A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors.

Background: This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results: Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier: NCT01316263.

Open-label, randomized study of individualized, pharmacokinetically (PK)-guided dosing of paclitaxel combined with carboplatin or cisplatin in patients with advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Variable chemotherapy exposure may cause toxicity or lack of efficacy. This study was initiated to validate pharmacokinetically (PK)-guided paclitaxel dosing in patients with advanced non-small-cell lung cancer (NSCLC) to avoid supra- or subtherapeutic exposure. PATIENTS AND METHODS: Patients with newly diagnosed, advanced NSCLC were randomly assigned to receive up to 6 cycles of 3-weekly carboplatin AUC 6 or cisplatin 80 mg/m(2) either with standard paclitaxel at 200 mg/m(2) (arm A) or PK-guided dosing of paclitaxel (arm B). In arm B, initial paclitaxel dose was adjusted to body surface area, age, sex, and subsequent doses were guided by neutropenia and previous-cycle paclitaxel exposure [time above a plasma concentration of 0.05 µM (Tc>0.05)] determined from a single blood sample on day 2. The primary end point was grade 4 neutropenia; secondary end points included neuropathy, radiological response, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 365 patients randomly assigned, grade 4 neutropenia was similar in both arms (19% versus 16%; P = 0.10). Neuropathy grade ≥2 (38% versus 23%, P < 0.001) and grade ≥3 (9% versus 2%, P < 0.001) was significantly lower in arm B, independent of the platinum drug used. The median final paclitaxel dose was significantly lower in arm B (199 versus 150 mg/m(2), P < 0.001). Response rate was similar in arms A and B (31% versus 27%, P = 0.405), as was adjusted median PFS [5.5 versus 4.9 months, hazard ratio (HR) 1.16, 95% confidence interval (CI) 0.91-1.49, P = 0.228] and OS (10.1 versus 9.5 months, HR 1.05, 95% CI 0.81-1.37, P = 0.682). CONCLUSION: PK-guided dosing of paclitaxel does not improve severe neutropenia, but reduces paclitaxel-associated neuropathy and thereby improves the benefit-risk profile in patients with advanced NSCLC. CLINICAL TRIAL INFORMATION: NCT01326767 (https://clinicaltrials.gov/ct2/show/NCT01326767).

[Gastrointestinal stromal tumours bigger than 20 cm: experience with imatinib chemotherapy in neoadjuvant intention]. / Gastrointestinale Stromatumore größer als 20 cm: Erfahrungen mit Imatinib in neoadjuvanter Intention.

The size of the primary tumour is considered the most important risk factor for the development of metastasis or local recurrence in case of gastrointestinal stromal tumour (GIST). Until now no prospective data are available in the literature about the role of neadjuvant therapy with Imatinib. Between 2009 and 2012 seven patients with a giant GIST > 20 cm underwent a neadjuvant treatment with Imatinib, a radical operation, followed by an adjuvant therapy. These patients were controlled with regard to peri- and postoperative morbidity and disease-free survival. Two patients were considered not resectable and one patient showed liver metastasis at the time of diagnosis. RECIST responses to the neoadjuvant Imatinib were: 2/7 patients with stable disease, 3/7 partial response, 2/7 partial response with down-staging (resectable disease). Because of the following tumour localisations (6 gastric and 1 rectal), six gastrectomies (one en-bloc with left pancreas) and one Holm operation were performed. The patient with simultaneous liver metastasis developed a tumour progression during the follow-up but the others are still tumour free after 2 years. We detected a significant tumour volume regression due to the neadjuvant chemotherapy in cases of GIST > 20 cm (30 %). Our series showed good results for a neadjuvant therapy in cases of giant GIST with the achievement of 100 % R0 resection without a high morbidity rate (in the literature a tumor size > 10 cm and poor localisation is associated to a high risk of R1 - 2 and high morbidity). Peri- and postoperative morbidity are acceptable and the tumour free survival at 2 years is 85 %.

