Modified Bova score for risk stratification and short-term outcome in acute pulmonary embolism.

INTRODUCTION: Risk stratification in acute pulmonary embolism (PE) is crucial to identify those patients with a poorer prognosis. We aimed to investigate a modified Bova score for risk stratification in acute PE. MATERIALS AND METHODS: We performed a retrospective analysis of PE patients treated in the internal medicine department. Both haemodynamically stable and unstable PE patients, ≥ 18 years with measurements of cardiac troponin I (cTnI) and existing echocardiography were included in the analysis. RESULTS: Data from 130 patients were included for this retrospective analysis. Three patients (2.3%) died in hospital; 84 patients had a Bova score of < 4 points and 46 ≥ 4 points. PE patients with a score ≥ 4 points were older (71.2 ± 13.8 vs. 66.3 ± 15.5 years, p = 0.0733), died more frequently during the in-hospital course (6.5% vs. 0.0%, p = 0.0183), had a more prevalent high-risk PE status (10.9% vs. 1.2%, p = 0.0122), more often had right ventricular dysfunction (100.0% vs. 35.7%, p < 0.000001), presented more frequently with syncope/collapse (21.7% vs. 3.6%, p = 0.00101) and had a higher heart rate (104.6 ± 23.5 vs. 90.0 ± 20.6/min, p = 0.000143), shock index (0.91 ± 0.59 vs. 0.62 ± 0.18, p = 0.000232), cTnI (0.36 ± 0.42 vs. 0.03± 0.10ng/ml, p < 0.000001) and creatinine (1.32 ± 0.50 vs. 1.03 ± 0.27 mg/dl, p = 0.000170). Adjusted multivariate logistic regressions revealed significant associations between the Bova score and in-hospital death (OR 4.172, 95% CI 1.125-15.464, p = 0.0326) as well as pneumonia based on PE-related lung infarction (OR 1.207, 95% CI 1.005-1.449, p = 0.0442). ROC analysis for Bova score predicting in-hospital death and pneumonia based on PE-related lung infarction showed area under the curve values of 0.908 and 0.606 with Bova score cut-off values of 3.5 points and 1.5 points, respectively. CONCLUSIONS: The modified Bova score is highly effective to predict poorer outcome in acute PE.

Cardiac troponin I for predicting right ventricular dysfunction and intermediate risk in patients with normotensive pulmonary embolism.

BACKGROUND: Right ventricular dysfunction (RVD) and cardiac troponin I (cTnI) are important tools for risk stratification in pulmonary embolism (PE). We investigate the association of RVD and cTnI in normotensive PE patients and calculate a cTnI cut-off level for predicting RVD and submassive PE. METHODS: Clinical, laboratory, radiological and echocardiagraphic data were analysed. Patients were categorised into groups with or without RVD and compared focussing on cTnI. Effectiveness of cTnI for predicting RVD and submassive PE was tested. RESULTS: One hundred twenty-nine normotensive PE patients, 71 with and 58 without RVD, were included. Patients with RVD were older (75.0 years (61.3/81.0) vs. 66.0 years (57.7/75.1), P = 0.019). cTnI (0.06 ng/ml (0.02/0.23) vs. 0.01 ng/ml (0.00/0.03), P < 0.0001) and D-dimer values (2.00 mg/l (1.08/4.05) vs. 1.23 mg/l (0.76/2.26), P = 0.016) were higher in PE with RVD. cTnI was associated with RVD (OR 3.95; 95 % CI 1.95-8.02, p = 0.00014). AUC for cTnI diagnosing RVD was 0.79, and for submassive PE0.87. Cut-off values for cTnI predicting RVD and submassive PE were 0.01 ng/ml, with a negative predictive value of 73 %. cTnI was positively correlated with age, D-dimer and creatinine. CONCLUSIONS: In normotensive PE patients, cTnI is helpful for risk stratification and excluding RVD. cTnI elevation is correlated with increasing age and reduced kidney function.

[Gender-specific differences in hemodynamically stable patients with acute pulmonary embolism]. / Geschlechtsspezifische Unterschiede bei hämodynamisch stabilen Patienten mit akuter Lungenarterienembolie.

