Inflammatory myofibroblastic tumor of the pancreas with regional lymph node involvement

Inflammatory myofibroblastic tumors (IMT) can be found in virtually any location of the human body. Histologically a mesenchymal aspect predominates and makes these mostly benign tumors apt to be erroneously diagnosed as a soft tissue sarcoma. Cases showing infiltrative growth and local recurrence further complicate the assessment. Localization of an IMT in the pancreas is extremely rare. Clinical investigations regularly lead to the putative diagnosis of a malignant tumor and only subsequent histological examination can establish the correct tumor classification. We present the case of a 62-year-old woman with IMT of the pancreas. Evidence of lymph node involvement has not yet been reported in this setting.     

Fever and neutropenia in children with cancer: diagnostic parameters at presentation

We evaluated 91 episodes of fever in 46 profoundly neutropenic children with cancer, in a search for any symptom, sign or laboratory test that would serve to identify patients with septicemia and differentiate them from those in no immediate need of prompt antimicrobial therapy. Seventeen episodes (19%) were bacteremias, 59 (64%) were suspected septic infections, 9 (10%) were focal bacterial infections and 6 (7%) proved not to be bacterial infections. We were unable to detect any parameter, either on admission or after two days of antimicrobial therapy (except for blood culture findings), that would be helpful in differentiating bacteremia from an episode not of bacterial origin. We focused on serum levels of C reactive protein and found them unreliable on an individual level. Prompt institution of antimicrobial therapy at the occurrence of fever results in low mortality, but does not allow assignment of cases to different categories.     

Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6

Bupropion is applied in depression and smoking cessation. Genetic polymorphisms in cytochrome P450 2B6 (CYP2B6) may cause variability in bupropion pharmacokinetics since hydroxylation is known to be mediated by CYP2B6. Bupropion may be a probe drug for CYP2B6 activity in humans. Bupropion pharmacokinetics were studied after a single oral dose of 150 mg in 121 healthy male volunteers. The amino acid polymorphisms R22C, Q172H, S259R, K262R and R487C were analysed by polymerase chain reaction and restriction fragment length polymorphism and plasma concentrations were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed by non-parametric methods and by population pharmacokinetic modelling. A unimodal distribution of bupropion and hydroxybupropion kinetic parameters was detected with a mean (range) area under the curve (AUC) of 3.64 (0.89-8.14) micromol.h/l for bupropion and 25.5 (6.72-75.3) micromol.h/l for hydroxybupropion. Population kinetic analysis revealed that bupropion total clearance via CYP2B6 alleles *1, *2, *5 and *6 did not differ, but clearance via allele *4 was 1.66-fold higher compared to wild-type allele *1 (P=0.001). Corresponding to the high clearance of bupropion, carriers of the CYP2B6 genotype *1/*4 had significantly higher Cmax of hydroxybupropion compared to all other genotypes (P=0.03). Only a minor fraction of the variability in bupropion and hydroxybupropion kinetics could be explained by the known CYP2B6 amino acid variants, in particular by the CYP2B6*4 allele. The role of this allele should also be studied in other CYP2B6 substrates, including cyclophosphamide, halothane, mianserin, promethazine and propofol.     

Influence of CYP2D6 genotype and medication on the sparteine metabolic ratio of psychiatric patients

OBJECTIVE: To investigate the influence of CYP2D6 genotype and medication on the reliability of phenotyping in a naturalistic setting of psychiatric inpatients. METHODS: The phenotype of 160 psychiatric inpatients was estimated by taking the urinary metabolic ratio (MR) of the concentrations of sparteine to 2- and 5-dehydrosparteine. Genotyping identified CYP2D6*1, *3, *4, *5 and *6 alleles as well as duplication of the CYP2D6 gene. All subjects underwent detailed drug history including drug dose and therapeutic drug monitoring to control compliance and abuse of other psychotropic drugs. These data were compared with those of 195 unmedicated healthy Germans. RESULTS: The cumulative distribution of the MR in patients showed a significant shift to higher MR when compared with that of healthy subjects (P < or = 0.001). Patients medicated either with selective serotonin reuptake inhibitors (SSRIs, P < or = 0.001), antipsychotic drugs (P= 0.002) or other drugs known to be substrates or inhibitors of CYP2D6 (P < or = 0.001) showed a significantly higher mean MR than unmedicated patients. However, there was no significant effect of tricyclic antidepressants on the MR. Healthy subjects with CYP2D6 deficiency were separated by a MR of greater than 20 from those who expressed functional CYP2D6. Seven patients carrying at least one functional CYP2D6 allele revealed a MR of greater than 20, indicating the occurrence of phenocopying. CONCLUSION: The results of phenotyping may be falsified by drugs known to be substrates or inhibitors of CYP2D6; thus, this method is not sufficiently reliable. However, since we observed the phenomenon of phenocopying only in patients treated with a SSRI such as fluoxetine, fluvoxamine or paroxetine, we conclude that sparteine phenotyping of medicated patients detects CYP2D6 deficiency correctly, provided that patients treated with these SSRIs are excluded.     