Pemetrexed in patients with refractory soft tissue sarcoma: a non-comparative multicenter phase II study of the German Sarcoma Group AIO-STS 005.

BACKGROUND: This study evaluated efficacy and safety of pemetrexed in patients with refractory soft tissue sarcoma. METHODS: Patients received pemetrexed intravenously at a dose of 500 mg/m² every 21 days until progression or unacceptable toxicity. The primary endpoint was objective tumor response. RESULTS: Fourty-eight of 53 screened patients were included and received a total of 200 cycles (median 2; range 1-30). Median age was 53 years (range, 20-81). The observed toxicity profile was favorable. NCI-CTC hematologic grade 3/4 toxicity consisted of neutropenia in 13 %, anemia in 15 %, and febrile neutropenia in 4 % of patients of patients, respectively. Non-hematologic CTC grade 3/4 toxicity consisted of elevated ASAT/ALAT in 10 %, hyperglycemia in 6 %, infection with or without neutropenia in 6 %, nausea in 2 % and stomatitis in 2 % of patients. No other grade 3 toxicities and no treatment-related toxic deaths were observed. Overall response as defined by RECIST was 5 %, 16 patients experienced stable disease (40 %). The estimated 3- and 6-months progression-free rates were 33.3 % and 14.6 %, respectively. CONCLUSIONS: In patients with refractory STS, pemetrexed is well tolerated and moderately effective. The confirmed objective response rate in STS is low, however, disease stabilizations are seen in a high proportion of patients (ClinicalTrials.gov NCT00427466).

Effect of concurrent chemotherapy and hyperthermia on outcome of preoperative radiotherapy of high-risk soft tissue sarcomas.

BACKGROUND AND PURPOSE: As treatment results for high-risk soft tissue sarcoma are still disappointing, treatment intensification is warranted. We performed a retrospective analysis of multimodal preoperative treatment to evaluate the additional effect of concurrent chemotherapy and/or locoregional hyperthermia in comparison to radiotherapy alone. PATIENTS AND METHODS: Between 1999 and 2011, 28 patients were treated with neoadjuvant radiotherapy to a median 45 Gy for high-risk soft tissue sarcoma. All tumors were deep-seated and grade 2 or 3, 86% (n = 24) larger than 5 cm. Multimodal treatment (n = 12) consisted of ifosfamide (n = 7), locoregional hyperthermia (n = 3), or both modalities (n = 2) concurrent to radiotherapy. RESULTS: Prognostic factors (grade, size, histology, location) were balanced in the groups with and without concurrent multimodal treatment. There was a significant improvement of disease-specific survival (100% vs. 70% at 3 years, p = 0.03) with multimodal treatment. Distant metastases-free survival was influenced, but was not statistically significant. Local control and disease-free survival did not differ in the two groups. CONCLUSION: Our data suggest that multimodal treatment with ifosfamide and/or locoregional hyperthermia in combination with neoadjuvant radiotherapy might improve outcome in high-risk soft tissue sarcomas.

The soluble form of the receptor of advanced glycation endproducts increases after bariatric surgery in morbid obesity.

