Neoantigen prediction and computational perspectives towards clinical benefit: recommendations from the ESMO Precision Medicine Working Group.

BACKGROUND: The use of next-generation sequencing technologies has enabled the rapid identification of non-synonymous somatic mutations in cancer cells. Neoantigens are mutated peptides derived from somatic mutations not present in normal tissues that may result in the presentation of tumour-specific peptides capable of eliciting antitumour T-cell responses. Personalised neoantigen-based cancer vaccines and adoptive T-cell therapies have been shown to prime host immunity against tumour cells and are under clinical trial development. However, the optimisation and standardisation of neoantigen identification, as well as its delivery as immunotherapy are needed to increase tumour-specific T-cell responses and, thus, the clinical efficacy of current cancer immunotherapies. METHODS: In this recommendation article, launched by the European Society for Medical Oncology (ESMO), we outline and discuss the available framework for neoantigen prediction and present a systematic review of the current scientific evidence. RESULTS: A number of computational pipelines for neoantigen prediction are available. Most of them provide peptide major histocompatibility complex (MHC) binding affinity predictions, but more recent approaches incorporate additional features like variant allele fraction, gene expression, and clonality of mutations. Neoantigens can be predicted in all cancer types with high and low tumour mutation burden, in part by exploiting tumour-specific aberrations derived from mutational frameshifts, splice variants, gene fusions, endogenous retroelements and other tumour-specific processes that could yield more potently immunogenic tumour neoantigens. Ongoing clinical trials will highlight those cancer types and combinations of immune therapies that would derive the most benefit from neoantigen-based immunotherapies. CONCLUSIONS: Improved identification, selection and prioritisation of tumour-specific neoantigens are needed to increase the scope of benefit from cancer vaccines and adoptive T-cell therapies. Novel pipelines are being developed to resolve the challenges posed by high-throughput sequencing and to predict immunogenic neoantigens.

The influence of various reef sounds on coral-fish larvae behaviour.

The swimming behaviour of coral-reef fish larvae from 20 species of 10 different families was tested under natural and artificial sound conditions. Underwater sounds from reef habitats (barrier reef, fringing reef and mangrove) as well as a white noise were broadcasted in a choice chamber experiment. Sixteen of the 20 species tested significantly reacted to at least one of the habitat playback conditions, and a range of responses was observed: fishes were (1) attracted by a single sound but repelled by none (e.g. white-banded triggerfish Rhinecanthus aculeatus was attracted by the barrier-reef sound), (2) repelled by one or more sounds but attracted by none (e.g. bridled cardinalfish Pristiapogon fraenatus was repelled by the mangrove and the bay sounds), (3) attracted by all sounds (e.g. striated surgeonfish Ctenochaetus striatus), (4) attracted and repelled by several sounds (e.g. whitetail dascyllus Dascyllus aruanus was attracted by the barrier-reef sound and repelled by the mangrove sound) and (5) not influenced by any sound (e.g. convict surgeonfish Acanthurus triostegus). Overall, these results highlight two settlement strategies: a direct selection of habitats using sound (45% of the species), or a by-default selection by avoidance of certain sound habitats (35%). These results also clearly demonstrated the need to analyse the influence of sounds at the species-specific level since congeneric and confamilial species can express different behaviours when exposed to the same sounds.

Parenting Stress Undermines Mother-Child Brain-to-Brain Synchrony: A Hyperscanning Study.

Synchrony refers to the coordinated interplay of behavioural and physiological signals that reflect the bi-directional attunement of one partner to the other's psychophysiological, cognitive, emotional, and behavioral state. In mother-child relationships, a synchronous pattern of interaction indicates parental sensitivity. Parenting stress has been shown to undermine mother-child behavioural synchrony. However, it has yet to be discerned whether parenting stress affects brain-to-brain synchrony during everyday joint activities. Here, we show that greater parenting stress is associated with less brain-to-brain synchrony in the medial left cluster of the prefrontal cortex when mother and child engage in a typical dyadic task of watching animation videos together. This brain region overlaps with the inferior frontal gyrus, the frontal eye field, and the dorsolateral prefrontal cortex, which are implicated in inference of mental states and social cognition. Our result demonstrates the adverse effect of parenting stress on mother-child attunement that is evident at a brain-to-brain level. Mother-child brain-to-brain asynchrony may underlie the robust association between parenting stress and poor dyadic co-regulation. We anticipate our study to form the foundation for future investigations into mechanisms by which parenting stress impairs the mother-child relationship.

Identification of viable myocardium by echocardiography during dobutamine infusion in patients with myocardial infarction after thrombolytic therapy: comparison with positron emission tomography.

