PAS-positive lymphocyte vacuoles can be used as diagnostic screening test for Pompe disease

Screening of blood films for the presence of periodic acid-Schiff (PAS)-positive lymphocyte vacuoles is sometimes used to support the diagnosis of Pompe disease, but the actual diagnostic value is still unknown. We collected peripheral blood films from 65 untreated Pompe patients and 51 controls. Lymphocyte vacuolization was quantified using three methods: percentage vacuolated lymphocytes, percentage PAS-positive lymphocytes, and a PAS score depending on staining intensity. Diagnostic accuracy of the tests was assessed using receiver operating characteristic (ROC) curves. All three methods fully discerned classic infantile patients from controls. The mean values of patients with milder forms of Pompe disease were significantly higher than those of controls, but full separation was not obtained. The area under the ROC curve was 0.98 for the percentage vacuolated lymphocytes (optimal cutoff value 3; sensitivity 91%, specificity 96%) and 0.99 for the percentage PAS-positive lymphocytes and PAS score (optimal cutoff value 9; sensitivity 100%, specificity 98%). Our data indicate that PAS-stained blood films can be used as a reliable screening tool to support a diagnosis of Pompe disease. The percentage of PAS-positive lymphocytes is convenient for use in clinical practice but should always be interpreted in combination with other clinical and laboratory parameters.     

High relapse rate in children with non-advanced nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL or nodular paragranuloma) treated with chemotherapy only

Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare variant of Hodgkin's lymphoma (HL) in children. Since specific immunohistochemical staining has become available, NLPHL can be separated from classical Hodgkin's lymphoma (cHL) more accurately. Scarce information is available about pediatric NLPHL treated with chemotherapy only. Therefore, clinical characteristics, treatment, response and outcome of seven pediatric NLPHL patients, median age 9.2 years (range 7.5 - 14.2 years), diagnosed between 1986 - 2003 among 58 HL patients, uniformly treated in a single center with chemotherapy only, were evaluated. The median follow-up time was 4.2 years (range 2.1 - 10.2 years). NLPHL patients were stage I (n = 5), II (n = 2), whereas cHL, median age 11.4 years (range 3.3 - 15.9 years), were stage I (n = 8), II (n = 17), III (n = 9), IV (n = 1). Upfront treatment of NLPHL patients consisted of six courses of epirubicin, bleomycin, vinblastine and dacarbazine (EBVD) without radiotherapy, whereas cHL patients received six courses of EBVD (n = 14) or 4 - 6 courses of EBVD/MOPP (mitoxin, oncovin, procarbazine, prednison; n = 21). Chemotherapy was used as primary treatment thereby aiming to avoid radiotherapy with potential serious side effects to growing jaws and thyroid. All seven patients reached complete remission (CR). Four patients relapsed, of which three locally. These three were salvaged with second-line chemotherapy without radiation therapy (RT) and are in second CR. One patient relapsing with stage III disease was salvaged by EBVD/MOPP followed by autologous BMT and is also in second CR for 36 months. The event-free survival (EFS) is 43% and overall survival (OS) 100%. This study shows that apart from histology, immunohistochemistry (ICH) is required for diagnosing NLPHL. Moreover, it illustrates that although cure of pediatric NLPHL is feasible with chemotherapy only, high dosages of cytotoxic drugs are necessary as salvage treatment in a relatively high proportion of patients after relapse.     

No effect of statin therapy on silent myocardial ischemia in patients with type 2 diabetes without manifest cardiovascular disease

OBJECTIVE: Coronary artery disease is the most important cause of mortality in patients with type 2 diabetes. We aimed to determine the prevalence of silent myocardial ischemia (SMI) and the effect of statin therapy on SMI in type 2 diabetic patients without manifest cardiovascular disease. RESEARCH DESIGN AND METHODS: A randomized, placebo-controlled, double-blind trial was performed in 250 patients with type 2 diabetes without manifest cardiovascular disease. Patients were given either 0.4 mg cerivastatin or placebo daily. In August 2001, when cerivastatin was withdrawn from the market, cerivastatin 0.4 mg was replaced by 20 mg simvastatin without deblinding the study. The primary end point was the change in ischemic episodes, duration, and burden as measured by 48-h ambulatory electrocardiography (AECG) over 2 years. RESULTS: At baseline, 47 of 233 (20%) evaluable ambulatory electrocardiograms showed evidence of ischemia. After 2 years, there was a trend toward more ischemia in both treatment groups, without significant differences between the changes in ischemic parameters (episodes P = 0.498; duration P = 0.697; burden P = 0.798) in the two treatment groups. Cardiovascular events occurred in 12 patients in the placebo group and in two patients in the statin group (P = 0.006). There was no relationship between these cardiovascular events and the presence of SMI at baseline. CONCLUSIONS: SMI occurred in 20% of type 2 diabetes patients without manifest cardiovascular disease. There was no effect from 2 years of statin therapy on SMI. In contrast, we observed a significantly lower cardiovascular event rate on statin therapy. AECG may not be a proper tool for risk stratification in patients with type 2 diabetes.     

Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre.