OBJECTIVE: The increased cardiovascular (CV) disease risk in patients with morbid obesity (MO) cannot be fully explained by traditional CV risk factors. Activation of the receptor of Advanced Glycation Endproducts (RAGE) leads to inflammation via the NF κß (nuclear factor κß) pathway. The soluble form of RAGE (sRAGE), which is present in plasma, can bind to ligands of RAGE and avoids interaction of RAGE with proinflammatory ligands. We investigated sRAGE levels in patients with MO and compared them with healthy lean controls (CO), before and after bariatric surgery. DESIGN: We conducted a cross-sectional study and a 24-month longitudinal study. SUBJECTS: We included 85 patients (mean age: 41 ± 12 years; mean body mass index (BMI): 45.4 ± 7.9 kg m(-2)) with MO in comparison with 40 CO (mean age: 42 ± 13 years; mean BMI: 26.0 ± 5.5 kg m(-2)). All patients were investigated before and 2 years after bariatric surgery. Apart from weight and CV risk markers (blood pressure, lipids), a glucose tolerance test (75 g), renal and inflammation parameters were assessed. sRAGE levels were assessed by a commercial ELISA. To investigate the associations of the observed reductions of values, delta (Δ) of parameters were calculated. RESULTS: Patients with MO had significant lower sRAGE levels than CO: 1010 ± 514 vs 1501 ± 674 pg ml(-1); P<0.001. In the longitudinal study, sRAGE levels increased significantly after bariatric surgery from 1010 ± 514 to 1261 ± 710 pg ml(-1); P=0.008. In the correlation analysis, ΔsRAGE levels were associated with Δ1-h and Δ2-h postprandial glucose, Δfasting insulin, Δ2-h postprandial insulin, ΔHOMA (homeostatic model assessment)-insulin resistance (ΔHOMA-IR), Δγ-glutamyl transferase and Δtriglycerides. In a multivariate model, Δ1-h and Δ2-h postprandial glucose, Δ2-h postprandial insulin and ΔHOMA-IR predicted ΔsRAGE. CONCLUSION: Patients with MO have significantly lower sRAGE levels compared with non-obese CO, but sRAGE levels increase significantly after weight loss induced by bariatric surgery. As high sRAGE levels inhibit the activation of inflammatory pathways, our results might help understand the beneficial effects of bariatric surgery regarding CV morbidity and mortality.

Clear-cell sarcoma of the soft tissue--a rare diagnosis with a fatal outcome.

Clear-cell sarcomas account for less than 1% of all soft tissue tumours. They most often occur in middle-aged adults as a deeply located lesion with predilection to the tendons and aponeuroses. The aim of the present study was to show possible influencing factors on the outcome after surgical treatment in a detailed case series. We reviewed the medical records of 11 patients with the diagnosis of a clear-cell sarcoma of the soft tissue. These cases were analysed with regard to age, gender, localisation, tumour size, recurrence free survival and overall survival. A minimum follow up of 12 months was achieved. The mean age at the point of diagnosis was 47.9 years. Metastases occurred after a mean of 19.2 months. In the cases with a tumour diameter >5 cm, metastases occurred earlier. When treated in a specialist centre, metastases occurred later. Patients died a mean of 18.4 months after developing metastatic disease. Patients with tumour size >5 cm at the point of primary diagnosis died earlier than patients with a tumour size <5 cm. It is important to detect clear-cell sarcomas as soon as possible and the final surgical treatment should be performed in a centre familiar with the treatment of soft tissue tumours not only to prolong overall survival, but also to treat the patient in a multiprofessional team.

Thrombopoietic cells and the bone marrow vascular niche.

Megakaryocytes and platelets have been known to secrete angiogenic growth factors for a long time. However, there is little in vivo data on the regulation of angiogenesis by thrombopoietic cells. Both megakaryocytes and platelets are known to carry and release a multitude of both pro- and antiangiogenic mediators. Thus, it remained unknown how the "angiogenic phenotype" of thrombopoietic cells would be determined. Our group established that platelets contribute to angiogenesis as carriers of SDF-1, which is released by platelets in response to stimulation with hematopoietic cytokines. Indeed, even the action of VEGF-A seems to be mediated in part by the release of SDF-1 from stimulated platelets, thereby attracting proangiogenic hematopoietic cells. Moreover, the analysis of murine plasma and serum showed that similar to VEGF-A, SDF-1 is almost exclusively derived from platelets, and only trace amounts are detectable in platelet poor plasma. Because tumor patients' platelets have been shown to contain lower amounts of thrombospondin (Tsp), we generated Tsp-1 and Tsp-2 double knockout mice by crossing the single knockout lines. Interestingly, megakaryocytes and platelets derived from these mice confer a proangiogenic phenotype both in the bone marrow and in reperfusion of ischemic hindlimbs, thereby verifying the hypothesis of pro- and antiangiogenic platelet constituents "in balance."

