Quantitation using HRMS: A new tool for rapid, specific and sensitive determination of catecholamines and deconjugated methanephrines metanephrines in urine.

Urinary catecholamines and their methylated metabolites are biochemical indicators of pheochromocytoma, paraganglioma and neuroblastoma. A rapid and precise analytical method based on solid-phase extraction (SPE) and liquid chromatography separation coupled to high-resolution mass spectrometry (LC-HRMS) was developed and validated to measure urinary catecholamines (epinephrine (E), norepinephrine (NorE), dopamine (D)) and total methylated metabolites (normetanephrine (NorMN), metanephrine(MN) and 3-methoxytyramine (3-MT)) in a clinical setting. Results of 51 urine specimens measured using this LC-HRMS method were compared with a liquid chromatography assay with electrochemical detection (LC-EC). Urine samples (200 µL) were spiked with an internal standard solution followed by SPE purification. In the case of total methylated metabolites, urine was hydrolyzed before SPE purification. Separation was achieved on an Acclaim Mixed Mode WCX column, with an 8.5 min runtime. All compounds were detected in electrospray positive ionization mode with a parallel reaction monitoring acquisition and quantified with a linear regression (r2 > 0.998) between 2 and 200 µg/L (10.9-1090; 11.8-1182 nmol/L) for E and NorE respectively and between 10 and 1000 µg/L for others (65.2-6520; 50.7-5070; 54.5-5450 ; 59.8-5980 nmol/L for D, M, NorMN and 3-MT, respectively). Overall imprecision and bias did not exceed 15%. No significant matrix effect was observed. Correlation between the two assays was good except for epinephrine. Epinephrine concentrations measured by LC-EC method were slightly higher than values obtained with LC-HRMS method but without impact on clinical decision. This LC-HRMS assay provides a new tool for simultaneous quantitative catecholamine determination and was successfully applied in routine for the screening or follow up of pheochromocytoma, paraganglioma and neuroblastoma. LC-HRMS method offers significant advantages compared to LC-EC with good sensitivity, an unambiguous analyte determination and high sample throughput.

[Phaeochromocytoma and paraganglioma]. / Phéochromocytome et paragangliome.

Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that arise from the adrenal medulla or sympathetic and parasympathetic ganglia. These tumors produce most often catecholamines in excess, causing hypertension and sometimes severe acute cardiovascular complications. The diagnosis is based on plasma or urines metanephrines measurements and on conventional and nuclear medicine imaging. Catecholamines-producing PPGL is very unlikely if levels are normal. The diagnosis of PPGL cannot be made without visualization of a tumor. Therapeutic management consists mostly of surgical excision, after drug preparation, and should be done in referral centers. About 40% of pheochromocytomas and paragangliomas occur in the context of an autosomal inherited syndrome, making genetic testing essential. The follow-up must be prolonged because a metastatic evolution or a recurrence can be observed in about 15% of the cases.

Voriconazole and squamous cell carcinoma after lung transplantation: A multicenter study.

This study evaluated the independent contribution of voriconazole to the development of squamous cell carcinoma (SCC) in lung transplant recipients, by attempting to account for important confounding factors, particularly immunosuppression. This international, multicenter, retrospective, cohort study included adult patients who underwent lung transplantation during 2005-2008. Cox regression analysis was used to assess the effects of voriconazole and other azoles, analyzed as time-dependent variables, on the risk of developing biopsy-confirmed SCC. Nine hundred lung transplant recipients were included. Median follow-up time from transplantation to end of follow-up was 3.51 years. In a Cox regression model, exposure to voriconazole alone (adjusted hazard ratio 2.39, 95% confidence interval 1.31-4.37) and exposure to voriconazole and other azole(s) (adjusted hazard ratio 3.45, 95% confidence interval 1.07-11.06) were associated with SCC compared with those unexposed after controlling for important confounders including immunosuppressants. Exposure to voriconazole was associated with increased risk of SCC of the skin in lung transplant recipients. Residual confounding could not be ruled out because of the use of proxy variables to control for some confounders. Benefits of voriconazole use when prescribed to lung transplant recipients should be carefully weighed versus the potential risk of SCC. EU PAS registration number: EUPAS5269.