BACKGROUND AND AIM: Pulmonary embolism (PE) is potentially life-threatening. Aim of this study was to identify genderspecific differences in acute PE and in risk stratification of hemodynamically stable PE patients. METHODS: We analysed retrospectively the data of 129 patients with PE (59.7% women) and compared female and male patients regarding clinical, laboratory and technical parameters. ROC curve and Youden Index were calculated to analyse cardiac troponin I (cTnI) for predicting of right ventricular dysfunction (RVD) and D-Dimer for predicting submassive PE. RESULTS: 129 patients were included in this study. Female patients were older (median 73.0 [25th percentile: 65.0/75th percentile: 81.0] vs. 65.5 [55.2/76.6] years, p = 0.0095) and had more frequent submassive PE (82.7% vs. 64.0%, p = 0.03) with higher systolic pulmonary artery pressure (38.00 ±â€Š18.23 vs. 27.87 ±â€Š17.32 mmHg, p = 0.0018). Multivariable regression analysis showed a strong association between cTnI and RVD (OR, 2.84; 95%CI: 1.52-5.32, p = 0.0011). Association between cTnI and RVD was stronger in male PE patients (OR, 27.67; 95%CI: 3.28-233.31, p = 0.0023) than in female (OR, 1.52; 95%CI: 0.79-2.93, p = 0.21). Area under the curve (AUC) for efficiency of cTnI predicting RVD was higher in male patients (0.92 vs. 0.69). AUC for efficiency of D-Dimer predicting submassive PE was similar in both genders (0.65 vs. 0.62). Genderspecific cTnI cut-off values indicating for RVD, were similar in male and female (> 0.00 vs. > 0.01 ng/ml). D-Dimer values above 1.08 mg/dl in male and 1.41 mg/dl in female indicated for submassive PE. CONCLUSION: Normotensive female PE patients are in mean older and have more frequently submassive PE stadium. cTnI is associated with RVD. cTnI as risk stratification marker for predicting RVD is more effective in male.

[Cyclic vomiting syndrome (CVS) in adults - frequently overlooked?]. / Zyklisches Erbrechenssyndrom (CVS) beim Erwachsenen - eine häufig übersehene Erkrankung?

CVS (cyclic vomiting syndrome) is a functional disorder that can occur in all age groups. Adults typically develop CVS in middle age (around the 35th year of life). CVS is characterised by recurrent stereotypic episodes of nausea and vomiting lasting hours or some days. Between these episodes there are intervals free of symptoms. The main symptoms include nausea, vomiting and often abdominal pain. CVS is a rare disorder in adult patients. Because of the lack of awarness, making the correct diagnosis is not easy und often delayed for some months or years. There is no specific test to secure the diagnosis. The accurate diagnosis is based on the typical anamnestic report and the exclusion of other disorders associated with a recurrent vomiting. No standard evidence-based treatment is currently available either to manage the acute vomiting episode or to manage the prophylactic therapy. For the acute treatment of the vomiting episodes antiemetic, antimigraine and sedative medications were used. The medications frequently used for the prophylactic therapy are amitriptyline and propranolol.

Microsatellite instability and Beta2-Microglobulin mutations as prognostic markers in colon cancer: results of the FOGT-4 trial.

BACKGROUND: High-level microsatellite instability (MSI-H) has been reported as a prognostic marker in colon cancer. We here analysed the prognostic significance of MSI and mutations of the Beta2-Microglobulin (B2M) gene, which occur in about 30% of MSI-H colon cancer, in the cohort of the prospective FOGT-4 (Forschungsruppe Onkologie Gastrointestinale Tumoren, FOGT) trial. METHODS: Microsatellite instability status was determined using standard protocols (NCI/ICG-HNPCC panel and CAT25) in 223 colon cancer lesions. Beta2-Microglobulin mutation status was evaluated by exon-wise sequencing in all MSI-H lesions. RESULTS: Patients with MSI-H (n=34) colon cancer presented with a significantly lower risk of relapse after 12 months of follow-up compared with MSS (n=189) colon cancer patients (5 year time to relapse: MSI-H 0.82 vs MSS 0.66, P=0.03). No significant difference in overall survival was detected. Beta2-Microglobulin mutations were identified in 10 (29.4%) out of 34 MSI-H colon cancers and were associated with a complete absence of disease relapse or tumour-related death events (P=0.09). CONCLUSION: The risk of late disease relapse was significantly lower in patients with MSI-H compared with MSS colon cancer. Moreover, B2M mutations may contribute to the favourable outcome of MSI-H colon cancer patients and should therefore be evaluated as a potential prognostic marker in future clinical trials.