POSTNATAL DEVELOPMENT OF RENAL FUNCTION IN PRE-TERM AND FULL-TERM INFANTS

ABSTRACT. Aperia, A., Broberger, B., Klinder, G., Herin, P. and Zetterström, R. (Department of Paediatrics, Karolinska Institute, St. Göran's Children's Hospital, Stockholm and Huddinge Hospital, Huddinge, Sweden). Postnatal deveopment of renal function in preterm and full-term infants. Acta Paediatr Scand, 70:183, 1981. –This study has been designed to examine the effect of gestational age (GA) on the postnatal development of renal function and has been performed in pre-term (PT) infants (GA=30–34 weeks) and in full-term (FT) infants (GA=39–41 weeks). Postnatal age has ranged from 1–35 days. From 8 hour urine samples collected after spontaneous voiding and a capillary blood sample, determinations have been made of the clearance of creatinine (C_Cr), the fractional excretion of β₂-microglobulin (FE_β2) and the fractional excretion of sodium (FE_Na). In some infants receiving fluid parenterally, simultaneous determinations were made of the clearance of creatinine and inulin. As judged from this study, C_Cr is a reliable indicator of the glomerular filtration rate (GFR). GFR was almost the same in newborn PT and FT, but from 0.3–1 week of age GFR increased significantly more rapidly in FT than in PT. From 1–5 weeks of age GFR increased at approximately the same rate in PT and FT infants. The absolute value for GFR in 3–5 weeks old infants was lower in PT than in FT. FE_β2 was higher in PT than in FT infants during the entire first month of life and FE_Na was higher in PT than in FT infants during the first week of life, suggesting a glomerular tubular imbalance at least at the level of the proximal tubule in PT infants. It is concluded that different stages of maturation will alter the preconditions for the renal adaptation to extrauterine life during at least the first month of life. Therefore special attention must be paid to the limited renal function in PT during their entire first month of life.     

Prostatic evaluation by transrectal sonography with histopathologic correlation: the echopenic appearance of early carcinoma

Fifty-two patients with clinical stage A and B carcinomas of the prostate were imaged by ultrasound (US) transrectally with a 5-MHz linear array transducer and transabdominally with a 3-MHz sector scanner prior to radical prostatectomy. The fresh specimens of 44 prostate glands were scanned in a water bath with a 5-MHz linear array transducer in multiple planes. In all cases, histopathologic correlation was obtained. Prostatic carcinoma presented as an echopenic lesion in 54% of the specimens, as a slightly hypoechoic area in 22%, and could not be identified in 24% because of its isoechoic characteristics. In contrast to many previous reports, no instance of echogenic cancer was observed.     

Divergent Kinetics of hsp70 Induction in Oniscus asellus (Isopoda) in Response to Four Environmentally Relevant Organic Chemicals (B[a]P, PCB52, γ-HCH, PCP): Suitability and Limits of a Biomarker

