Victor Kalff

F-18 fluorodeoxyglucose positron emission tomography staging in radical radiotherapy candidates with nonsmall cell lung carcinoma

Successful treatment of nonsmall cell lung carcinoma (NSCLC) with radical radiotherapy (RT) requires accurate delineation of tumor extent. Conventional computed tomography–based noninvasive staging often estimates intrathoracic thoracic tumor extent incorrectly and fails to detect distant metastasis. High sensitivity and specificity are reported for F‐18 fluorodeoxyglucose (FDG) positron emission tomography (PET) staging in potentially resectable NSCLC. The authors investigated FDG‐PET staging in radical RT candidates with unresectable NSCLC.

Clinical Impact of 18F Fluorodeoxyglucose Positron Emission Tomography in Patients With Non–Small-Cell Lung Cancer: A Prospective Study

PURPOSE To prospectively study the impact of (18)F fluorodeoxyglucose (FDG) positron emission tomography (PET) on clinical management of patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS One hundred five consecutive patients with NSCLC undergoing (18)F FDG PET were analyzed. Before PET, referring physicians recorded scan indication, conventional clinical stage, and proposed treatment plan. PET scan results were reported in conjunction with available clinical and imaging data, including results of computed tomography (CT). Subsequent management and appropriateness of PET-induced changes were assessed by follow-up for at least 6 months or until the patients death. RESULTS Indications for PET were primary staging (n = 59), restaging (n = 34), and suspected malignancy subsequently proven to be NSCLC (n = 12). In 27 (26%) of 105 of cases, PET results led to a change from curative to palliative therapy by upstaging disease extent. Validity of the PET result was established in all but one case. PET appropriately downstaged 10 of 16 patients initially planned for palliative therapy, allowing either potentially curative treatment (four patients) or no treatment (six patients). PET influenced the radiation delivery in 22 (65%) of 34 patients who subsequently received radical radiotherapy. Twelve patients considered probably inoperable on conventional imaging studies were downstaged by PET and underwent potentially curative surgery. PET missed only one primary tumor (5-mm scar carcinoma). CT and PET understaged three of 20 surgical patients (two with N1 lesions < 5 mm and one with unrecognized atrial involvement), and PET missed one small intrapulmonary metastasis apparent on CT. No pathological N2 disease was missed on PET. CONCLUSION FDG PET scanning changed or influenced management decisions in 70 patients (67%) with NSCLC. Patients were frequently spared unnecessary treatment, and management was more appropriately targeted.

Evidence for increased noradrenaline release from subcortical brain regions in essential hypertension

Objective: To test whether the activation of the sympathetic nervous system that is common in essential hypertension derives from subcortical noradrenergic neuronal excitation. Design and methods: We performed a radionuclide cerebral venous sinus scan, using technetium-99m, to establish which internal jugular vein predominantly drained the cortical (the major jugular vein) and which the subcortical (minor jugular vein) brain regions. Blood samples were then collected simultaneously from catheters placed percutaneously in the brachial artery or radial artery and high in the internal jugular vein in 11 untreated hypertensive patients and 18 normotensive subjects, for determination of the plasma concentrations of noradrenaline, its precursor dihydroxyphenylalanine (DOPA) and its metabolite dihydroxyphenylglycol (DHPG) to calculate their rates of overflow into the cerebrovascular circulation. Results: In normotensive subjects blood flow determined by thermodilution was significantly higher in the major than in the minor jugular vein. The noradrenaline spillovers into the major and minor jugular veins calculated during infusions of L-[3H]-7-noradrenaline were similar in healthy subjects. The noradrenaline spillover from subcortical regions into the minor jugular vein was significantly higher in the hypertensives than in the normal subjects, as was the overflow of DHPG. In contrast, cortical noradrenaline and DHPG overflows into the major jugular vein were similar in hypertensive and normotensive subjects. Overflow of DOPA into the minor jugular vein, which derives largely from precursor turnover in dopaminergic neurons, was similar in hypertensive and normotensive subjects. Subcortical noradrenaline spillover correlated with neurochemical indices of sympathetic nervous system activity, with total body noradrenaline spillover (r=0.56, P<0.05) in normal and hypertensive subjects combined, and with renal noradrenaline spillover in the six hypertensive patients tested (r=0.91, P<0.05). Conclusion: These results suggest that increased subcortical noradrenaline release is a possible cause of peripheral sympathetic activation in essential hypertension.