[Stereotypical episodes of vomiting for 11 years in a 33-year-old patient]. / 33-jähriger Patient mit stereotypen Erbrechensepisoden seit 11 Jahren.

A 33-year-old man was admitted because of severe vomiting. For the last 11 years, he had suffered recurrent stereotypical episodes of vomiting lasting 3-4 days. The episodes of vomiting occurred 10-15 times a year. Moreover his brother and his mother had similar symptoms. Thus, (familial) cyclic vomiting syndrome was diagnosed. With the help of antiemetic and sedative drugs, the acute vomiting episode was stopped. Prophylactic therapy with amitriptyline was started, which led to a symptom-free period of 3.5 years without a new episode of vomiting.

[Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) as primary diagnostic tool for unclear lesions in the upper gastrointestinal tract]. / Endosonographie mit Feinnadelpunktion in der Primärdiagnostik unklarer Raumforderungen im oberen Gastrointestinaltrakt.

BACKGROUND: Endoscopic Ultrasound (EUS) and the EUS guided fine-needle Aspiration (EUS-FNA) increasingly plays an important role in the diagnostic evaluation of lesions or lymph nodes in the mediastinum and upper gastrointestinal tract of unknown origin. The objective of this study was to assess safety and accuracy of EUS-FNA in two secondary and tertiary health care providers. METHODS: Prospectively, from Mai 2003 to June 2007, all patients underwent EUS with devices from Pentax (FG38UX, EC3830UT) with EUS-FNA (Cook or Mediglobe) at Johannes Gutenberg University and Catholic Hospital in Mainz. In all cases, cytology and extracted cells were histological examined by the same pathologists. In case of negative EUS results, patients were observed for at least 12 months after initial diagnosis later by reanalysis, CT-scan and follow-up clinical data to confirm the diagnosis. RESULTS: In total, 776 patients with EUS and 167 EUS-FNA (21.5 %) could be evaluated. Median age was 62 years, 68 % of patients were male. Patients underwent EUS-FNA in the mediastinum (n = 54), pancreas (73), stomach (13), liver, adrenal glands and rectum (n = 6). The complication rate of EUS-FNA was very low with only 0.6 %, mainly consistent of one minor haemorrhage at the aspiration site. A clear histological diagnosis could not be achieved in 12.5 % (21/167). Statistical analyses of all EUS-FNA revealed a sensitivity of 77.8 % (95 %CI 67,2 - 86,3) and a specificity of 98.5 % (95 % CI 92,2 - 100), with a positive and negative predictive value of 98.4 % and of 78.1 %, respectively. The overall accuracy was 87 % (95 %CI 80,4 - 92,0). CONCLUSION: EUS combined with FNA is a safe tool for first histological evaluation of unidentified lesions or lymph nodes in the mediastinum and upper gastrointestinal tract, indicative for gastrointestinal cancers.

[Primary infection with Epstein-Barr virus in a 77-year-old patient with B symptoms and hepatitis -- a case report]. / 77-jähriger Patient mit Epstein-Barr-Virus-Erstinfektion mit B-Symptomatik und Hepatitis -- ein Fallbericht.

Epstein-Barr virus (EBV) infection has a prevalence of 90 % and is - depending on the immune status of the host - associated with a broad spectrum of clinical manifestations. By presenting a case report we would like to demonstrate an unusual clinical course of a primary infection with EBV in an elderly patient. A 77-year-old patient was admitted to hospital in reduced health condition because of a persisting bronchopulmonary infection with B symptoms. The patient had already been treated with antibiotics. Because of elevated liver enzymes, a liver biopsy was performed. Histopathology revealed moderate acute hepatitis with cholangitis und endothelialitis, pointing to an EBV-induced hepatitis. Serological examinations confirmed the diagnosis, revealing a primary infection with positive EBV VCA IgM and IgG. EBV PCR of the liver tissue was positive, viral genome could be demonstrated within lymphocytes. A short period later the patient was discharged to reconvalescence. This case report demonstrates an unusual primary infection with EBV at the age of 77 with atypical clinical symptoms and hepatitis. The relevance of EBV in the differential diagnosis of atypical infectious diseases with hepatitis of unknown aetiology is strengthened on taking data reports from the literature into consideration.

