Intense cholesterol lowering therapy with a HMG-CoA reductase inhibitor does not improve nitric oxide dependent endothelial function in type-2-diabetes--a multicenter, randomised, double-blind, three-arm placebo-controlled clinical trial.

Disturbances in nitric oxide (NO) metabolism resulting in endothelial dysfunction play a central role in the pathogenesis of atherosclerosis in hypercholesterolemia and in individuals with type 2 diabetes. It is unclear whether lipid lowering therapy with HMG-CoA-reductase inhibitors might improve endothelial function in subjects with type 2 diabetes as it is demonstrated in non-diabetic subjects with hypercholesterolemia. We examined the influence of 0.2 mg and 0.8 mg cerivastatin on endothelial function in a multicenter, randomised, double-blind, and three-arm placebo-controlled clinical trial. Endothelial function was assessed by nitric oxide-dependent flow mediated vasodilatation (FMD) of the brachial artery. A total of 103 patients with type 2 diabetes were enrolled in the study. Bayer Company undertook a voluntary action to withdraw cerivastatin from market, therefore the study was terminated earlier. At this point 77 patients were randomised, of which 58 completed the study (mean age 60 +/- 8 years, HbA1c 7.4 +/- 0.9 %). At baseline mean FMD was disturbed in all three therapy arms (5.18 +/- 2.31 % in the placebo group, 3.88 +/- 1.68 in the 0.2-mg cerivastation group, and 4.86 +/- 2.25 in the 0.8-mg cerivastatin group). Despite a significant reduction in cholesterol and LDL-cholesterol-levels after 12 weeks of treatment (decrease in LDL-cholesterol - 26.8 +/- 13.9 % in the 0.2-mg group and - 40.3 +/- 16.0 % in the 0.8-mg group, p = 0.0001, ANCOVA) there was no difference in flow mediated vasodilatation (p = 0.52 and p = 0.56 vs. placebo, respectively, ANCOVA). HbA1c, CRP, and HDL-cholesterol did not change during the study. Furthermore no difference in safety profile between cerivastatin and placebo was found. Despite a significant improvement in lipid profile under statin therapy, no improvement of endothelial dysfunction in terms of nitric oxide bioavailability could be detected.

Response to initial treatment of multisystem Langerhans cell histiocytosis: an important prognostic indicator.

BACKGROUND: Reliable prediction of prognosis allowing risk-adapted therapy remains a major issue in the management of multisystem Langerhans cell histiocytosis (LCH). In a recent publication of the International LCH Study Group, response to initial therapy appears to be a reliable outcome predictor. The aim of this study is to test this observation in a cohort of patients treated with more intensive initial therapy. Furthermore, we compare the predictive value of response to initial therapy to some other well-established stratification systems. PROCEDURE: Response to initial combination chemotherapy (prednisolone, vinblastine, and etoposide) at 6 weeks and its prognostic value was evaluated retrospectively in 63 patients with multisystem LCH from the DAL-HX 83 and 90 Studies, and correlated to some established scoring systems from the literature. RESULTS: After 6 weeks of therapy, 50/63 (79%) patients qualified as responders, 4/63 (7%) patients showed intermediate response, and 9/63 (14%) patients did not respond. Probability of survival at 5 years was 0.94 +/- 0.03 for responders, 0.75 +/- 0.22 for patients with intermediate response, and only 0.11 +/- 0.10 for non-responders. CONCLUSIONS: Response to initial therapy appears to be a reliable prognostic predictor. Compared to the published international LCH-I Study, our results suggest that more intensive initial treatment allows a better discrimination between responders and non-responders. This allows to identify a subgroup of patients with extremely poor prognosis (mortality rate 90%) relatively early in the disease course.

Treatment of multisystem Langerhans cell histiocytosis. Results of the DAL-HX 83 and DAL-HX 90 studies. DAL-HX Study Group.

