 years. The distribution of sex, age, tumor volume, tumor site, disease extension, or histologic response did not differ between the four fusion type groups. We did not observe any significant prognostic value of the fusion type on the risk of progression or relapse. The only slight difference was that the risk of progression or relapse associated with nontype 1/nontype 2 EWS-FLI1 fusions was 1.38 (95% CI, 0.96 to 2.0) times higher than risk associated with other fusion types, but it was not significant (P = .10). Conclusion In contrast to retrospective studies, the prospective evaluation did not confirm a prognostic benefit for type 1 EWS-FLI1 fusions.

Two hundred and fourteen patients with benign giant cell tumor of bone (GCTB), treated from 1980 to 2007 at the Department of Orthopedics of the University of Muenster (Germany), were analyzed in a retrospective study.The mean age was 33.3 years with a female-to-male ratio of 1.2 : 1. The mean follow up was 59.8 months. The recurrence rate of patients who received first treatment at our institution was 16.6%. The most common primary treatment was curettage (188 patients) usually followed by adjuvant local therapy. The effects of bone cement (PMMA), burring and hydrogen peroxide (H(2)O(2)) were statistically analyzed and the influence of a subchondral bone graft on the recurrence rate was evaluated.PMMA alone (n = 52) reduces the likelihood of recurrence by the factor 8.2, additional high-speed burring (n = 39) by the factor 3.9 (compared to PMMA only). H(2)O(2) (n = 42) seems to have an additional effect comparable to that of phenol although it did not reach statistical significance.The combination of all adjuncts (PMMA, burring, H(2)O(2) - n = 42) reduces the likelihood of recurrence by the factor 28.2 compared to curettage only and therefore should be recommended as a standard treatment. If the tumor reaches close to the articulating surface a subchondral bone graft (n = 42) can be performed without risking a higher recurrence rate. We add seven cases of pulmonary metastases and two cases of multicentricity to the literature. Bisphosphonates and interferon alpha may have a beneficial effect.

During successful chemotherapy of osteosarcomas tumour size does not diminish significantly because the therapy has limited impact on the mineralized matrix of the tumour. Treatment response is considered successful if, histologically, more than 90% of tumour cells show necrosis.To determine if osteosarcomas change their water diffusion during preoperative chemotherapy in relation to the amount of tumour necrosis.Eight patients (age 11-19 years) with histologically proven limb osteosarcoma underwent T1-weighted, fat-suppressed T2-weighted and contrast-enhanced T1-weighted spin-echo imaging together with diffusion-weighted EPI sequences (b = 700) at 1.5 T before and after five cycles of standard chemotherapy. Tumour volume and apparent diffusion coefficient (ADC) maps were calculated before and after chemotherapy. The degree of tumour necrosis after chemotherapy was assessed using the histological Salzer-Kuntschik classification (grades 1-6).During chemotherapy, the ADC values of osteosarcomas changed significantly. The ADC of untreated tumour was 2.1 +/- 0.4 x 10(-3) mm(2)/s (mean +/- SD) (95% CI 1.6-2.0). The ADC of chemotherapy-treated sarcomas was 2.5 +/- 0.4 x 10(-3) mm(2)/s (95% CI 1.8-2.2). Necrotic areas, which were confirmed by macroscopic examination, showed ADC values up to 2.7 x 10(-3) mm(2)/s. Four patients with little viable tumour tissue within the neoplasm (Salzer-Kuntschik grades 1-2) had an increase in ADC of 0.4 up to 0.7 x 10(-3) mm(2)/s. Four patients with larger areas of viable tumour (Salzer-Kuntschik grade 4) showed a lesser increase in ADC of 0.0 up to 0.3 x 10(-3) mm(2)/s. The differences in ADC values in tumour tissue before and after chemotherapy were highly significant (P = 0.01).During chemotherapy of osteosarcomas, tumour ADC changes are related to the degree of tumour necrosis.

Background Periprosthetic osteolysis is a major cause of aseptic loosening in joint arthroplasty. This study investigates the impact of CT (calcitonin) deficiency and CT substitution under in-vivo circumstances on particle-induced osteolysis in Calca -/- mice. Methods We used the murine calvarial osteolysis model based on ultra-high molecular weight polyethylene (UHMWPE) particles in 10 C57BL/6J wild-type (WT) mice and twenty Calca -/- mice. The mice were divided into six groups: WT without UHMWPE particles (Group 1), WT with UHMWPE particles (Group 2), Calca -/- mice without UHMWPE particles (Group 3), Calca -/- mice with UHMWPE particles (Group 4), Calca -/- mice without UHMWPE particles and calcitonin substitution (Group 5), and Calca -/- mice with UHMWPE particle implantation and calcitonin substitution (Group 6). Analytes were extracted from serum and urine. Bone resorption was measured by bone histomorphometry. The number of osteoclasts was determined by counting the tartrate-resistant acid phosphatase (TRACP) + cells. Results Bone resorption was significantly increased in Calca -/- mice compared with their corresponding WT. The eroded surface in Calca -/- mice with particle implantation was reduced by 20.6% after CT substitution. Osteoclast numbers were significantly increased in Calca -/- mice after particle implantation. Serum OPG (osteoprotegerin) increased significantly after CT substitution. Conclusions As anticipated, Calca -/- mice show extensive osteolysis compared with wild-type mice, and CT substitution reduces particle-induced osteolysis.