PURPOSE: To compare the efficacy and safety of doxorubicin and docetaxel (AT) with fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy for metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients (n = 216) were randomly assigned to either AT (doxorubicin 50 mg/m(2) and docetaxel 75 mg/m2) or FAC (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); both regimens were administered on day 1, every 3 weeks. RESULTS: A median number of six cycles was delivered in both arms, with a median relative dose-intensity of more than 98%. Median time to progression (TTP) and median overall survival (OS) were significantly longer for patients on AT compared with FAC (TTP: 8.0 v 6.6 months, respectively; P = .004; and OS: 22.6 v 16.2 months, respectively; P = .019). The overall response rate (ORR) was significantly higher in patients on AT compared with FAC (58% v 37%, respectively; P = .003). The ORR on AT was also higher in patients with visceral disease compared with FAC patients with visceral disease (59% v 36%, respectively; P = .003). There were no differences in grade 3 to 4 neutropenia and infections (AT 89% v FAC 84% and AT 12% v FAC 9%, respectively). Neutropenic fever was more common in AT-treated patients than FAC-treated patients (33% v 9%, respectively; P < .001). Grade 3 to 4 nonhematologic toxicity was infrequent in both arms. Congestive heart failure was observed in 3% and 6% of patients on AT and FAC, respectively. CONCLUSION: In this phase II to III study, AT resulted in a significantly longer TTP and OS and a higher objective ORR than FAC. First-line AT is a valid treatment option for patients with MBC.     

Pharmaceutical quality control of the investigational polymer-conjugated platinum anticancer agent AP 5280

AP 5280 is a novel polymer-conjugated platinum anticancer agent currently in Phase I clinical trials. In order to guarantee the quality of AP 5280 drug substance for use in the manufacture of a drug product for intravenous human use, an array of tests was utilized for its quality control. Proton nuclear magnetic resonance (1H NMR) spectroscopy and infrared (IR) spectroscopy were employed for structural identification. The molecular weight (MW) and MW distribution, which play a large role in the distribution of AP 5280 in vivo, were determined by Size Exclusion Chromatography (SEC). Platinum binding assessment was performed using platinum nuclear magnetic resonance (195Pt NMR) spectroscopy. The free platinum content and release profile of small platinum species, measured using Flameless Atomic Absorption Spectroscopy (F-AAS), were determined as a measure of molecular integrity, a very important aspect of its assumed mechanism of action. The total platinum content of the copolymer was determined employing flame Atomic Absorption Spectroscopy (AAS). The combined results of the analyses performed on AP 5280 drug substance provided a meaningful picture of its structure, size, and integrity--an excellent basis for its quality control.     

Respiratory herpes simplex virus type 1 infection/colonisation in the critically ill: marker or mediator?

BACKGROUND: The clinical significance and pulmonary pathogenicity of herpes simplex virus type 1 (HSV-1) in mechanically ventilated, critically ill patients are unclear. OBJECTIVE: To determine the clinical features and course of respiratory HSV-1 infections/colonisations in the critically ill, in order to evaluate the contribution to outcome. DESIGN: A retrospective cohort study in the intensive care unit of an university hospital, involving 22 patients with a HSV-1 isolated from bronchoalveolar lavage (BAL) fluid, divided into survivors (n = 13) and non-survivors (n = 9). All patients except for one survivor had been intubated and were mechanically ventilated. RESULTS: Non-survivors had acquired HSV-1 sooner on mechanical ventilation than survivors. Prior chronic heart disease was more prevalent in non-survivors than in survivors and, at the time of HSV-1 isolation, the mean creatinine level was higher (P < 0.05) in the former. Survivors had a somewhat greater fall in body temperature after a 10-day course of antiviral therapy than non-survivors, but the lung radiographic abnormalities prior to and after the course did not differ. There were no major differences in cardiorespiratory variables between outcome groups and causes of death and were judged not to relate, in general, to HSV-1. CONCLUSIONS: Critically ill patients in whom HSV-1 from BAL is isolated, have about 40% chance of dying, mainly because of severe underlying disease and comorbidity, which may predispose to endogenous reactivation of the virus. There is no clinical evidence for direct cardiorespiratory pathogenicity and beneficial effects of antiviral therapy. HSV-1 isolated from lung secretions may thus be a marker rather than a mediator of severe illness.     

The low dose (1 microg) ACTH stimulation test for assessment of the hypothalamo-pituitary-adrenal axis

Traditional testing of the hypothalamo-pituitary-adrenal axis function has relied essentially upon the insulin tolerance test or the metyrapone challenge: both tests are not only uncomfortable, but carry also real dangers. The standard ACTH stimulation test uses an extremely hyperphysiological amount (250 microg) of ACTH to evaluate a physiologic response, which may result in false normal responses. The proposed low dose (1 microg) ACTH test is more physiological and more sensitive, especially in cases of mild adrenal insufficiency and allows also to assess pituitary-adrenal suppression after long-term treatment with glucocorticoids. According to the rules of evidence-based medicine, the low dose ACTH test should replace the conventional 250 microg test when evaluating for central adrenal insufficiency.