Leflunomide for BKvirus: Report of Seven Kidney-Transplanted Children.

BACKGROUND: Leflunomide is an immunosuppressive agent commercialized for treatment of rheumatoid arthritis. Because of its immunosuppressive and possible antiviral properties, leflunomide has been evaluated in some case series of BKVAN with favorable results, mostly in adult patients. Leflunomide targeted levels are usually between 50 and 100 mg/L in kidney transplant adult patients. Data in pediatric population are scarce. OBJECTIVE: To assess the effect of leflunomide on BKvirus in kidney-transplanted children. METHODS: Therapeutic drug monitoring of leflunomide is routinely performed by measuring its active metabolite, teriflunomide, using a simple HPLC-UV method. Pediatric kidney transplant patients with at least one teriflunomide sample between 2010 and 2017 were retrospectively included in this study. Viremia control was defined as undetectable BK viremia or a decrease of more than 1 log in the viral load from the baseline after two months of treatment. Adverse events were recorded. RESULTS: A total of 7 patients from 3 centers was included. 6 were only kidney transplant recipients; 1 was a lung-kidney transplant recipient with cystic fibrosis. All patients reported high load BK viremia but none developed BKVAN. For 67% of the patients, complete BK viral clearance was observed during leflunomide treatment with drastic immunosuppressive therapy reduction. Mycophenolate was indeed discontinued in almost all patients. Of note, leflunomide concentrations were significantly higher when viremia was controlled. Only 33% of the observed concentrations were >40 mg/L. The patient with cystic fibrosis had lower concentrations with higher drug doses. No hepatotoxicity was observed in this study and no patient experienced graft rejection. Leflunomide was suspected to cause hemolytic anemia and one patient experienced biological pancreatitis. CONCLUSION: This study evidenced the wide interindividual variability of the exposure and supported the routine practice of leflunomide with a suggested target level of 30-40 mg/L in pediatric kidney transplanted patient. However, because of the very limited number of patients in our series, further investigations are needed to validate this suggestion.

Prevalence and Risk Factors of Sleep Disturbance in a Large HIV-Infected Adult Population.

This cross-sectional study evaluates the prevalence and factors associated with sleep disturbances in French adult HIV-infected outpatients. Patients fullfilled a self-administered questionnaire on their health behavior, sleep attitudes (Pittsburgh sleep quality index, PSQI), quality of life and depression; 1354 patients were enrolled. Median sleeping time was 7 h. Poor sleep quality was observed in 47 % of the patients, and moderate to serious depressive symptoms in 19.7 %. Factors significantly associated with sleep disturbances were depression, male gender, active employment, living single, tobacco-smoking, duration of HIV infection, nevirapine or efavirenz-including regimen. Prevalence of poor sleepers is high in this HIV adult outpatient population. Associated factors seem poorly specific to HIV infection and more related to social and psychological status. Taking care of these disturbances may prove to be an effective health management strategy.

Factors influencing posaconazole plasmatic concentrations in patients presenting with acute myeloid leukemia.

PURPOSE: The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing. PATIENTS AND METHODS: We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays<500ng/mL were considered as under dosed. RESULTS: Fifty-nine assays (43 patients) were performed during induction (n=22) or consolidation (n=37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3-28). The median PSZ blood plasma concentration was 375ng/mL (<200-1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P=0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P=0.008) were associated with underdosing, contrary to feeding difficulties (P=0.07) and digestive disorders (P=0.5). The multivariate analysis confirmed the impact of PPI use (P=0.01) and the cause of hospitalization (P=0.003). CONCLUSION: This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML.

Neutrophil gelatinase-associated lipocalin, a marker of tubular dysfunction, is not increased in long-term virologically controlled patients receiving a tenofovir/emtricitabine + nevirapine regimen.