Mature specimens of the isopod Oniscus asellus were maintained on soil and leaf litter to which was added different concentrations of either benzo[a]pyren (B[a]P), 2,2′,5,5′-tetrachlorobiphenyl (PCB52), γ-hexachlorocyclohexane (γ-HCH), or pentachlorophenol (PCP) for a maximum of 14 days. Time-dependent investigation of the body level of the 70 kD stress protein group (hsp70) in the isopods revealed a significant but transient induction of the hsp70 response after about 24 h of exposure to PCB52 or B[a]P. Despite continuous exposure, the hsp70 level decreased subsequently and ended up close to or below the control level independent of the concentration of PCB52 or B[a]P in the substrate. All applied PCP or γ-HCH concentrations also resulted in an initial peak of hsp70 response after 24 h of exposure and a second peak after several days of exposure, as well as an elevated hsp70 level throughout the period of exposure. Although acute stress conditions posed by all four organic chemicals were monitored by stress protein induction, hsp70 can act as a biomarker of chronic exposure and effect for PCP and γ-HCH only. Received: 9 April 1998/Accepted: 16 August 1998     

Bronchoscopic features and bronchoscopic intervention for endobronchial hamartoma

Background and objective: Bronchoscopic resection of endobronchial hamartomas has been reported to have a favourable outcome. This study describes the bronchoscopic features of endobronchial hamartoma and reports the clinical outcome of bronchoscopic intervention. Methods: A retrospective analysis was conducted of patients with histologically proven endobronchial hamartomas, diagnosed in the 10‐year period 1999–2009 to elucidate the clinical, radiological and bronchoscopic features of hamartoma and to describe the clinical outcomes. Results: Seventeen of the 135 patients with pulmonary hamartomas were diagnosed as having endobronchial hamartomas. CXR was abnormal in 11 of the 17 patients. On chest CT (n = 16), the median diameter of the lesion was 15.6 mm. Calcification and areas of focal fat in the lesion, the diagnostic CT findings of pulmonary hamartoma, were found in two of 16 (12.5%) patients. At bronchoscopy (n = 16), all tumours had a mass appearance and most were smooth surfaced round masses (50.0%) with 18.8% having a ‘stalk’. Bronchoscopic forceps biopsies were performed in 13 patients, which resulted in five patients (38.5%) being diagnosed with endobronchial hamartoma. Fifteen patients were treated with rigid or flexible bronchoscopic resection, one had lobectomy, and one had no intervention. No procedure‐related mortalities or late complications developed. Conclusions: Bronchoscopic intervention appears to be a safe and effective method to resect endobronchial hamartomas.     

Effect of CYP2B6*6 and CYP2C19*2 genotype on chlorpyrifos metabolism

Chlorpyrifos (CPF) is a widely used organophosphorus (OP) pesticide. CPF is bioactivated by cytochrome P450s (CYPs) to the potent cholinesterase inhibitor chlorpyrifos oxon (CPF-O) or detoxified to 3,5,6-trichloro-2-pyridinol (TCPy). Human CYP2B6 has the highest reported Vmax)/Km (intrinsic clearance--CL(int)) for bioactivation while CYP2C19 has the highest reported CL(int) for detoxification of CPF. In this study, 22 human liver microsomes (HLMs) genotyped for common variants of these enzymes (CYP2B6*6 and CYP2C19*2) were incubated with 10 μM and 0.5 μM CPF and assayed for metabolite production. While no differences in metabolite production were observed in homozygous CYP2C19*2 HLMs, homozygous CYP2B6*6 specimens produced significantly less CPF-O than wild-type specimens at 10 μM (mean 144 and 446 pmol/min/mg, respectively). This correlated with reduced expression of CYP2B6 protein (mean 4.86 and 30.1 pmol/mg, for CYP2B6*6 and *1, respectively). Additionally, CYP2B6*1 and CYP2B6*6 were over-expressed in mammalian COS-1 cells to assess for the first time the impact of the CYP2B6*6 variant on the kinetic parameters of CPF bioactivation. The Vmax for CYP2B6*6 (1.05×10? pmol/min/nmol CYP2B6) was significantly higher than that of CYP2B6*1 (4.13×10? pmol/min/nmol CYP2B6) but the K(m) values did not differ (1.97 μM for CYP2B6*6 and 1.84 μM for CYP2B6*1) resulting in CL(int) rates of 53.5 and 22.5 nL/min/nmol CYP2B6 for *6 and *1, respectively. These data suggest that CYP2B6*6 has increased specific activity but reduced capacity to bioactivate CPF in HLMs compared to wild-type due to reduced hepatic protein expression, indicating that individuals with this genotype may be less susceptible to CPF toxicity.