Prevalence of thrombophilia and catheter-related thrombosis in cystic fibrosis.

Venous thrombosis in children and young adults is frequently associated with predisposing conditions and with an indwelling catheter or totally implantable venous access device (TIVAD). These systems are commonly used for the delivery of antibiotic therapy in patients with cystic fibrosis (CF). We reviewed our CF center's history of catheter-related events over 13 years and prospectively investigated the presence of risk factors for thrombosis in 66 children and adults with CF (age, 3-38 years; 32 females). Five thrombotic events had occurred in 4 patients, 2 of whom carried the factor V Leiden mutation. Five asymptomatic patients were diagnosed with heterozygous mutations of the factor V or prothrombin gene. Functional activity of protein C was decreased in 13 subjects, with a correlation to impaired liver function. Protein S activity was abnormal in 20 patients and was related to CF genotype. Anti-phospholipid antibodies (APA) were present in 6 asymptomatic patients. A reinvestigation after 3 years confirmed protein S deficiency in 12 of 14 patients, while most abnormalities for protein C or APA were inconsistent. In conclusion, a thrombophilic state was detected in 53% of patients, and 2 out of 4 subjects with TIVAD-related thrombosis carried a genetic defect. It may thus be helpful to include a hemostatic evaluation in the clinical decision process for or against TIVAD insertion in eligible CF patients.

Inflammatory pseudotumors of the central nervous system: report of 3 cases and a literature review.

Inflammatory pseudotumors (IPs), mostly benign lesions characterized by fibrotic ground tissue and polyclonal mononuclear infiltrate, may affect all organ systems. IPs originating in the central nervous system (IP-CNS) are very rare, and their distinct histopathologic features are poorly characterized. Three otherwise healthy patients (age 8, 15, and 17 years) presented with focal neurologic symptoms (seizures, n = 2; headaches, n = 1), corresponding to a left temporal, left occipital, and left frontal IP, respectively, extending from meningeal structures into brain tissue. After resection, no recurrence was observed in patient 1 during 5 years of follow-up, whereas patient 2 developed a rapidly progressive local recurrence and a second intracerebral lesion despite antiviral, immunosuppressive, antibiotic, and radiation therapy. In patient 3, who also showed local recurrences, sequential histopathologic investigations revealed transformation to a semimalignant fibrohistiocytic tumor. In this patient, anaplastic lymphoma kinase (ALK) expression was also positive, whereas it was negative in patient 1. A detailed literature analysis confirmed that most IP-CNS arise from dural/meningeal structures (n = 34). Intraparenchymatous (n = 7), mixed intraparenchymatous/meningeal (n = 4), and intraventricular lesions (n = 7) or IP extending per continuitatem from intracerebral to extracerebral sites (n = 5) were rare. The recurrence rate was 40% within 2 years in general. It was increased after incomplete resection and in female patients (multivariate Cox regression model, P < 0.02). Although rare, IP-CNS are important differential diagnoses among tumor-like intracranial lesions. Their potential risk of malignant transformation and high risk of recurrence necessitate close follow-up, especially when resection is incomplete. Prospective multicenter trials are needed to optimize classification and treatment of this rare inflammatory lesion.

Effect of DNase on exercise capacity in cystic fibrosis.

DNase can reduce viscosity and facilitate expectoration of airway secretions in cystic fibrosis (CF) lung disease. We evaluated its effect on exercise performance in relation to resting pulmonary function. Fifteen sputum-producing CF patients (aged 9-28 years; FEV1 22-83% predicted) performed spirometry, body plethysmography, nitrogen washout, and incremental cardiopulmonary exercise testing before and after 8 weeks of first-time treatment with daily inhaled rhDNase. Most subjects reported increased amounts and fluidity of sputum. The effect on objective parameters was heterogeneous, without statistical significance. Groupwise, FEV1 increased by 6% without correlation to baseline values; individual patients gained up to 40%. Indices of hyperinflation and air trapping were slightly raised. Maximal workload and oxygen uptake (V'O2) increased by up to 20% in a number of patients. The treatment effect on V'O2 was neither related to baseline levels of pulmonary function and exercise capacity nor to the change in FEV1. Ventilatory equivalents for oxygen and carbon dioxide during exercise were slightly but insignificantly lower after DNase treatment; minimal O2 saturation was unaffected. We conclude that improvement of exercise performance with DNase is restricted to a subgroup of CF patients and may not be predicted or identified by spirometry and subject report alone.