Although the recurrence rate of giant cell tumors of bone (GCTB) is relatively high exact data on treatment options for the recurrent cases is lacking. The possible surgical procedures range from repeated intralesional curettage to wide resection. Two hundred and fourteen patients with histologically certified GCTB have been treated at the authors department from 1980 to 2007. Sixty-seven patients with at least one local recurrence were included in this study. The mean follow-up was 77.3 months. The data was evaluated according the re-recurrence rate with regard to the surgical procedure for the recurrence. The mean time until the first local recurrence was 22.0 months; the mean number of recurrences per patient was 1.4. The recurrence occurred in 69.7% (46 out of 66 patients) within the first 2 years. If after intralesional procedures (curettage or intralesional resection) no adjunct was used the re-recurrence rate was 58.8% (10 out of 17 patients) and decreased to 21.7% (5 out of 23 patients) if a combination of all adjuncts (PMMA + burring) was used. The likelihood of re-recurrence was reduced by the factor 5.508 which was clearly significant (P = 0.016). In case of wide resection no re-recurrence occurred. Seven patients (10.5%) developed pulmonary metastases. Fourteen patients (20.9%) finally received an endoprosthesis; 12 due to tumor recurrence, 2 due to secondary arthritis. Recurrent GCTB can be treated by further curettage with additional burring and cementing with an acceptable re-recurrence rate of 21.7%. The rate of patients finally needing an endoprosthesis is 20.9%. Due to the high rate of pulmonary metastases recurrent GCTB may be considered as a severe disease.

In patients with sepsis, hemodynamic support is often complicated by a tachyphylaxis against conventional vasopressor agents. Bolus infusion of terlipressin, a vasopressin analog, has been reported to increase mean arterial pressure in patients with catecholamine-resistant septic shock. However, bolus infusion of terlipressin may be associated with severe side effects, including pulmonary vasoconstriction and impairment of oxygen delivery. We hypothesized that continuous low-dose infusion of terlipressin may reverse sepsis-related systemic arterial hypotension with reduced side effects as compared with the traditional concept of bolus administration. Twenty-seven adult sheep were instrumented for chronic study. After a baseline measurement, Salmonella typhosa endotoxin (10 ng.kg-1.min-1) was continuously administered for the next 40 h. After 16 h of endotoxemia, the surviving sheep (n = 24) were randomly assigned to be treated with either a continuous infusion of terlipressin (2 mg for 24 h), bolus injections of terlipressin (1 mg every 6 h), or placebo (normal saline; each n = 8). Continuous infusion of terlipressin permanently reversed endotoxin-induced systemic arterial hypotension (P < 0.001) and improved left ventricular stroke work index in all sheep (P < 0.05). Intermittent bolus injections of terlipressin were linked to decreases in heart rate and cardiac index and increases in pulmonary vascular resistance index (each, P < 0.001). These unwanted side effects were prevented by continuous low-dose infusion of the drug. In conclusion, continuous infusion of terlipressin stabilized hemodynamics and improved myocardial performance in endotoxemic ewes without obvious side effects. Continuous low-dose terlipressin infusion may represent a useful alternative treatment of arterial hypotension related to sepsis and systemic inflammatory response syndrome.

Duchenne and Becker muscular dystrophies (DMD and BMD) are associated with decreased total nitric oxide (NO). However, mechanisms leading to NO deficiency with consequent muscle-cell degeneration remain unknown. To address this issue, we examined skeletal muscles of DMD and BMD patients for co-expression of NO synthase (NOS) with nitrotyrosine and transcription factor CREB, as well as with enzymes engaged in NO signaling. Employing immunocytochemical labeling, Western blotting and RT-PCR, we found that, in contrast to the most commonly accepted view, neuronal NOS was not restricted to the sarcolemma and that muscles of DMD and BMD patients retained all three NOS isoforms with an up-regulation of the inducible NOS isoform, CREB and nitrotyrosine. We suggest that enhanced nitrotyrosine immunostaining in muscle fibers as well as in the vasculature of DMD and BMD specimens reflects massive oxidative stress, resulting in withdrawal of NO from its regular physiological course via the scavenging actions of superoxides.