Conceptual model for improving the link between exposure and effects in the aquatic risk assessment of pesticides.

Assessment of risks to aquatic organisms is important in the registration procedures for pesticides in industrialised countries. This risk assessment consists of two parts: (i) assessment of effects to these organisms derived from ecotoxicological experiments (=effect assessment), and (ii) assessment of concentration levels in relevant environmental compartments resulting from pesticide application (=exposure assessment). Current procedures lack a clear conceptual basis for the interface between the effect and exposure assessments which may lead to a low overall scientific quality of the risk assessment. This interface is defined here as the type of concentration that gives the best correlation to ecotoxicological effects and is called the ecotoxicologically relevant concentration (ERC). Definition of this ERC allows the design of tiered effect and exposure assessments that can interact flexibly and efficiently. There are two distinctly different exposure estimates required for pesticide risk assessment: that related to exposure in ecotoxicological experiments and that related to exposure in the field. The same type of ERC should be used consistently for both types of exposure estimates. Decisions are made by comparing a regulatory acceptable concentration (=RAC) level or curve (i.e., endpoint of the effect assessment) with predicted environmental concentration (=PEC) levels or curves (endpoint of the exposure assessment). For decision making based on ecotoxicological experiments with time-variable concentrations a tiered approach is proposed that compares (i) in a first step single RAC and PEC levels based on conservative assumptions, (ii) in a second step graphically RAC and PEC curves (describing the time courses of the RAC and PEC), and (iii) in a third step time-weighted average RAC and PEC levels.

Liposarcoma of the Spermatic Cord: Impact of Final Surgical Intervention--An Institutional Experience.

BACKGROUND: Paratesticular liposarcomas are almost always mistakenly diagnosed as inguinal hernias subsequently followed by inadequate operation. METHODS: 14 consecutive patients with paratesticular liposarcoma were retrospectively reviewed. Preoperative management was evaluated. Disease-free and overall survival were determined. RESULTS: In 11 patients primary and in 3 patients recurrent liposarcoma of the spermatic cord were diagnosed. Regarding primary treatment in primary surgical intervention resection was radical (R0) in 7 of 14 (50%) patients, marginal (R1) in 6 (43%) patients, and incomplete with macroscopic residual tumour (R2) in 1 (7%) patient. Primary treatment secondary surgical intervention was performed in 4 patients: resection was radical (R0) in 3 (75%) patients and marginal (R1) in 1 (25%) patient. Regarding secondary treatment in recurrent disease resection was marginal (R1) in 3 patients (100%). Final histologic margins were negative in 10 patients with primary disease (71%) and positive in 4 patients with subsequent recurrent disease. After radical resection disease-free survival rates at 3 years were 100%. Overall survival at 4.5 years (54 (18-180) months) was 64%. CONCLUSION: An incomplete first surgical step increases the number of positive margins leading to local recurrences and adverse prognoses. Aggressive surgery should be attempted to attain 3-dimensional negative margins.

Enhanced anticoagulant response to activated protein C in patients with IDDM.

Anticoagulant response to activated protein C (APC) was studied in 40 healthy subjects and 67 patients with insulin-dependent diabetes mellitus (IDDM) using a modified activated thromboplastin time assay. Results are expressed in terms of the APC sensitivity ratio (APC SR). In addition, plasma levels of protein C, total and free protein S (PS), coagulation factors V and VIII, and prothrombin fragment 1+2 (F1+2) were measured. Patients with IDDM and a urinary albumin excretion rate (UAER) < 30 mg/24 h showed a median APC SR of 2.5 (interquartile range 2.3-2.9). In patients with a UAER between 30 and 300 mg/24 h, the median APC SR was 2.7 (2.7-2.9). Both values were significantly greater than the median APC SR of 2.1 (2.0-2.5) observed in healthy control subjects (P < 0.001). Also, the percentage of subjects with an APC SR < or = 2.0 was markedly smaller in both patient groups. Factor V and VIII levels were not significantly different between IDDM patients and healthy subjects. Grouping of IDDM patients according to the APC SR revealed significantly enhanced levels of total PS (P < 0.05) and factor VIII (P < 0.01) in patients with a poor anticoagulant response to APC (APC SR < or = 2.0) compared with those with an APC SR > 2.7. The negative correlation of the APC SR in diabetic patients with both coagulation and anticoagulation factors indicates a complex role of this parameter in regulating the coagulation system in IDDM.

