Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status

BackgroundThere are currently no reliable biomarkers for malignant pheochromocytomas and paragangliomas (PPGLs). This study examined whether measurements of catecholamines and their metabolites might offer utility for this purpose.MethodsSubjects included 365 patients with PPGLs, including 105 with metastases, and a reference population of 846 without the tumour. Eighteen catecholamine-related analytes were examined in relation to tumour location, size and mutations of succinate dehydrogenase subunit B (SDHB).ResultsReceiver-operating characteristic curves indicated that plasma methoxytyramine, the O-methylated metabolite of dopamine, provided the most accurate biomarker for discriminating patients with and without metastases. Plasma methoxytyramine was 4.7-fold higher in patients with than without metastases, a difference independent of tumour burden and the associated 1.6- to 1.8-fold higher concentrations of norepinephrine and normetanephrine. Increased plasma methoxytyramine was associated with SDHB mutations and extra-adrenal disease, but was also present in patients with metastases without SDHB mutations or those with metastases secondary to adrenal tumours. High risk of malignancy associated with SDHB mutations reflected large size and extra-adrenal locations of tumours, both independent predictors of metastatic disease. A plasma methoxytyramine above 0.2 nmol/L or a tumour diameter above 5 cm indicated increased likelihood of metastatic spread, particularly when associated with an extra-adrenal location.ConclusionPlasma methoxytyramine is a novel biomarker for metastatic PPGLs that together with SDHB mutation status, tumour size and location provide useful information to assess the likelihood of malignancy and manage affected patients.     

Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates

Dipeptide-derived compounds, bearing various P2 residues and a diaryl pyrrolidin-2-yl phosphonate at the P1 position, were evaluated as dipeptidyl peptidase 8 (DPP8) inhibitors. With these products, irreversible inhibition of DPP8 was observed. To obtain inhibitors with an improved activity and selectivity profile, a set of selected analogues containing a diaryl isoindolin-1-ylphosphonate at P1 was synthesized and evaluated. Within this latter series, compound 2e was shown to be a potent, irreversible inhibitor of DPP8, demonstrating very low affinity for DPP IV and DPP II.     

Maternal glucose concentration influences fetal growth, gestation, and pregnancy complications.

Using 1990-1995 data, the authors examined the influence of post-challenge maternal glucose concentration on pregnancy outcome in 1,157 nondiabetic US gravidas. After control for potential confounding variables and comparing gravidas with lower glucose concentrations (<99 mg/dl) with the others, they found that mean birth weight increased by 50 g and 200 g with glucose concentrations of 99-130 mg/dl and >130 mg/dl, respectively. Increased maternal glucose concentration also was associated with an increased risk of large-for-gestation fetuses (p for trend < 0.001) and a decreased risk of fetal growth restriction (p for trend < 0.05). The association between glucose and gestation was inverse and significantly shortened when glucose concentrations were higher. Maternal complications increased twofold or more with high glucose concentrations and included cesarean section and clinical chorioamnionitis. Chorioamnionitis in combination with high maternal glucose concentration increased the risk of very preterm delivery almost 12-fold. These observations extend Pedersen's hypothesis-that high concentrations of maternal glucose give rise to increased nutrient transfer to the fetus and increase fetal growth, beyond the model of maternal diabetes (Acta Endocrinol 1954;16:330-42). They raise the question of whether higher, but seemingly normal maternal glucose concentration predisposes to or is a marker for placental inflammation and infection.     

Evaluation of proliferation parameters in in vivo bromodeoxyuridine labelled lung cancers

In a series of 44 bronchial biopsies from patients suspected of having endobronchial lung carcinoma, the validity of proliferating cell nuclear antigen (PCNA) and Ki67 antigen as proliferative indicators was evaluated in ethanol fixed, paraffin embedded tissue. The percentages of cells positive for these markers were compared to the in vivo bromodeoxyuridine (BrdU) labelling index. A good correlation was found between PCNA immunoreactivity and BrdU labelling index, while Ki67-antigen expression showed a significant relation with BrdU labelling index and with PCNA expression. All three parameters showed a trend towards similar values for the individual cases. Based on the fact that Ki67 antigen is expressed in all cycling cells, whereas replicon-associated PCNA and BrdU only reflect the S-phase fraction, the differences between Ki67-antigen scores on the one hand and BrdU and PCNA scores on the other were smaller than expected. In order to determine the degree of concordance between immunohistochemically and flow cytometrically detected proliferation variables, BrdU incorporation was measured using both methods in duplicate bronchial specimens. Discrepancies in labelling indices were observed predominantly in DNA diploid samples, with consistently lower values in the flow cytometrically analysed specimens. In tumour specimens with an aneuploid DNA content, flow cytometric determination of proliferative activity yielded results similar to those obtained by tissue section examination. We conclude that the scores for PCNA and Ki67 antigen, immunohistochemically detected in ethanol fixed, paraffin embedded tissue reflect functional proliferative activity.     