OBJECTIVES: Tenofovir may be associated with nephrotoxicity. Several studies have shown that an early increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) may predict the occurrence of acute kidney injury. We investigated urine and plasma NGAL in patients on long-term treatment with nevirapine associated with either tenofovir/emtricitabine or abacavir/lamivudine. PATIENTS AND METHODS: We studied 40 virologically controlled Caucasian patients on stable treatment (median >4 years) with tenofovir/emtricitabine + nevirapine (n = 20) or abacavir/lamivudine + nevirapine (n = 20), and no history of kidney disease, high blood pressure or diabetes. Plasma immunovirological parameters (NGAL and C-reactive protein) and urinary NGAL, ß2-microglobulin and α1-microglobulin were measured during a routine clinical visit. RESULTS: Median concentrations of NGAL were in the normal range, but were significantly higher in the abacavir/lamivudine group compared with the tenofovir/emtricitabine group both in the plasma, at 74.9 and 66.0 ng/mL (P = 0.032), respectively, and in the urine, at 36.1 and 12.8 ng/mL (P = 0.017), respectively. CONCLUSIONS: Plasma and urinary NGAL concentrations remained in the normal range in this long-term virologically controlld population without any overt renal disease. The usefulness of NGAL in detecting sub-clinical renal dysfunction appears to be very limited.

High frequency of vitamin D deficiency in HIV-infected patients: effects of HIV-related factors and antiretroviral drugs.

OBJECTIVES: The aim of this study was to assess 25-hydroxyvitamin D (vitamin D) status in an HIV-infected adult population and to define HIV- and antiretroviral-related factors associated with vitamin D deficiency. METHODS: Using data from a prospective cohort of HIV-infected adult patients followed in five French centres (Dat'AIDS cohort), we evaluated the prevalence of vitamin D deficiency/insufficiency (<30 ng/mL). A multiple linear regression model was used to examine risk factors for vitamin D deficiency (≤10 ng/mL). RESULTS: Vitamin D deficiency/insufficiency was observed in 86.7% of the 2994 patients, including 55.6% with vitamin D insufficiency and 31.1% with vitamin D deficiency. In multivariate analysis, factors associated with vitamin D deficiency were current smoking [adjusted OR (aOR) 1.55], estimated glomerular filtration rate ≥90 mL/min/1.73 m(2) (aOR 1.51), vitamin D measurement not performed in summer (aOR 0.27), CD4 <350 cells/mm(3) (aOR 1.37 for CD4 200 to <350 and 1.62 for CD4 <200 cells/mm(3)) and antiretroviral therapy (aOR 2.61). Gender, body mass index, age, coinfection and previous AIDS were not associated factors. In the antiretroviral-treated population (n = 2660), besides the same factors found in the whole population, efavirenz was the only drug to be significantly associated with deficiency, with an aOR of 1.89 (95% CI 1.45-2.47). CONCLUSIONS: Vitamin D deficiency is frequent in this HIV-infected population. Patients on antiretroviral therapy are at higher risk of vitamin D deficiency than antiretroviral-naive patients, with an increased risk in patients receiving efavirenz. No effect of the other antiretrovirals, including the latest (etravirine, darunavir, raltegravir), was found.

Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis.

BACKGROUND AND OBJECTIVE: Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune-compromised patients such as organ-transplant recipients. Recently, voriconazole has been approved for first-line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung-transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter's tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without. METHODS: Lung-transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student's t-test. Statistical significance was defined by P-value <0.05. RESULTS: Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12.3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14.9 days vs. 8.3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole. CONCLUSION: This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung-transplant recipients a median of 12.3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.

Valganciclovir prophylaxis for cytomegalovirus infection in thoracic transplant patients: retrospective study of efficacy, safety, and drug exposure.