Does positron emission tomography change management in primary rectal cancer? A prospective assessment

Purpose: The influence of positron emission tomography in the management of recurrent rectal cancer is well established but its role in primary rectal cancer remains uncertain. This study therefore prospectively assesses the impact of position emission tomography scanning on the management of primary rectal cancer. Methods: Forty-six patients with advanced primary rectal cancer referred for consideration of adjuvant preoperative therapy underwent position emission tomography scanning. The referring physicians prospectively recorded each patient’s stage following conventional imaging and the proposed treatment plan prior to position emission tomography scanning. This was then compared with subsequent stage and actual management implemented, and the appropriateness of position emission tomography-induced changes was noted by subsequent clinical follow-up. Results: The surgical management of 36 of 46 patients (78 percent) was unchanged as a result of position emission tomography, even though position emission tomography upstaged disease in 3 of 36 cases (8 percent) and downstaged disease in 5 of 36 cases (14 percent). In 8 of 46 cases (17 percent), management was altered because of the position emission tomography scan findings, including 6 cases (13 percent) in which surgery was cancelled and 2 other cases (4 percent) in which the radiotherapy field was changed. Where available, follow-up confirmed the appropriateness of position emission tomography-induced management change in each case. Two patients had a change in therapy independent of the position emission tomography scan due to clinical circumstances. Overall tumor stage was changed following position emission tomography in 18 of 46 patients (39 percent). Conclusion: Position emission tomography scanning appears to accurately change the stage or appropriately alter the therapy of almost a third of patients with advanced primary rectal cancer. In view of this, we suggest that position emission tomography scanning be considered part of standard workup for such patients, particularly if neoadjuvant chemoradiation is being considered as part of primary management.

Direct determination of homovanillic acid release from the human brain, and indicator of central dopaminergic activity

The plasma concentration of the dopamine (DA) metabolite, homovanillic acid (HVA), is used as an indicator of central nervous system dopaminergic activity. Using percutaneously inserted catheters we were able to obtain blood samples simultaneously from the right and left internal jugular veins. Veno-arterial HVA plasma concentration differences combined with adjusted organ plasma flows were used, according to the Fick Principle, to determine the HVA overflow from the brain. The HVA overflow from the liver was also measured. HVA overflow from the brain represented 12% of the total body HVA production. A similar amount was released from the liver, illustrating the limited validity of peripheral plasma HVA measurements as an indicator of central dopaminergic activity. HVA release from the human brain displayed a degree of asymmetry, the overflow into the left internal jugular vein being 36% greater than that into the right. Cerebral venous blood flow scans indicated that cortical cerebral regions drained preferentially into the right internal jugular; by inference the higher HVA overflow on the left originated from dopamine-rich subcortical brain areas. Since HVA in plasma may arise from the metabolism of DA existing either as a neurotransmitter or a norepinephrine (NE) precursor we measured the internal jugular vein plasma concentrations of NE, and its metabolite dihydroxyphenylglycol (DHPG), to determine whether they displayed a similar pattern of release to HVA. The overflow of both NE and DHPG into the right internal jugular vein was approximately double that on the left. Since the overflow of HVA did not parallel that of NE and DHPG it may be inferred that the origin of much of the subcortically produced HVA is from dopaminergic neurons and not from the metabolism of precursor DA in noradrenergic neurones or cerebrovascular sympathetic nerves.

Quantitative evaluation of regional substrate metabolism in the human heart by positron emission tomography

Meaning interpretation of metabolic images obtained by positron emission tomography for evaluation of cardiac disease requires a knowledge of the normal variation in regional myocardial substrate metabolism. Recent studies with fluorine-18 (F-18) fluorodeoxyglucose suggest inhomogeneity of myocardial glucose metabolism in the normal human heart, which may relate to substrate availability. Therefore, quantitative evaluation of myocardial oxidative metabolism and glucose metabolism, as derived by dynamic positron emission tomography with carbon-11 (C-11) acetate and F-18 fluorodeoxyglucose, was performed in nine healthy male volunteers. All were studied under tightly controlled metabolic conditions of hyperinsulinemic-euglycemic clamping with and without a concurrent lipid emulsion infusion. Significant inhomogeneity of regional glucose metabolism was noted although it was less than that described under fasting conditions. Glucose utilization was 13% lower in the septum compared with the lateral wall both without and with lipid infusion (0.34 vs. 0.39 mumol/g per min, respectively, p less than 0.05; and 0.33 vs. 0.38 mumol/g per min, respectively, (p less than 0.05). Relatively decreased septal glucose utilization could not be explained by decreased metabolic demand because C-11 clearance constants were marginally higher in the septum than in the lateral wall in both studies (0.055 vs. 0.054 per min, respectively, p = NS; and 0.061 vs. 0.056 per min, respectively, p less than 0.05). Relatively decreased septal glucose utilization could reflect regional variation in substrate use and possible preferential free fatty acid utilization by the septum. These data provide a useful framework for assessing altered cardiac metabolism in disease and support standardization of metabolic conditions during metabolic imaging with positron emission tomography.

Longitudinal study of ventricular function after the Mustard operation for transposition of the great arteries: a long term follow up.

An earlier study of 25 patients who were investigated by radionuclide angiography after a Mustard procedure showed that they had had evidence of right and left ventricular dysfunction at rest and with exercise. Twenty one (mean age 17.0 years (range 13.7-20.6) 11 female patients) of the original 25 patients were followed up a mean of 4.3 years later (mean 14.6 years (range 12.5-16.0) after the procedure). The group means for resting right and left ventricular ejection fraction and exercise response were not significantly different from those reported five years before. Individual changes in values were within the normal variation seen in serial studies. This long term longitudinal follow up of patients after the Mustard operation showed that although some patients still had right and left ventricular dysfunction, resting ventricular function and exercise response remained stable over a five year period. This preservation of cardiac function may contribute to the long term survival of patients after the Mustard procedure.