Adenosine attenuates the vasoconstrictor response to the cold pressor test in humans.

The forearm vasoconstrictor response to a standardized cold pressor test (CPT) was studied twice in eight healthy subjects, once during local intraarterial infusion of adenosine and once during infusion of equipotent dosages of the control vasodilator sodium nitroprusside (SNP). During local SNP infusion, the forearm vascular resistance (FVR) decreased from 70 +/- 14 to 30 +/- 7 arbitrary units (AU). Adenosine induced a comparable vasodilator response, with a decrease in FVR from 56 +/- 14 to 28 +/- 6 AU. Subsequent cold exposure induced a mean percentage increase in FVR of 62 +/- 17% during SNP, whereas the increase was only 27 +/- 12% during adenosine infusion (p = 0.014). There were no differences in the calculated cold-induced changes in forearm production of norepinephrine (NE) between the SNP and the adenosine tests. We conclude that adenosine attenuates forearm vasoconstrictor response to the CPT, probably by a postjunctional mechanism of action.     

Intravenous instrumentation alters the autonomic state in humans

Intravascular instrumentation may induce syncope or presyncope. It is not known whether asymptomatic subjects also have autonomic reactions, albeit concealed. We addressed this issue by studying 44 healthy young male subjects of various levels of fitness, ranging from inactivity to athletic [mean maximal oxygen uptake was 49.1 (SD 10.7) ml·kg^–1·min^–1, range 28.7–71.9 ml·kg^–1·min^–1]. The autonomic response to venous cannulation was quantified by measuring heart rate before cannulation (HR1), after cannulation (HR₂), and after complete pharmacological autonomic blockade (HR₀ = the intrinsic heart rate). The sympathovagal balance before and after cannulation was computed as HR₁/HR₀ and HR₂/HR₀, respectively. The group means of heart rate and sympathovagal balance decreased significantly (paired Student's t-test P <0.01) from 62.5 to 59.9 beats·min^–, and from 0.71 to 0.68, respectively. The maximal decrease in heart rate was 8.8 beats·min^–1, and in the sympathovagal balance was 0.11. Our study demonstrated that the asymptomatic subjects responded to intravenous instrumentation with a concealed autonomic reaction. Thus, from our findings it would seem that intravenous instrumentation interferes with measurements relating to autonomic nervous system activity.     

Von Hippel-Lindau disease

Von Hippel-Lindau disease (VHL) is an autosomal dominant inherited cancer syndrome. The disease was diagnosed in three patients: a 22-year-old woman who presented with decreased vision due to retinal angiomatosis and in whom a renal carcinoma was diagnosed five years later at a routine VHL analysis, a man aged 44 who died with bilateral renal cysts and clear-cell carcinomas with metastases, who had a positive family history but in whom no regular control investigations had been performed, and a 31-year-old man who also had a positive family history, but who presented with epididymal cystadenoma and who in the subsequent decades developed cerebral and renal neoplasms that all were detected at routine examinations and subsequently removed. These case histories emphasize the importance of: (a) early recognition of patients presenting with a 'sporadic VHL-like' tumour, (b) frequent screening and early treatment of VHL patients and (c) nephron sparing surgery in VHL patients. The prognosis and quality of life of patients with VHL disease has significantly increased by early detection and treatment of asymptomatic tumours, in particular in the eye and kidney.     

Reduced risk of stroke recurrence due to hypotensive medication, irrespective of the initial blood pressure

The 'Perindopril protection against recurrent stroke study' (PROGRESS) demonstrated that for patients with a history of stroke or transient ischaemic attack during the previous 5 years, a blood-pressure-lowering regimen based on the combination of a diuretic and an angiotensin-converting enzyme (ACE) inhibitor, reduces the risk of stroke recurrence (fatal and non-fatal) by 28% (95%-CI: 17-38). This effect was irrespective of the initial neurological diagnosis (ischaemic or haemorrhagic stroke) and blood pressure level. Patients who were treated with just the ACE inhibitor did not exhibit these effects. This large-scale clinical trial demonstrates that hypotensive medication in the form of a diuretic combined with an ACE inhibitor is a beneficial strategy for the secondary prevention of stroke in normotensive and hypertensive patients.