Expression and regulation by interferon-gamma of the membrane-bound complement regulators CD46 (MCP), CD55 (DAF) and CD59 in gastrointestinal tumours.

The membrane-bound complement inhibitors CD46 (membrane cofactor protein), CD55 (decay-accelerating factor) and CD59 (protectin) protect tumour cells against lysis by activated complement. In this study, a total of 14 (3 gastric, 3 colonic and 8 pancreatic) gastrointestinal tumour cell lines were examined for the expression of CD46, CD55 and CD59 with respect to the regulatory efficacy of interferon-gamma (IFN-gamma). The effects of IFN-gamma on mRNA and protein expression levels of CD46, CD55 and CD59 were evaluated by Northern blot hybridisation, RT-PCR, flow cytometry and immunostaining. In unstimulated cell lines, CD46 and CD59 transcripts were expressed at comparable levels, whereas the basal expression of CD55 mRNA was heterogeneous. The complement inhibitor proteins were detected in all cell lines using specific antibodies. Additional immunohistochemical stainings of gastrointestinal tissue specimens supported these findings. IFN-gamma evoked a weak induction of certain transcripts in a subset of the cell lines. Upregulation of protein expression was only observed in HT29 cells for CD55 and CD59 and was accompanied by a marked increase of the corresponding transcripts. We conclude that membrane-bound complement inhibitors are broadly expressed in gastrointestinal tumour cells and vary in their susceptibility to IFN-gamma. Thus, they may be involved in tumour escape mechanisms in gastric, pancreatic and colorectal cancer.

[Palliative chemotherapy in metastatic and locally advanced gastrointestinal tumor]. / Palliative Chemotherapie beim metastasierten bzw. lokal fortgeschrittenen gastrointestinalen Tumor.

Systemic chemotherapy ensures better quality of life than supportive treatment alone in incurable patients. Mean survival for the total group of patients with gastric, pancreatic and colorectal cancer can be extended only by months, however, this does not preclude that in individual cases survival time may reach years. The future of tumor therapy consists in sooner treatment of early stages and improved adjuvant therapeutic methods.

Detection of the DCC gene product in normal and malignant colorectal tissues and its relation to a codon 201 mutation.

Protein expression of the putative tumour-suppressor gene DCC on chromosome 18q was evaluated in a panel of 16 matched colorectal cancer and normal colonic tissue samples together with DCC mRNA expression and allelic deletions (loss of heterozygosity, LOH). Determined by a polymerase chain reaction (PCR)-LOH assay, 12 of the 16 (75%) cases were informative with LOH occurring in 2 of the 12 cases. For DCC mRNA, transcripts could be detected in all analysed normal tissues (eight out of eight) by RT-PCR, whereas 6 of the 15 tumours were negative. DCC protein expression, investigated by immunohistochemistry using the monoclonal antibody 15041 A directed against the intracellular domain, was homogeneously positive in all normal tissue samples. In tumour tissues, no DCC protein was seen in 11 out of 16 samples (69%). For the DCC codon 201, we found a loss of a wild-type codon sequence caused by mutation or LOH in at least 8 out of 15 cases (53%) compared with the corresponding normal tissue. DCC protein expression was undetectable in eight of the nine tumours missing both wild-type codons. Only one of the five tumours with retained DCC protein expression had no detectable wild-type codon 201. In addition, 9 out of 15 normal tissue specimens were mutated in codon 201. In two out of three cases with homozygous wild-type codons in peripheral blood lymphocyte (PBL) DNA, mutations were already observed in the tumour adjacent normal colonic mucosa. We conclude that DCC immunostaining should be introduced in the clinicopathological routine because of its strong correlation with the known prognostic markers 18q LOH and mutation of codon 201.