Impact of weight loss on inflammatory proteins and their association with the insulin resistance syndrome in morbidly obese patients.

OBJECTIVE: Obesity is closely linked to the insulin resistance syndrome (IRS), type 2 diabetes, and cardiovascular disease, the primary cause of morbidity and mortality in these patients. Elevated levels of C-reactive protein (CRP) and interleukin-6 (IL-6), indicating chronic subclinical inflammation, have been associated with features of the IRS and incident cardiovascular disease. METHODS AND RESULTS: We studied the cross-sectional and longitudinal relation of CRP, IL-6, and tumor necrosis factor-alpha (TNF-alpha) with features of the IRS in 37 morbidly obese patients with different stages of glucose tolerance before and 14 months after gastric surgery. Weight loss after gastric surgery induced a significant shift from diabetes (37% vs 3%) to impaired glucose tolerance (40% vs 33%) and normal glucose tolerance (23% vs 64%). The baseline concentration of IL-6 was correlated with TNF-alpha (r=0.59, P<0.01) and CRP (r=0.44, P<0.05) levels. TNF-alpha, IL-6, and CRP were significantly correlated with insulin resistance estimated by the homeostatic model assessment (r=0.48, P<0.05; r=0.56, P<0.01; and r=0.35, P<0.05, respectively). Concentrations of CRP and IL-6 decreased after weight loss (median, 8.6 and interquartile range, 2.7/14.5 vs 2.5 and 1.2/4.1 mg/L; P<0.006, and 5.13 and 2.72/12.15 vs 3.95 and 1.97/5.64 pg/mL, P<0.02, respectively), whereas serum levels of TNF-alpha remained unchanged (8.6 and 6.3/18.8 vs 11.7 and 5.8/17.2 pg/mL; NS.). Multiple regression analysis revealed that the decrease in insulin resistance remained independently and significantly correlated with the decrease in IL-6 concentrations (P<0.01) and the decrease in body mass index with the decrease in CRP (P<0.05), respectively. CONCLUSIONS: Weight loss in morbidly obese patients induces a significant decrease of CRP and IL-6 concentrations in association with an improvement of the IRS.

High prevalence of abnormal circadian blood pressure regulation and impaired glucose tolerance in adults with hypopituitarism.

Patients with hypopituitarism have an increased mortality from cardiovascular events. Reduced nocturnal blood pressure decline (non-dipping) and impaired glucose tolerance are considered as cardiovascular risk factors. To evaluate the role of these risk factors in patients with hypopituitarism we determined the 24-hour blood pressure regulation and glucose tolerance status in hypopituitary patients with and without growth hormone (GH) deficiency. Sixty-one hypopituitary subjects 5 +/- 3 years after brain surgery because of macroadenoma, 61 patients with type 2 diabetes mellitus (T2DM), and 20 healthy controls were included. Forty-four hypopituitary patients were GH deficient and 28 of these on GH treatment. Non-dipping was observed in 41 % (n = 7) of hypopituitary subjects with normal GH release, in 46 % (n = 13) of patients on GH therapy, and in 69 % (n = 11) of untreated GH deficient patients. Untreated GH deficient patients had a higher systolic night/day ratio (1.00 +/- 0.03) compared to non GH deficient (0.92 +/- 0.02; p < 0.02) and GH treated hypopituitary patients (0.93 +/- 0.01; p < 0.02). The rate of non-dipping in hypopituitarism was comparable to that in T2DM. Pathologic glucose tolerance was diagnosed in 30 % of the hypopituitary patients. The prevalence of non-dipping was independent of glucose metabolism in hypopituitary patients. All controls had normal night time blood pressure fall and glucose metabolism. The high prevalence of nocturnal non-dipping and glucose intolerance detected in this cohort might contribute to the increased cardiovascular risk of hypopituitary patients.