To assess the presence of viable myocardium salvaged by coronary artery reperfusion, 17 patients with acute anterior myocardial infarction were studied. Each received intravenous thrombolysis within the first 3 h of symptoms and underwent two-dimensional echocardiography before and during dobutamine infusion (10 micrograms/kg per min) 7 +/- 4 days after admission and positron emission tomography 9 +/- 5 days after admission. Echocardiography and positron emission tomography were again performed 9 +/- 7 months later. Six comparable segments specific for the territory of the left anterior descending artery were selected for comparison of the two techniques. Wall thickening was evaluated by using an echocardiographic score index. Segmental perfusion and glucose uptake were measured and normalized to the peak activity. A ratio of glucose uptake to perfusion was calculated for each segment. Concordant interpretation of the two techniques was found in 79% of affected segments for both acute and follow-up studies. Positron emission tomography revealed the presence of viable myocardium in 11 patients (group 1); perfusion was within normal limits in 5 of these (group 1A). Myocardial thickening improved with dobutamine infusion in these five patients, the echocardiographic score index decreasing from 12 +/- 2 at rest to 7.8 +/- 1.3 during dobutamine infusion (p = 0.003). Functional recovery was demonstrated in all five patients (follow-up score index 7.4 +/- 1.7). Six patients exhibited decreased perfusion but an abnormally high glucose to perfusion ratio (group 1B); their score index improved with dobutamine from 14.8 +/- 2.2 to 12 +/- 2.1 (p = 0.05), but late functional recovery was found in only one of the six patients (mean follow-up score index in group 1B 16 +/- 1.7). In the six remaining patients in whom no viable myocardium was detected with positron emission tomography (group 2), the echocardiographic score index did not change with dobutamine (15 +/- 0.9 to 14.7 +/- 0.8, p = NS) and there was no functional recovery (follow-up score index 15.5 +/- 1.0). Echocardiography during dobutamine infusion is a promising method to unmask viable myocardium in acute myocardial infarction. Early recovery of perfusion in the area at risk is associated with a good functional outcome, whereas a high glucose to perfusion ratio indicates jeopardized myocardium that frequently loses viability.

Measurement of left-to-right shunts by gated radionuclide angiography: concise communication.

Gated cardiac blood-pool scans allow comparison of left- and right-ventricular stroke volume. We have applied these measurements to the quantification of left-to-right shunts (QP/QS) in nine patients with atrial septal defects, one patients with partial anomalous pulmonary venous return, four patients with ventricular septal defects, and two patients with patent ductus arteriosus. None of these patients had combined lesions. QP/QS was measured as the right-ventricular (RV) stroke counts divided by the left-ventricular (LV) stroke counts and as the LV stroke counts divided by the RV stroke counts in patients with RV and LV diastolic volume overload respectively. All patients had also QP/QS measurements by oximetry and first-pass radionuclide angiography. The stroke-count measurements indicated the overloaded ventricle in all patients. QP/QS determined by equilibrium gated studies correlated well with those obtained by oximetry (r = 0.79). Reproducibility of the equilibrium measurements was good. We conclude that gated cardiac blood-pool scans can measure left-to-right shunts and can distinguish between shunts with RV and LV volume overload.

Evaluation of right-ventricular function by gated blood-pool scintigraphy.

The purpose of this paper is to review several modalities that can be helpful in evaluating right-ventricular (RV) function. We have investigated the role of functional imaging in analysis of regional RV function and in selection of RV region of interest (ROI). From this we have derived a method to determine the RV ejection fraction using a single RV ROI. The analysis is performed in a modified LAO projection; Fourier phase and amplitude functional images are used to help trace the ROI and study wall-motion abnormalities. This method is compared with the double-ROI technique of Maddahi. Values of RV ejection fraction obtained with one ROI correlate well with those obtained using two ROIs (r = 0.95). The regression equation is used to correct for the single-ROI underestimation. The inter- and intra-observer variability is better for the single- than for the double-ROI technique. RV function studies are performed in normal volunteers and in patients with a variety of cardiac disorders. Changes in RV ejection fraction caused either by direct alteration of RV function or by altered loading conditions are documented. Analysis of regional RV function demonstrates RV free wall as well as septal perturbations, further characterizing the extent of dysfunction and providing some etiologic information. We conclude that: 1. RV ejection fraction can be measured by the use of an adequate single diastolic ROI; and 2. A simple equilibrium gated technique can provide detailed information about global and regional RV function that should be systematically added to the analysis of the parameters for left-ventricular function.

Pre- and postoperative myocardial and blood pool scans in a case of left ventricular aneurysm: Case report.

Myocardial perfusion scans (using 131Cs) and blood pool scans (113mIn) were performed on a patient before and after resection of a left venticular aneurysm. Although the huge aneurysm was revealed by preoperative scans, preservation of a significant mass of myocardium was evident. Postoperative scans show the reconstructed heart and the amount of residual damage. The operative findings confirmed the reliability of the scan information.