Oral ganciclovir (GCV) was replaced by prodrug valganciclovir (vGCV) for cytomegalovirus (CMV) prophylaxis. We assessed retrospectively (2005-2007) vGCV effectiveness and safety during prophylaxis and 4 months after, in heart (HTx) and lung transplantation (LTx), including lung transplant for cystic fibrosis (CFTx). Patients with stable renal function received vGCV 900 mg daily during 3-6 and 8-12 months in HTx and LTx. Effectiveness was assessed by antigenemia (pp65Ag) and a GCV therapeutic drug monitoring to document exposure. A total of 32 patients (11 HTx, 7 LTx, and 14 CFTx) received vGCV for 106+/-67 days in HTx versus 270+/-85 days in LTx and CFTx. Doses were 700+/-225, 915+/-60, and 820+/-150 mg/24 h in HTx, LTx, and CFTx showing acceptable mean trough GCV 0.75+/-0.5 mg/L. Two of 9 cases of neutropenia were attributable to vGCV. Three CMV donor-positive/recipient-negative CFTx patients presented positive pp65Ag; 2 developed CMV disease (6%). We found that vGCV 900 mg, adapted to renal function, was effective and safe for long CMV prophylaxis together with efficient exposure in thoracic transplantation.

Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients.

BACKGROUND: Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels. METHODS: VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data. RESULTS: The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements. CONCLUSIONS: TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

[Biochemical diagnosis of pheochromocytoma and neuroblastomas]. / Diagnostic biochinique du phéochromocytome et du neuroblastome.

Pheochromocytoma and neuroblastoma are distinct tumours, but their biological diagnosis is based on secretion increase of one or several catecholamines. Assays have to be very sensible and specific for an early diagnosis. 24 hours urinary catecholamines and metabolites are currently measured, but technical improvements permit plasma metanephrine assay, an excellent indicator of pheochromocytoma. HPLC coupled to electrochemical detection represents the most efficient methodology. After a review of urinary and plasma assay methods, the authors show usual values of catecholamines, metanephrines, HVA and VMA, according to ages, and give examples of results encountered in classical or not tumours and in falsely positive cases. Urinary metanephrine assay is the most sensible and specific in biological diagnosis of pheochromocytoma, while catecholamines and VMA assays lack of sensibility. Results have to be given by 24 hours and by creatinine ratio. Metanephrine assay can be performed also in plasma and exhibits the same interest. However, in urine as in plasma, in case of renal failure, results cannot be interpreted. Neuroblastoma biological diagnosis is based classically on HVA, VMA, and dopamine assays, nowadays only in 24 hours urine (or in urinary micturition for screening), and results are also expressed as creatinine ratio. But even if several assays are advisable, 5% of the neuroblastoma cases do not produce increased catecholamine values. In some cases, metanephrine assay could be of interest. After the age of 12 months, clinical expression of neuroblastoma is dramatic in 70% of cases. So, a biological screening has been experimented in several countries including France. A French translation of the consensus conference report (1998) is appended, which shows the complexity of neuroblastoma screening. Now, there is no evidence that early tumour detection by screening lessens the mortality rate, but a weak benefit is not excluded.

Clinical pharmacology of immunosuppressive drugs: year 2000--time for alternatives.

Perspectives in immunosuppressive drug therapy have changed rapidly in the past few years with the appearance on the market of several new entities. Used for organ transplantation, bone-marrow transplantation and more recently in some auto-immune diseases, the usual classical scheme consisting of corticoids, azathioprine (1970) and cyclosporin (1980), with or without an induction period with antilymphocyte antibodies, has varied little except for the monoclonal antibody OKT3. The considerable evolution due to the introduction of cyclosporin almost twenty years ago has reached its limits. The new perspectives offer two aspects: (1) on one hand, the specificity of each compound: tacrolimus, Prograf, Fujisawa; mycophenolate mofetyl (MMF), CellCept, Roche; cyclosporin, Neoral, Novartis; basiliximab, Simulect, Novartis; and dacliximab, Zenapax, Roche; monoclonal humanized antibodies, rapamycine or sirolimus, Rapamune, Wyeth; or its derived form RAD Novartis; (2) on the other hand, all these products represent alternatives to the present scheme in a field where coprescription is the rule. These alternatives encounter one main difficulty: the evaluation and the organization of the different possible combinations have to be done within a small series of patients. It is essential to note that the market authorizations have been given on the basis of a precise scheme of dosage regimen from the pivotal studies and that extrapolation from these conditions, in particular choice of the doses, has required thorough reflection. These recent developments need optimization between an improvement of immunosuppression and a higher risk for infection and malignancy.

Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV.

OBJECTIVE: To estimate the change in survival of patients with AIDS-related progressive multifocal leukoencephalopathy (PML), in relation to the introduction of protease inhibitors (PI). DESIGN: The French Hospital Database on HIV (FHDH) is a prospective cohort of 70 224 HIV-infected subjects. This study included the patients diagnosed with PML between 1 July 1995 and 30 June 1997. PML diagnosis was both presumptive and confirmed. We compared the survival probability according to the diagnosis period (period 1 or 2, before or after introduction of PI in France on 1 April 1996). Cox's model was used to calculate the relative hazards of death according to the antiretroviral regimen. RESULTS: The study included 246 patients, 109 diagnosed during period 1 and 137 during period 2. In all, 131 patients received an antiretroviral combination that included PI. By 31 December 1997, a total of 131 deaths had been reported. The probability of survival at 6 months for patients from period 2 was nearly twice as high as for patients from period 1 (60.5 versus 34.5%). In comparison with patients receiving no treatment, the risk of death in patients on combination therapy not including PI was reduced by 38% [relative hazard (RH) 0.62, 95% confidence interval (CI) (0.41; 0.95), P = 0.026] and in patients on combination therapy with PI, by 63% [RH 0.37, 95% CI (0.22; 0.64), P = 0.0004]. CONCLUSION: This study of a large cohort of patients diagnosed with PML (n = 246), provides evidence that a combination antiretroviral regimen, especially one including PI, confers marked survival benefits.

[Immunosuppression: a case of mucoviscidosis]. / Immunosuppression: cas particulier de la mucoviscidose.

Cystic fibrosis is a recessive disease that causes changes in mucus secretions, affecting different systems: respiratory, digestive, pancreatic, hepatic; resulting in obstructions and secondary infections. Transplantation may be used for the most severe forms and is then complicated by the pediatric context, the existence of malabsorption and secondary infections and the type of transplantation (pulmonary and/or hepatic). The follow-up is characterized by pulmonary infections and pulmonary chronic rejection. In our experience, the initiation of the immunosuppressive treatment must avoid corticoids in the early post-transplantation days and have recourse to intravenous cyclosporin (CyA) 2 mg/kg/day, given on average for one month in an oral form. In case of persistent acute rejection, tacrolimus (FK 506) is instituted. Oral CyA (10-12 mg/kg/day) seems more sensitive to malabsorption syndrome than FK 506 (0.2 mg/kg/day). In both cases, the development of an inhibitory metabolic interaction in the presence of itraconazole must be taken into account: used against aspergillosis, itraconazole is metabolized as CyA and FK 506 by Cyt P450 3A4. The intensity of the interaction is twofold for CyA versus fivefold for FK 506. The strategy for the use of other recently available immunosuppressives such as mycophenolate is under evaluation.

[Limitations of the protein profile for diagnostic orientation in initial internal medicine consultation. Prospective study on 76 patients]. / Limites du profil protéique d'orientation diagnostique en consultation initiale de médecine interne. Etude prospective chez 76 malades.

Determination of the protein profile of orientation (PPO) is now considered by some authors as a means of improving the diagnosis in internal medicine. The feasibility of systematizing this practice was investigated in 76 outpatients (79 included, three excluded secondarily) seen for pathology of undetermined diagnosis. The 79 patients (mean age: 52 years) underwent the classical biological explorations plus PPO. The physicians were divided into two groups (seniors and assistants). Two complete clinical files were established for each patient, with one difference concerning inflammatory and immunologic data: one file included the minimum number of tests considered necessary by the physician and the other the complete PPO (nine proteins). Each file (with or without PPO) was randomly distributed to one of two physicians in the same group. Each physician filled in a diagnostic evaluation sheet indicating whether there was organic pathology or not, the main diagnosis (inflammatory, neoplastic, infectious or other), the secondary diagnosis and the hypothesis of probability. The relevance of the clinical opinion was analyzed by an internal medicine specialist from outside the department with 40 years of clinical experience. The duration of symptoms before the medical visit was from 3 weeks to 5 years (mean 6 months). A diagnosis of organic pathology was reached for three out of four patients. Sixty-seven patients were seen again after a minimum of 6 months, and nine were lost to follow-up. Diagnostic efficiency was no greater for cases with PPO, which appears to be a biological examination of second intention. We suggest that the term "protein profile of orientation" be replaced by "broad protein profile."