BACKGROUND: The prognosis of children with multisystem Langerhans cell histiocytosis (LCH) has improved with the application of chemotherapy. However, treatment strategies used varied from conservative approach with treatment only during disease exacerbation to intensive chemotherapy starting immediately after diagnosis. No single drug or regimen has been proven to be superior to the others. Thus, optimal treatment of multisystem LCH remains still an unsolved problem. PATIENTS: Three hundred and twenty-four patients enrolled in the DAL-HX 83 and DAL-HX 90 studies were retrospectively re-evaluated by using the current definition for disease extent. Sixty-three patients fulfilling the criteria for multisystem LCH (involvement of > or = 2 organ systems) were object of the present study. These were 33 males and 30 females, median age at diagnosis 11.5 months (range, birth-13 years 2 months). The median observation time was 7 years 6 months (4 years-11 years 8 months). METHODS: All patients had morphologically confirmed diagnosis, which was additionally verified through demonstration of CD1a antigen, presence of Birbeck granules or central pathologic review. Uniform evaluation including a complete medical history and physical examination, laboratory tests (complete blood count, liver function tests, coagulation profile) and radiographic survey (skeletal survey and/or radionuclide bone scan) was performed in all patients. Additional investigations (bone marrow tap, CT, MRI etc.) were performed upon specific indications. The 63 patients with multisystem LCH were evaluated with respect to response to therapy, clinical course, outcome and development of permanent disabilities. The results of the DAL-HX studies were compared with the results of the first randomized international clinical trial on multisystem LCH (LCH-I). RESULTS: Response to 6 weeks of initial therapy showed a clear discrimination between responders and non-responders, with only 6% of the patients having intermediate response. When correlated to survival response to initial therapy appears to be a powerful prognosticator in multisystem LCH. There were some typical patterns of clinical course. Complete disease resolution at some point of the clinical course was documented in 50 (79%) patients. Thirty-five of them remained disease free, while 15 experienced one or more episodes of disease reactivation. Chronic reactivating course without complete disease resolution was observed in one patient. Deteriorating disease with fatal outcome was shown in 12 (19%) patients. The overall survival after 5 years of observation was 81%. One or more disease-related permanent disabilities were documented in 24 patients, in 4 of them these were shown at diagnosis and in 20 patients these developed after therapy had been commenced. Despite more intensive chemotherapy, the overall survival in DAL-HX 83/90 cohort was comparable with that in LCH-I studies. However, LCH-I compares unfavorably to DAL-HX 83/90 in some very important aspects. With respect to reactivation rate, reactivation free interval and development of permanent disabilities better results were achieved with the more intensive initial and prolonged continuation therapy concept of the DAL-HX studies. Even after extended analysis it remains unclear whether the superiority of the DAL-HX studies has to be attributed to the administration of continuous steroids, to the combination of vinblastine and etoposide, or to the prolonged continuation therapy including mercaptopurine. Answers to these questions are expected from the ongoing international clinical trial LCH-II.

Outcome of peripheral blood stem cell mobilization in advanced phases of CML is dependent on the type of chemotherapy applied.

High-dose chemotherapy with autologous transplantation of in vivo purged PBSC is a novel investigational approach to treating chronic myelogenous leukemia (CML) patients not responsive to conventional therapy with interferon-alpha (IFN-alpha) and not eligible for allogeneic transplantation. PBSC mobilization using either '5+2/7+3'-type chemotherapy or 'mini-ICE/ ICE' chemotherapy was investigated in 43 patients with advanced phases of Philadelphia (Ph)-positive CML. Thirty patients were in late chronic phase (>12 months post diagnosis) and 13 patients in accelerated phase (AP) or blast crisis (BC). Contamination with Ph-positive cells was evaluated in harvests from 37/43 patients. The outcome of PBSC mobilization was dependent on the type of chemotherapy administered: a complete or major cytogenetic response (<35% Ph-positive metaphases) in leukapheresis collections was obtained in ten of 15 patients treated with 'mini-ICE/ICE' but in only three of 28 patients treated with '5 + 2/7 + 3' chemotherapy. One patient (1/43) in blast crisis died during mobilization therapy (2%). Twenty-five patients underwent PBSC transplantation and all of them engrafted successfully. Transplantation-related mortality was 0%. The data show that in advanced phases of CML the chance of harvesting Ph-negative peripheral blood stem cells depends on the type of chemotherapy used for mobilization.

Multiple primary neoplasms in childhood: data from the German Children's Cancer Registry.