Hypomagnesemia in type II diabetes: effect of a 3-month replacement therapy.

OBJECTIVE: To investigate the effects of long-term high-dose oral magnesium (Mg) therapy (30 mmol/day) in patients with type II diabetes. Low plasma magnesium levels have been reported in type II diabetes and are associated with insulin resistance and diabetic late complications. RESEARCH DESIGN AND METHODS: Forty patients with type II diabetes and hypomagnesemia were observed in a randomized double-blind placebo-controlled trial for 3 months (body mass index: 28 +/- 4 kg/m2; HbA1c: 7.4 +/- 0.8%). Plasma and urine magnesium and metabolic control parameters were determined, and side effects were considered, especially with regard to patients' compliance. RESULTS: A significant increase in plasma magnesium levels was observed after 3 months of treatment (Mg: 0.73 +/- 0.8 vs. 0.81 +/- 0.1 mmol/l), reaching magnesium levels of the control group (0.88 +/- 0.8 mmol/l; NS); metabolic control, however, was not altered (HbA1c: 7.2 +/- 0.7 vs. 7.4 +/- 0.9%). Six months after the end of the trial, plasma magnesium declined to pretreatment levels (Mg: 0.73 +/- 0.07 mmol/l). The prevalence of side effects was high at the beginning and was reduced significantly during treatment. CONCLUSIONS: We conclude that oral magnesium replacement therapy corrects hypomagnesemia after a minimum treatment period of 3 months. These observations might be important for the prevention of diabetic late complications.

[Pulmonary infection in neutropenia]. / Pulmonale Infektion bei Neutropenie - Fall 1/2015.

UNLABELLED: MEDICAL HISTORY AND CLINICAL COURSE: A 42-year-old patient with hairy cell leukemia had been treated for 3 years by a hematologist in private practice. Initially the patient received 1 course of cladribine upon which the disease went into complete remission. 6 weeks ago a relapse was diagnosed and combination therapy with cladibrin and rituximab was initiated. Now the patient presented to the emergency room with shortness of breath and pain when breathing. INVESTIGATIONS, TREATMENT AND COURSE: In the chest x-ray, patchy infiltrates and pleural effusions were found on both sides. The subsequently performed computed tomography showed bilateral compactions with an Halo suspicious for fungal infiltrates. Upon admission to the hospital, an empirical antibiotic therapy with clarithromycin and piperacillin/tazobactam was initiated, which was later escalated to meropenem and linezolid. Additionally, an antifungal therapy with voriconazole was started and later switched to liposomal amphotericin B. At his admission, a positive aspergillus antigen could be detected in the microbiological laboratory. Under antimycotic treatment the aspergillus antigen was repeatedly negative. The patient presented with pronounced cytopenias and after a switch of therapy to vemurafenib and filgrastim, the hematopoiesis could only be stimulated insufficiently. The patient was transferred to the intensive care unit three days after admission with severe respiratory failure. He died on day 8 after admission. AUTOPSY AND DIAGNOSIS: Diagnosis was consistent with relapse of hairy cell leukemia with positive BRAF mutation and a bone marrow infiltration > 80 %. Autopsy revealed a significant hepato-splenomegaly, a lack of erythro-, granulo- and thrombopoiesis. Clots interspersed with fungal hyphae were found in both lungs and an infarction of the spleen with evidence of fungal hyphae was detected. The cultural findings post mortem on yeast or mold were negative. CONCLUSION: Patients with refractory hairy cell leukemia and prolonged neutropenia are at increased risk for systemic fungal infections. Therefore, prohylactic antimycotic therapy should be considered early in this group of patients. The therapeutic approach of vemurafenib in treatment-refractory hairy cell leukemia is promising and offers an additional treatment option. In the present case, the patient could unfortunately not be stabilized due to the septic complications.