CENTRAL NERVOUS SYSTEM NORADRENERGIC CONTROL OF SYMPATHETIC OUTFLOW IN NORMOTENSIVE AND HYPERTENSIVE HUMANS

We applied transmitter washout methodology, sampling internal jugular venous plasma via a percutaneously placed catheter, to study CNS norepinephrine release in humans and its relation to peripheral sympathetic activity. Norepinephrine overflows into the venous drainage of the brain, as do its precursor, DOPA, and metabolites DHPG and MHPG, indicating that the blood-brain barrier provides an incomplete impediment to their outward flux from the brain. Pharmacological testing with two drugs which altered CNS norepinephrine turnover, the tricyclic antidepressant desipramine and the ganglionic blocker, trimethaphan, demonstrated a direct relation existed between CNS norepinephrine release and sympathetic nerve firing rates. In essential hypertension, the sympathetic activation commonly present was associated with, and possibly caused by increased CNS release of norepinephrine, manifested in elevated overflow of norepinephrine, MHPG and DHPG from the brain. Bilateral jugular sampling, coupled with a cerebral venous sinus scan to delineate the drainage pattern, demonstrated that this increased norepinephrine release was confined to subcortical forebrain regions.

Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack : reduction by a selective serotonin reuptake inhibitor

Since the brain neurotransmitter changes characterising panic disorder remain uncertain, we quantified brain noradrenaline and serotonin turnover in patients with panic disorder, in the absence of a panic attack. Thirty-four untreated patients with panic disorder and 24 matched healthy volunteers were studied. A novel method utilising internal jugular venous sampling, with thermodilution measurement of jugular blood flow, was used to directly quantify brain monoamine turnover, by measuring the overflow of noradrenaline and serotonin metabolites from the brain. Radiographic depiction of brain venous sinuses allowed differential venous sampling from cortical and subcortical regions. The relation of brain serotonin turnover to serotonin transporter genotype and panic disorder severity were evaluated, and the influence of an SSRI drug, citalopram, on serotonin turnover investigated. Brain noradrenaline turnover in panic disorder patients was similar to that in healthy subjects. In contrast, brain serotonin turnover, estimated from jugular venous overflow of the metabolite, 5-hydroxyindole acetic acid, was increased approximately 4-fold in subcortical brain regions and in the cerebral cortex (P < 0.01). Serotonin turnover was highest in patients with the most severe disease, was unrelated to serotonin transporter genotype, and was reduced by citalopram (P < 0.01). Normal brain noradrenaline turnover in panic disorder patients argues against primary importance of the locus coeruleus in this condition. The marked increase in serotonin turnover, in the absence of a panic attack, possibly represents an important underlying neurotransmitter substrate for the disorder, although this point remains uncertain. Support for this interpretation comes from the direct relationship which existed between serotonin turnover and illness severity, and the finding that SSRI administration reduced serotonin turnover. Serotonin transporter genotyping suggested that increased whole brain serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.

Monoaminergic Neuronal Activity in Subcortical Brain Regions in Essential Hypertension

In this study we aimed to elucidate the role of central noradrenergic, dopaminergic, adrenergic and serotonergic neuronal systems in the development of essential hypertension. Fifteen untreated essential hypertensive subjects (aged 44 +/- 3 years) and 32 healthy volunteers (aged 38 +/- 3 years) participated in this study. By combining direct blood sampling techniques with cerebral blood flow scans we were able to differentiate between cortical and subcortical venous drainage of the brain. Veno-arterial MHPG, HVA and 5-HIAA plasma concentration gradients combined with internal jugular vein plasma flows were used, according to the Fick Principle, to derive metabolite spillovers which in turn were used as indicators of central noradrenergic, dopaminergic and serotonergic neuronal activity, respectively. These amine systems, in both the brainstem and forebrain, have been implicated in the regulation of sympathetic outflow and blood pressure. Total body noradrenaline spillover to plasma was concurrently measured to assess the relationship between central monoamine turnover and sympathetic activity. Compared to their healthy counterparts the hypertensive subjects had an elevated release of MHPG from subcortical brain regions (1.4 +/- 0.3 v 0.5 +/- 0.2 nmol/min, p < 0.05). An inverse relationship between blood pressure and subcortical HVA overflow existed, with the HVA overflow being significantly lower in the hypertensives (0.5 +/- 0.2 v 2.1 +/- 0.5 nmol/min, p < 0.05). Subcortical 5-HUAA overflow did not differ between the two groups, and adrenaline spillover from the brain was not detected in either group. Subcortical MHPG overflow was significantly correlated with total body NA spillover to plasma (p < 0.05). These results indicate that reciprocal aberrations in subcortical noradrenaline and dopamine turnover exist in essential hypertension. Although the physiological significance of this remains to be unequivocally elucidated we postulate that elevated subcortical noradrenergic activity, presumably in the forebrain where noradrenergic neurons are pressor, may cause sympathoexcitation and play a role in the development of essential hypertension.