The German Children's Cancer Registry (GCCR) has documented all malignancies during the first 15 years of life in Germany since 1980. In a series of 20,388 cancer cases to the end of 1995, 127 children with multiple primary neoplasms up to the age of 15 years were identified. The children were monitored for 82,591 person-years with a mean observation time of 4.1 years. Relative and cumulative risk for the occurrence of second malignant neoplasms were estimated only for the first 15 years of life, as follow-up data beyond childhood are incomplete and valid data on the incidence of cancer in adolescents and adults are not available in Germany. The overall standardised incidence ratio for a second malignancy was 12.5 (95% CI: 10.4-14.9) which implies an absolute excess risk of 141.5 per 10(5). The estimated cumulative risk within 10 years after the first malignancy was 1.9% (95% CI: 1.5-2.3). It is expected that the risk will alter with prolongation of follow-up beyond childhood.

Pulmonary nodules: detection with low-dose vs conventional-dose spiral CT.

The purpose of the study was the evaluation of low-dose spiral CT in the detection and assessment of contours of pulmonary nodules. In a prospective investigation 71 consecutive chest CT examinations were acquired both at 30 and 200 mA. Films were interpreted independently by two radiologists. According to the size, nodules were divided into four categories: 10 mm; nodule shape was registered. With both protocols, 240 nodules were detected. The correlation coefficient for both methods was 0.89. Discrepancies were found most frequently in nodules near to pulmonary vessels. Nodule size estimation did not differ more than one size category. Eight spiculated nodules were identified by both techniques. Low-dose spiral CT of the chest has a high sensitivity in the detection of pulmonary nodules. If clinical circumstances require dose minimization, low-dose spiral CT may be advocated as an alternative screening method to conventional dose spiral CT.

Clinical and morphological characteristics in Streptococcus bovis endocarditis: a comparison with other causative microorganisms in 177 cases.

AIM: To compare the clinical and morphological characteristics of patients with Streptococcus bovis endocarditis with those of patients with endocarditis caused by other microorganisms. METHODS: 177 consecutive patients (Streptococcus bovis, 22; other streptococci, 94; staphylococci, 44; other, 17) with definite infective endocarditis according to the Duke criteria were included. All patients underwent transthoracic and transoesophageal echocardiography. In 88 patients, findings from surgery/necropsy were obtained. RESULTS: S bovis endocarditis was associated with older patients, with a higher mortality (p = 0.04), and with a higher rate of cardiac surgery (p < 0.001) than other microorganisms, although embolic events were observed less often (p = 0.02). Pathological gastrointestinal lesions were detected in 45% of the patients. Multiple valves were affected in 68% of the patients with S bovis endocarditis and in 20% of those with other organisms (p < 0.001). Moderate or severe regurgitation occurred more often in S bovis endocarditis than with other microorganisms (p = 0.05). When surgery or necropsy was performed, infectious myocardial infiltration of the left ventricle was confirmed histopathologically in 36% of the patients with S bovis endocarditis and in 10% of those with other organisms (p = 0.002). CONCLUSIONS: S bovis endocarditis is a severe illness because of the more common involvement of multiple valves, and of the frequent occurrence of haemodynamically relevant valvar regurgitation and infectious myocardial infiltration.

[Clinical relevance of thoracic CT in intensive care and emergency medicine]. / Klinische Relevanz der Thorax-CT in Intensiv- und Notfallmedizin.

PURPOSE: Evaluation of the impact, indications, and therapeutic efficiency of chest CT in intensive-care and emergency patients. MATERIALS AND METHODS: Retrospective assessment of 741 consecutive chest CT, or which 74% were acquired in the spiral technique, in intensive-care and emergency patients. Chest CT scans and respective clinical data were compared. RESULTS: 16% of all examinations were indicated to resolve questions arising from the chest radiogram, 10% to confirm or exclude pulmonary embolisms and 10% to confirm or exclude aortic dissection. In 10% a focus of infection was sought. 57% of all CT examinations had an impact on therapy, in 7% further diagnostic tests were prompted. Among a total of 588 clinical decisions based upon chest CT, the most frequent therapeutic conclusions consisted in: minimally invasive CT guided interventions in 17%. A new drug was administered in 13%, surgical intervention was performed in 13%, bed-side interventions such as insertion of a drainage tube in 13%, and a given pharmacological therapy was continued in 11%. CONCLUSION: Chest CT has a strong impact on patient management in emergency and critical-care medicine. CT guided interventions are frequently used in critically-ill patients. The introduction of the spiral technique has led to important new CT indications in the field of non-invasive vascular diagnosis, namely the assessment of pulmonary embolism and aortic dissection.