Are morphological or functional changes in the carotid artery wall associated with Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, or herpes simplex virus infection?

BACKGROUND AND PURPOSE: Chronic infection with Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus (CMV), and herpes simplex virus (HSV) has been implicated in the pathogenesis of atherosclerosis. The carotid intima-media thickness (IMT) can be taken to indicate early atherosclerosis, the presence of a carotid stenosis is a marker of a manifest carotid atherosclerosis, and an increase in arterial stiffness is used as marker of structural and functional changes in an atherosclerotic vessel wall. METHODS: In 504 patients (75% men; mean age 62.9 [SD 10] years), we measured the IMT and the elastic pressure modulus (EP; n=445) of the common carotid artery and the prevalence of a internal or external carotid artery stenosis. Blood samples were taken, and antibodies against C pneumoniae, H pylori, CMV, and HSV types 1 and 2 were evaluated. Statistical evaluation was performed with regression procedures and multivariate logistic regression analyses. RESULTS: Seropositivity for C pneumoniae was an independent predictor for a combined end point of highest category of IMT and carotid artery stenosis (OR 1.8, 95% CI 1.1 to 3.1; adjusted) for IgG titers. Independently, CMV increased the risk for the combined end point (OR 1.7, 95% CI 1.1 to 2.8; adjusted) for IgG titers and for IgA titers (OR 2.3, 95% CI 1.1 to 4. 9; adjusted). We found a significant correlation between IgG antibodies against CMV and EP; HSV type 2 IgG titers were associated with IMT and carotid stenosis, but the latter results were no longer significant after adjustment. There was no association with H pylori or HSV type 1. CONCLUSIONS: We found a significant association of IgG antibodies against C pneumoniae and CMV with early and advanced carotid atherosclerosis. CMV was also correlated to functional changes of the carotid artery, but this could not be confirmed after adjustment.

Cisapride versus placebo for 8 weeks on glycemic control and gastric emptying in insulin-dependent diabetes: a double blind cross-over trial.

In insulin-dependent diabetes mellitus, slow gastric emptying may make absorption unpredictable and foster glycemic instability. Cisapride accelerates emptying, but controlled long term studies are scarce, and effects on glycemic control unknown. We investigated, in patients with insulin-dependent diabetes mellitus and unstable glycemia, the effects of 10 mg cisapride 4 times daily for 8 weeks vs. placebo on glycemic control and gastric emptying under random, cross-over, double blind conditions. In 14 patients with delayed and 9 with nondelayed emptying, blood glucose variability over 28-week treatment periods separated by a 4-week wash-out and gastric emptying of a semisolid 1168-kJ meal immediately after the treatment periods were assessed. Cisapride did not affect glycemic control [SD of within-patient mean blood glucose, 4.2 mmol/L +/-0.1 (+/- SEM) vs. 4.0+/-0.1 mmol/L after placebo; hemoglobin A1c, 8.3+/-0.2% vs. 8.5+/-0.2%]. Emptying was faster after cisapride than after placebo in 8 of 14 patients with delayed vs. 7 of 9 with nondelayed emptying (P = NS) and in 11 of 15 without vs. 4 of 8 with cardiovascular autonomic neuropathy (P = NS). Autonomic neuropathy prevailed in 7 of 14 patients with delayed and 1 of 9 with nondelayed emptying. Blood glucose immediately before and during assessment of emptying was unrelated to the emptying rate, whereas blood glucose increases over fasting levels were greater with faster emptying (P<0.002). In conclusion, cisapride's effects were not different from those of placebo on glycemic control and gastric emptying, it did not differently affect patients with delayed vs. nondelayed emptying, and it slightly accelerated emptying (P = NS) in patients without, but not in those with, cardiovascular autonomic neuropathy. Blood glucose levels before and during assessment of emptying did not affect emptying, but the glucose rise over fasting levels was greater with faster emptying.