Analysis of 5-methyltetrahydrofolate in serum of healthy children.

5-Methyltetrahydrofolate (5MTHF) is the active one-carbon donor and the principal circulating form of plasma folates. It is involved in a number of metabolic and neurodevelopmental processes and analysis of cerebrospinal fluid (CSF) 5MTHF is of great importance in the diagnosis of cerebral folate deficiency (CFD). Serum 5MTHF levels and the 5MTHF serum/CSF ratio may be important additional parameters for the understanding of CFD. We developed a HPLC method for the measurement of 5MTHF in serum and established reference values for the pediatric population. Serum samples from 64 healthy children were extracted with Sep-Pak C18 cartridges and 5MTHF was separated by RP-HPLC and quantified by electrochemical detection. 5MTHF was separated from other folates and detected after 8.7 min with linearity of up to 1600 nmol/L. The detection limit was 4.5 nmol/L and recovery during solid-phase extraction for low and high concentrations of 5MTHF was 66 and 62%, respectively. Within-run imprecision (13.5%) was slightly higher than run-to-run imprecision (8.5%). 5MTHF levels in healthy children were found to be age-dependent, decreasing from 158.0 nmol/L in newborns to 60.1 nmol/L in children older than 16 years. The method we describe is sensitive, selective, and reliable for the analysis of 5MTHF from 400 microL of serum.

Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH).

BACKGROUND: Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN-beta) in children and adolescents with nasopharyngeal carcinoma, especially in high-risk patients, have been promising. METHODS: From 1992 to 2003, 59 patients (58 high-risk patients and 1 low-risk patient, median age 13 yrs; range, 8-25 yrs) were treated in the GPOH-NPC-91 study. The Stage II patient received irradiation as initial therapy. Fifty-eight patients received preradiation chemotherapy with methotrexate, cisplatin, and 5-fluorouracil. The cumulative radiation dose to primary sites was 59.4 Gy, a total dose of 45 Gy was delivered to the neck area. After irradiation, all patients were treated with 10(5) U recombinant IFN-beta/kg body weight 3 times a week for 6 months. RESULTS: After combination therapy, complete response was accomplished in 58 patients. In one patient, there was tumor progression during chemotherapy. In 3 patients, distant metastases were observed 14, 15, and 18 months after diagnosis, respectively. One patient had a local relapse 12 months after diagnosis. Fifty-four patients are still in first remission with a median follow-up of 48 months (range, 10-110 mos). Chemotherapy-related toxicity was mucositis Grade II, III, or IV in all patients and acute cardiotoxicity in 2 (3.5%) of the patients. Nephrotoxicity Grade I-II occurred in 8.8% of patients. CONCLUSIONS: The combination of initial chemotherapy, radiotherapy, and IFN-beta results in an excellent outcome. These results strongly support the development of a future treatment strategy along this line.

Effects of thickened feeding on gastroesophageal reflux in infants: a placebo-controlled crossover study using intraluminal impedance.