Complications and their impact after pneumatic dilation for achalasia: prospective long-term follow-up study.

BACKGROUND: With the exception of esophageal perforations, complications of pneumatic dilation are incompletely defined. This study analyzes the incidence of all complications of this procedure and their impact on the patients' clinical course. METHODS: Sixty-seven consecutive patients with achalasia underwent pneumatic dilation with a Browne-McHardy dilator. Patients were observed for 24 hours after treatment and evaluated 4 weeks later as well as at 2-year intervals for a mean follow-up period of 4.9 +/- 3.8 years. In patients with and without complications, the length of remission was evaluated by Kaplan-Meter life table analysis. RESULTS: Twelve patients (18%) developed morphologic complications consisting in one perforation, two intramural hematomas, and nine diverticula at the gastric cardia. Ten patients (15%) complained of prolonged postdilation chest pain. The 5-year remission rate in the latter patients was 51% compared to 42% for patients without complications and 11% for patients developing traumatic diverticula. Surgery was ultimately performed in one third of all patients, a rate that remained unaffected by the type of complication. CONCLUSIONS: Complications of pneumatic dilation are underestimated and underreported. More than 30% of all patients develop either prolonged pain or morphologic lesions. Although prolonged pain does not indicate an unfavorable prognosis, the appearance of diverticula may be associated with a shorter clinical remission.

Risk factors for diagnostic delay in achalasia.

This study investigates whether the frequently delayed diagnosis of achalasia is attributable to atypical symptoms, misleading diagnostic features, or the number of physicians consulted. Eighty-seven consecutive patients with newly diagnosed achalasia were prospectively investigated with the use of structured interviews as well as manometric, endoscopic, and radiographic studies. The mean duration of symptoms was 4.7 +/- 6.4 years. Quality and intensity of symptoms had no effect on early diagnosis. Among different radiographic and manometric features, only the width of the gastric cardia showed a significant correlation with a delay in diagnosis (P < 0.01). However, the most significant association was found between the duration of symptoms prior to considering the diagnosis of achalasia and the number of unsuccessful physician consultations (P = 0.001). We conclude that the frequent delay in the diagnosis of achalasia is not due to an atypical clinical presentation of this disease but rather to misinterpretation of typical findings by the physician consulted.

Applicability of the Poisson distribution to model the data of the German Children's Cancer Registry.

Since 1980 the German Children's Cancer Registry has documented all childhood malignancies in the Federal Republic of Germany. Various statistical procedures have been proposed to identify municipalities or other geographic units with increased numbers of malignancies. Usually the Poisson distribution, which requires the malignancies to be distributed homogeneously and uncorrelated, is applied. Other discrete statistical distributions (so-called cluster distributions) like the generalized or compound Poisson distributions are applicable more generally. In this paper we present a first explorative approach to the question of whether it is necessary to use one of these cluster distributions to model the data of the German Children's Cancer Registry. In conclusion, we find no indication that the Poisson approach is insufficient.

[Prognostic factors of small-cell bronchial carcinoma]. / Prognosefaktoren des kleinzelligen Bronchialkarzinoms.

137 patients with small cell lung cancer (SCLC) were retrospectively analysed. The median survival for all patients were 284 days, for limited disease patients 399 days, and for extensive disease patients 252 days. Univariate statistical analysis based on Kaplan-Meier-estimates and Log-Rank-Test showed the following prognostically beneficial factors: Limited disease stage (p = 0.009), NSE serum level less than 25 micrograms/l (p = 0.016), serum alkaline phosphatase less than 200 U/l (p = 0.035), normal serum albumin (p = 0.003) and activity index of minimum of 70 (p < 0.001). The patient age and sex did not image as relevant prognostical factors.

Rectal syphilis mimicking histiocytic lymphoma.

Homosexuality is being recognized with increasing frequency in the United States, and the physician must be knowledgeable of the presentations of venereal infection in this population. A 23-year-old man who denied homosexuality presented with a rectal mass and diffuse adenopathy. Biopsy of the mass was interpreted as histiocytic lymphoma. Subsequent serology had positive results for syphilis. Further questioning revealed a history of anorectal intercourse, and special stains of the mass revealed spirochetes. Syphilis must be considered in any young patient presenting with a rectal mass, regardless of the biopsy histologic characteristics or sexual history.