Detection of strands in native aortic valves by transesophageal echocardiography.

Prevalence and echocardiographic characteristics of strands on the leaflets of native aortic valves were examined. According to our data, the strands we found in 39% of patients are most likely Lambl's excrescences.

Correlations between hematopoietic progenitor cell counts as measured by Sysmex and CD34+ cell harvest yields following mobilization with different regimens.

PURPOSE: The Sysmex SE-9000 cell counter provides an estimate of immature cells referred to as hematopoietic progenitor cells (HPC). HPC counts should correlate with CD34+ counts in mobilized peripheral blood and apheresis to allow optimization of apheresis timing. METHODS: We correlated the HPC counts as measured in the immature information channel with CD34+ cell levels as determined by FACS (HPCA-2 antibody, Becton Dickinson) from mobilized peripheral blood in 40 samples (27 patients and three healthy donors) and in aphereses ( n=113, 41 patients and 20 healthy donors). RESULTS: In mobilized blood, HPC counts were correlated with CD34+ cells ( r=0.78, P<0.0001, n=40). The HPC counts were about 1.5-fold higher than CD34+ cell counts with a median (range) of 84 (1-747)/microl and 57 (1-370)/microl, respectively. In CD34+ selected cell preparations ( n=8), HPC counts were about fourfold lower than CD34+ cell counts with a median (range) of 179 (67-693)/microl and 760 (191-4309)/microl, respectively. In apheresis preparations, linear regression analyses were performed for the group of stem cell donors ( n=44), the group of lymphoma patients ( n=23), the multiple myeloma group ( n=21), and the group of solid tumors ( n=25). Interestingly, no correlation between HPC counts and CD34+ cell counts was found in the G-CSF-mobilized healthy donor group ( r=0.23, P=0.13). Pairing of HPC counts and CD34+ counts was effective in the group of patients receiving chemotherapy + G-CSF for stem cell mobilization: lymphoma group ( r=0.67, P=0.0005), multiple myeloma group ( r=0.56, P=0.008), and the group of solid tumors ( r=0.52, P=0.007). CONCLUSIONS: Lymphoma and multiple myeloma patients who were moderately pretreated and mobilized with chemotherapy and G-CSF showed the best results in correlation analyses even at low HPC counts. Therefore, HPC measurement can be used for timing of apheresis in these patients.

Nondipping of nocturnal blood pressure is related to urinary albumin excretion rate in patients with type 2 diabetes mellitus.

Although cardiovascular and cerebrovascular morbidity and mortality in type 2 diabetic patients is closely related to urinary albumin excretion rate (UAER), the causative mechanisms are not yet identified. The aim of our study was to define the circadian variation of blood pressure (BP) in 72 type 2 diabetic patients (mean age 60 years, mean diabetes mellitus duration: 12 years) in comparison with 41 nondiabetic controls with essential hypertension (mean age 58 years) by using ambulatory blood pressure measurement. Thirty diabetic patients had normal UAER (< 30 mg/24 h), 27 had microalbuminuria (30 to 300 mg/24 h), and 15 had persistent proteinuria (> 300 mg/24 h). Systolic blood pressure during both nighttime and daytime was significantly elevated in type 2 diabetic patients with macroalbuminuria compared to controls and patients with normal UAER. During nighttime even type 2 diabetic patients with microalbuminuria had significantly elevated systolic blood pressure compared to controls with essential hypertension. We also observed a correlation of nocturnal blood pressure to UAER (systolic: r = 0.32, P < .007 and diastolic: r = 0.24, P < .04). Nondipping (defined as a reduction of nocturnal BP < 10%) was observed in 80% of the macroalbuminuric, 74% of the microalbuminuric, but only in 43% of the normoalbuminuric type 2 diabetic patients and in 37% of the controls (P < .04). Since a loss of circadian variation of BP is closely related to vascular complications in nondiabetics, our findings may indicate an important relationship between nondipping of BP and the high morbidity and mortality rate in diabetic patients with increased UAER.