OBJECTIVE: Thickening of formula feedings is part of the therapeutic approach for gastroesophageal reflux (GER) in infants. However, its mechanism of action, especially regarding the occurrence of nonacid (pH >4) GER, has not yet been clearly described. The aim of this randomized, placebo-controlled crossover study was to examine the influence of formula thickened with carob (St. John's bread) bean gum on acid and nonacid GER. METHODS: Infants with recurrent regurgitation and without other symptoms were fed alternately (A-B-A-B-A-B) with thickened (A) and nonthickened (B) but otherwise identical formula. Documentation of GER episodes during the study was performed by simultaneous intraesophageal impedance measurement (intraluminal electrical impedance; IMP) and pH monitoring. The IMP technique is able to detect bolus movements inside a luminal organ. The use of multiple measuring segments on a single catheter allowed the analysis of direction, height, and duration of the bolus transport. Continuous videorecording and visual surveillance of regurgitation frequency and amount resulted in a severity score. RESULTS: Fourteen infants (42 +/- 32 days old) were examined during 6 feeding intervals each for a total measuring time of 342 hours. A total of 1183 GER episodes and 83 episodes of regurgitation were registered. Regurgitation frequency (15 vs 68 episodes) and amount (severity score 0.6 vs 1.8) were significantly lower after feedings with thickened formula. The difference regarding the occurrence of GER documented by IMP was also pronounced (536 vs 647 episodes). Although not statistically significant, maximal height reached by the refluxate in the esophagus was decreased after thickened feedings. Mean GER duration and the frequency of acid (pH <4) GER were not altered. CONCLUSIONS: Thickened feeding has a significant effect on the reduction of regurgitation frequency and amount in otherwise healthy infants. This effect is caused by a reduction in the number of nonacid (pH >4) GER episodes, but also because of a decrease of mean reflux height reached in the esophagus. However, the occurrence of acid GER is not reduced. The combination of IMP and pH monitoring allows the complete registration and description of these GER episodes. Thickening of formula feedings with carob bean gum is an efficient therapy for uncomplicated GER in infants.

Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux.

BACKGROUND: pH monitoring is the standard diagnostic tool for gastroesophageal reflux in infants. However, this method does not document the reflux of all kinds of fluid from the stomach into the esophagus, but only documents acid material. The parameters that define reflux episodes by pH monitoring have been derived empirically from observations of many infants considered healthy and ill. Acid reflux is a continuum, some reflux is normal and doubt exists as to how much reflux is abnormal. In this study, one of the standardized protocols for analyzing pH recordings was evaluated and compared with simultaneously obtained intraesophageal impedance measurement (IMP), a pH-independent method of detecting bolus movement within the esophagus. METHODS: The esophagi of 50 infants with reflux symptoms were measured, using both standard pH probe and multiple-site impedance measurement. A standard protocol for analyzing esophageal pH records was used. The sampling rate for pH values was 15/min. Acid reflux was defined as pH less than 4.0 (threshold pH) for at least 15 seconds (minimal duration) with at least 30 seconds (latency time) between separate episodes. The software used could adjust independently or in combinations the sampling rate and these reflux criteria. Thereby it was determined whether changes in the criteria for acid reflux improved the sensitivity and predictive value of pH monitoring when compared with reflux episodes defined by IMP. RESULTS: During 318 hours of recording in 50 infants, 1,887 episodes of reflux occurred according to IMP. Only 282 (14.9%) of the IMP-determined episodes were acid reflux episodes. No alkaline reflux episodes occurred. Among the 270 pH probe-determined episodes using the standard criteria of acid reflux, only 153 (sensitivity, 54.3%; positive predictive value, 56.7%) were accompanied by unmistakable retrograde bolus movement using IMP measurements. Retrograde bolus movement did not accompany the other 117 episodes. Using a sampling rate of 15/min, a pH threshold of 4.0, a minimal duration of reflux episodes of 8 seconds, and a latency time of 60 seconds, the positive predictive value of pH probe results increased to 60.7%. Variations in the sampling rate or criteria for defining acid reflux did not significantly improve the accuracy of the pH probe results versus IMP-defined episodes. CONCLUSIONS: Most reflux episodes that occur in infants are undetectable by standard pH probe monitoring. pH monitoring does not detect all reflux in the esophagus but is useful for detecting acidity in the esophagus and determining the duration of its presence. Combining pH monitoring with impedance measurement is a valuable diagnostic tool for gastroesophageal reflux in infants.