[Prostate carcinoma associated spontaneous factor VIII:C inhibitor hemophilia. Successful therapy of severe hemorrhagic complication with porcine factor VIII in a 75-year-old patient]. / Prostatakarzinom-assoziierte spontane Hemmkörperhämophilia. Erfolgreiche Therapie einer schweren Blutungskomplikation mit porzinem Faktor VIII bei einem 75jährigen Patienten.

Inhibitors of factor VIII are a rare condition in non-hemophiliacs, but they are frequently responsible for life threatening hemorrhage. Acquired factor VIII:C inhibitors represent the spontaneous development of autoantibodies that partially or completely neutralize the plasma coagulant activity of the clotting factor. The autoantibodies can arise in diverse clinical settings, in older adults they are frequently associated with immunologic disorders or malignancies. We report of a 75-year-old man with acquired factor VIII:C inhibitor associated with adenocarcinoma of the prostate and a successful treatment of a severe bleeding complication with porcine factor VIII. A 75-year-old man was admitted because of a hematoma of his right cheek and an isolated prolonged aPTT. Acquired factor VIII:C inhibitor was identified as the cause and immuno-suppressive therapy was begun. In the clinical course severe hemorrhaging occurred and was successfully treated with porcine factor VIII (Hyate:C). The initially high inhibitor titer of 32 Bethesda Units (BU) disappeared. As the cause of acquired factor VIII:C inhibitor a newly diagnosed adenocarcinoma of the prostate is likely. After complete remission of acquired factor VIII:C inhibitor radiation therapy was begun. Six months after severe hemorrhaging the patient was clinically stable and PSA levels were normal. This case demonstrates the necessity of a precise diagnosis and therapy regimen of this coagulopathy based on clinical and laboratory data. In the absence of hemorrhage immuno-suppressive therapy with corticosteroids is indicated, in a patient with severe bleeding and high inhibitor titer (> or = 5 BU) porcine factor VIII should be administered.

Chemotherapy in advanced pancreatic cancer.

Patients with advanced adenocarcinomas of the pancreas have an exceptionally poor prognosis. Modest activity has been demonstrated with single agents (response rates of 25% at best with 5-fluorouracil [5-FU] and mitomycin). Better results have not been obtained by combination chemotherapy. Improvements in the palliation have been achieved by treatment with 5-FU, folinic acid (FA), and interferon-alpha-2A (IFN-alpha) weekly in the context of a phase II trial. Of 57 evaluable patients, eight (14%) had a partial response (PR), eight (14%) a minor response (MR), and 28 (49%) had no change of disease (NC). The median survival time was 10 mo for patients with progressive disease. Twenty-two out of 36 patients with tumor-related pain whose tumors were affected in terms of PR, MR, and NC became free of pain during treatment. Fever (56%), nausea (37%), and diarrhea (33%) were common toxicities observed. Therefore, biochemical modulation of 5-FU with FA and IFN-alpha shows some positive effects in the treatment of pancreatic cancer with moderate toxicity.

The 9-O-acetylated disialosyl carbohydrate sequence of CDw60 is a marker on activated human B lymphocytes.

Gangliosides with a terminal 9-O-acetylated disialosyl group (CDw60 structures) show a restricted surface expression on human leukocytes. Hithereto, they have only been detected on subpopulations of human T lymphocytes. Using the defined CDw60 antibody UM4D4 and two new antibodies with preferential CDw60 activities, F6 and Z17, we demonstrate for the first time that CDw60 is an activation marker on human B lymphocytes. In vitro phorbol ester-stimulated human peripheral blood B lymphocytes as well as in vivo activated tonsillar B lymphocytes became CDw60 positive. CDw60 expression of these cells exceeds that of resting and activated T-lymphocytes.

alpha(1,3)Fucosyltransferase expression in E-selectin-mediated binding of gastrointestinal tumor cells.