A high serum level of beta human chorionic gonadotropin (hCG) normally indicates pregnancy in healthy women. We were confused by this finding in one of our patients. This 18-year-old girl presented with amenorrhoea of 1-month duration, a positive pregnancy test and a high beta-hCG serum level although taking contraceptives. Pregnancy was excluded by ultrasound. Three years previously, she had had an osteosarcoma of the humerus. The tumour initially had been wide resected and had shown a good response to neoadjuvant chemotherapy with COSS-96-protocol. We reviewed the original histological result and the literature about possible similar findings. We analysed therapeutic options and the value of beta-hCG levels as a therapy monitor. During examination we detected a recurrent osteosarcoma of the left humerus. The local relapse evidently expressed beta-hCG which, retrospectively, could only sparsely be shown in the primary resectate. After intralesional surgery, chemotherapy and radiotherapy levels of beta-hCG normalised. Osteosarcoma very rarely is able to produce a paraneoplastic syndrome by high levels of beta-hCG. This may well be of diagnostic value and offer an additional monitoring tool. It can indicate tumour recurrrence and dedifferentiation.

To evaluate fluorine 18 (18F) dopa positron emission tomography (PET) in comparison with established imaging procedures in gastrointestinal carcinoid tumors.After evaluation of the normal distribution of 18F dopa, 17 patients with histologically confirmed tumors were examined with 18F dopa PET. Results of 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) PET, somatostatin-receptor scintigraphy, and morphologic imaging (computed tomography and/or magnetic resonance imaging) were available for all patients. Results of the procedures were evaluated by two radiologists and two nuclear medicine specialists, whose consensus based on all available histologic, imaging, and follow-up findings was used as the reference standard.Ninety-two tumors were diagnosed: eight primary tumors, 47 lymph node metastases, and 37 organ metastases. 18F dopa PET led to 60 true-positive findings (seven primary tumors, 41 lymph node metastases, 12 organ metastases); FDG PET, 27 (two primary tumors, 14 lymph node metastases, 11 organ metastases); somatostatin-receptor scintigraphy, 52 (four primary tumors, 27 lymph node metastases, 21 organ metastases); and morphologic imaging, 67 (two primary tumors, 29 lymph node metastases, 36 organ metastases). This resulted in the following overall sensitivities: 18F dopa PET, 65% (60 of 92); FDG PET, 29% (27 of 92); somatostatin-receptor scintigraphy, 57% (52 of 92); morphologic procedures, 73% (67 of 92). Although the morphologic procedures were most sensitive for organ metastases, 18F dopa PET enabled best localization of primary tumors and lymph node staging.18F dopa PET is a promising procedure and useful supplement to morphologic methods in diagnostic imaging of gastrointestinal carcinoid tumors.

Using an endoscopic ultrasound (EUS) miniprobe, even highly stenotic esophageal cancers precluding the passage of a conventional probe can be examined without prior dilatation.To assess: (1) staging accuracy of conventional EUS probe and miniprobe, (2) variables influencing staging accuracy, (3) endoscopic features predicting tumor stage.Ninety-seven consecutive patients with esophageal cancer undergoing complete surgical resection were included. Preoperative EUS was performed using a conventional probe in nonstenotic tumors and a miniprobe in stenotic tumors. Accuracy of EUS for T and N stages was compared to pathohistological staging.Overall EUS staging accuracy was 73.2% for T stage and 74.2% for N stage. It was similar for the miniprobe used in stenotic tumors vs the conventional probe used in nonstenotic tumors. Based on EUS, 84.5% of the patients would have been assigned to the appropriate therapy protocol (primary surgery vs neoadjuvant therapy). Endoscopic tumor features had no influence on staging accuracy. Tumor length5 cm predicted advanced T and nodal positive stages.The miniprobe allows adequate EUS staging of stenotic esophageal tumors precluding the passage of a conventional probe. Therefore, dilatation therapy of stenotic cancers to conduct conventional EUS should be avoided.

8548 Background: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n=16) or ICE (n=15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P=0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P=0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P=0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.

Background Idiopathic portal hypertension (IPH) is a disorder of unknown etiology and is characterized clinically by portal hypertension, splenomegaly, and hypersplenism accompanied by pancytopenia. This study evaluates the pathogenic concept of the disease by a systematic review of the literature and illustrates novel pathologic and laboratory findings. Case Presentation We report the first case of uncontrolled splenic hyperperfusion and enlargement with subsequent hypersplenism leading to life-threatening complications of IPH in infancy and emergent splenectomy. Conclusions Our results suggest that splenic NO and VCAM-1, rather than ET-1, have a significant impact on the development of IPH, even at a very early stage of disease. The success of surgical interventions targeting the splenic hyperperfusion suggests that the primary defect in the regulation of splenic blood flow seems to be crucial for the development of IPH. Thus, beside other treatment options splenectomy needs to be considered as a prime therapeutic option for IPH.