The urinary metanephrine-to-creatinine ratio for the diagnosis of pheochromocytoma.

OBJECTIVE: To compare the operating characteristics of two tests for diagnosing pheochromocytoma: 1) measurement of the ratio between urinary metanephrine and creatinine levels and 2) measurement of urinary metanephrine levels alone. A second objective was to ascertain the reasons for false-positive test results. DESIGN: Cross-sectional study. SETTING: Hypertension referral center. PATIENTS: 1013 patients referred for hypertension and tested for pheochromocytoma. MEASUREMENTS: 24-hour urinary levels of metanephrine (measured using liquid chromatography) and creatinine. The presence of pheochromocytoma was confirmed at surgery. In patients with positive test results, the absence of pheochromocytoma was documented by negative results of retests and imaging procedures. RESULTS: Of 58 patients with increased metanephrine levels or increased metanephrine-to-creatinine ratios, 20 had pheochromocytoma and 38 did not. Of the 38 patients without pheochromocytoma, 15 had high metanephrine levels but normal metanephrine-to-creatinine ratios. The respective operating characteristics of measurement of urinary metanephrine levels and measurement of the metanephrine-to-creatinine ratio were as follows: sensitivity, 95% and 100%; specificity, 98% and 98%; positive predictive value, 46% and 47%; and negative predictive value, 100% and 100%. In 13 of the 23 patients who had a high metanephrine-to-creatinine ratio, various acute events may have caused hypersecretion of catecholamines. CONCLUSIONS: Measurement of the metanephrine-to-creatinine ratio is a sensitive and specific test for pheochromocytoma. However, acute events may increase urinary metanephrine excretion to the level that occurs with tumors.

Short-term effects of octreotide on blood pressure and plasma catecholamines and neuropeptide Y levels in patients with phaeochromocytoma: a placebo-controlled trial.

OBJECTIVE: The observation that phaeochromocytoma possess specific somatostatin binding sites led us to test the hypothesis that octreotide may have antisecretory potential in patients with phaeochromocytoma. We therefore compared the effects of octreotide and placebo on blood pressure and plasma catecholamines and neuropeptide Y. PATIENTS: Ten consecutive patients referred to a tertiary care centre for the diagnosis and treatment of a phaeochromocytoma. DESIGN AND MEASUREMENTS: We performed a crossover comparison of either three 100 micrograms subcutaneous injections of octreotide over one day or 3 injections of octreotide vehicle over another. Blood pressure was measured over 24 hours on each test day using an automatic ambulatory recorder. Blood samples were collected before (at 0800 and 0900 h) and after (at 1000, 1100, 1200, 1300 and 1500 h) placebo or octreotide injection. Plasma catecholamines were assayed by high-performance liquid chromatography and neuropeptide Y was determined using a two-site amplified enzyme immunoassay. All patients then underwent surgery and tumoral somatostatin binding site density was determined by quantitative autoradiography. RESULTS: Compared to placebo, octreotide did not alter mean 24-hour ambulatory blood pressure or plasma neuropeptide Y, or plasma or urinary catecholamine, levels. Although a moderate reduction in plasma noradrenaline was found in the two patients with the highest tumoral somatostatin binding site densities, overall octreotide-induced variations in plasma noradrenaline did not correlate with somatostatin binding site density. Blood glucose increased from 5.4 +/- 0.3 on placebo to 7.8 +/- 0.5 mmol/l on octreotide (P < 0.01). CONCLUSION: In the present controlled conditions, short-term administration of octreotide had no antisecretory effect in patients with phaeochromocytoma.