E-selectin recognizes the oncofetal antigen sialyl-Lewis X, which is highly expressed in adenocarcinoma. Five alpha(1,3)fucosyltransferases (FT) have been cloned that confer cell-surface expression of sialyl-Lewis X on transfected cells. We show here that 12/18 gastrointestinal-tumor cell lines bind specifically to immobilized E-selectin and that in sialyl-Lewis-X-positive cells binding is inhibited with a monoclonal antibody against sialyl-Lewis X. Using RT-PCR, we determined the expression of the alpha(1,3)fucosyltransferases III, IV, V, VI and VII in gastrointestinal tumor cells. Transcripts of FT IV and FT VII are abundantly expressed in all tested cells. Therefore no single fucosyltransferase could be correlated with the expression of sialyl-Lewis X and the ability of the tumor cells to bind to E-selectin. The data suggest that in gastrointestinal-tumor cells sialyl-Lewis X is necessary but not sufficient for E-selectin binding.

Elevated serum E-selectin in patients with liver metastases of colorectal cancer.

E-selectin, an endothelial cell adhesion molecule, mediates the initial step of leucocyte adhesion to activated vascular endothelium. The soluble isoform of E-selectin promotes angiogenesis in rat cornea. In the present study, we investigated whether leucocyte adhesion and angiogenesis are also involved in tumour progression and metastasis of colorectal cancer. Therefore, we determined the level of circulating soluble E-selectin in serum samples of 38 patients with colorectal cancer; 20 patients with non-metastatic and 18 patients with metastatic disease. Median levels of soluble E-selectin were found to be significantly higher in metastatic tumour disease (88.7 ng/ml, range 25-203 ng/ml) than in healthy controls (34.9 ng/ml, range 15-59 ng/ml, P = 0.01), in patients with primary tumours or with local recurrences (39.5 ng/ml, range 22-100 ng/ml). Furthermore, there was no correlation with the serum level of C-reactive protein, fibrinogen or tumour necrosis factor alpha suggesting that the elevation of E-selectin is independent of inflammation in tumour patients. Therefore, we propose that elevated soluble E-selectin may reflect increased neovascularisation in metastatic tumour tissue.

Combination of 5-fluorouracil, adriamycin, ifosfamide and cisplatin in metastatic adult soft tissue sarcoma: results of a phase II study.

Treatment results of advanced soft tissue sarcomas are still suboptimal. To evaluate the clinical effects of a combination therapy (FADIP) with Adriamycin (ADM), ifosfamide (IFO), cisplatin (DDP) plus continuous infusion of 5-fluorouracil (FU) as a synergistic factor for alkylating agents, a phase II study was initiated in patients with advanced soft tissue sarcomas of different histological subtypes. Fifty-six previously untreated patients with advanced soft tissue sarcomas of different histological subtypes (24 females, 31 males, median age 51.3 years, median Karnofsky performance status 80%) were included in this study. Treatment consisted of ADM 50 mg/m2 i.v. on day 1, IFO 4,000 mg/m2 i.v. on day 1, mesna 800 mg/m2 i.v. 3 x with 8-hour intervals on day 1 starting with IFO administration, FU 500 mg/m2 i.v. as 24-hour infusion on days 1 + 2, DDP 100 mg/m2 i.v. on day 2. This regimen was repeated every 4 weeks for at least 2 cycles. Major WHO grade III/IV hematological toxicity was observed in 35/56 patients. One toxic death due to severe neutropenia and fungal pneumonia occurred. Granulocyte colony-stimulating factor was administered in 8/35 neutropenic patients. Time to recovery was significantly reduced and no infectious complication was observed. WHO grade III/IV toxic diarrhea was observed in 8 patients requiring intravenous fluid replacement. WHO grade III/IV nausea occurred in 11 patients, 9/11 responded to symptomatic treatment with ondansetron alone. The overall response rate was 30.3%. The median duration of response (complete/partial response, CR/PR) was 18.1 months, the median progression-free interval was 4.5 months. The median survival time of all patients was 11.8 months, and 18.1 months in responding patients (CR/PR). Tumor-related pain was effectively reduced in 15/31 patients under treatment. FADIP produces comparable response rates to other standard treatment regimens in soft tissue sarcomas. Prolonged duration of response and median survival may be due to the use of continuous infusion of FU as a synergistic factor to alkylating agents. Granulocyte colony-stimulating factor is effective in reducing the otherwise observed high rate of WHO grade III/IV hematological toxicity with severe neutropenia.