Rapid method for the measurement of differential renal function: validation.

The precise measurement of glomerular filtration rate (GFR) and renal plasma flow (ERPF) usually requires continuous intravenous administration of adequate substances, with multiple blood and urine analysis, and does not allow measurement of separate renal function. Schlegel et al. and Gates described isotopic methods for the measurement of global and unilateral GFR and ERPF based on the determination by scintillation camera of the fraction of the injected dose ([99mTc]DTPA-[131I]hippuran) present in the kidneys 1-3 min after its administration. These methods require counting of the injected dose and correction for attenuation, but no blood or urine sampling. We have validated these techniques by simultaneous infusion of inulin and PAH in patients with various levels of global renal function (anuric to normal). To better define unilateral renal function we have also studied nine kidneys in patients either nephrectomized or with a nephrostomy enabling unilateral function measurement. A good correlation between inulin or PAH clearances and fractional uptake of [99mTc]DTPA or [131I]hippuran by the kidney was observed. Very good reproducibility of both isotopic techniques was shown. We conclude that determination of the fractional uptake of [99mTc]DTPA and [131I]hippuran between 1 and 3 min allows good and reproducible prediction of global and especially of unilateral kidney function with great rapidity and simplicity, rendering this technique suitable for clinical practice.

Technetium-99m-tetrofosmin myocardial imaging: a comparison with thallium-201 and angiography.

UNLABELLED: Images recorded after intravenous administration of 99mTc-tetrofosmin were compared to those obtained with 201Tl in a series of 40 patients with angiographically documented coronary artery disease. These patients were part of a Phase II tetrofosmin study and presented anamnestic or laboratory evidence suggestive of ischemic heart disease. METHODS: Thirty-seven patients had one or more coronary obstructions greater or equal to 70% of luminal diameter. Three patients studied after bypass surgery or angioplasty had patent grafts, absence of disease progression or no significant restenosis. Twenty-six patients had evidence of previous myocardial infarction. All images were processed into a common display format by a core laboratory. They were identified by code and read by concensus of four investigators. Each segment was classified as normal or abnormal and these readings were combined and categorized into normal, reversible, fixed or mixed regional defects. RESULTS: There was good segmental correspondence between thallium and tetrofosmin (kappa values ranged from 0.43 to 1.00). The ability of thallium and tetrofosmin to recognize and localize myocardial infarction was excellent, since corresponding abnormalities were present in respectively 24 and 25 of the 26 patients with previous myocardial infarction. Abnormalities in noninfarcted territories were recognized with both tracers in 16 of 28 patients presenting with coronary lesions involving vessels unrelated to the infarct. CONCLUSION: In comparison to rest tetrofosmin, thallium redistribution shows more reversibility in areas with myocardial infarction but less reversibility in areas of myocardial ischemia. Current Phase II results suggest that tetrofosmin is a sensitive and reliable tracer for detecting myocardial infarction and ischemia. Results should be confirmed in a larger group of patients.

Differential diagnosis of Alzheimer's disease with PET.

UNLABELLED: PET studies have demonstrated bilateral temporo-parietal hypoperfusion and hypometabolism in probable and definite Alzheimer's disease (AD), a pattern that may help differentiate AD from other dementias. METHODS: To evaluate the diagnostic power of cerebral metabolic distribution patterns for "cortical" degenerative dementias, PET scans obtained from 129 patients referred for differential diagnosis of dementia were analyzed visually. RESULTS: Sixty-five patients had a final clinical diagnosis of probable AD. Ninety-seven percent (97%) of those had abnormal metabolic scans and 94% showed a suggestive pattern of bilateral or unilateral temporo-parietal hypometabolism (with or without frontal involvement). Hypometabolism was unilateral in 23% of patients. Five subjects with a neuropathologically proven diagnosis of Alzheimer's disease had a suggestive metabolic pattern. One of those was an early case with frontal hypometabolism exceeding temporo-parietal involvement. Two patients with Alzheimer's-type dementia had isolated bilateral frontal hypometabolism. CONCLUSIONS: This alternative metabolic pattern may correspond to a non-Alzheimer pathology occurring in 10%-20% of patients suffering from clinically probable Alzheimer's disease. Most of the patients with possible but atypical Alzheimer's-type dementia showed isolated bilateral frontal involvement. This metabolic pattern probably corresponds to different diseases, such as Pick's disease, frontal lobe dementia or progressive subcortical gliosis.

Myocardial imaging with technetium-99m-tetrofosmin: comparison of one-day and two-day protocols.

UNLABELLED: There is no evidence of myocardial redistribution after tetrofosmin injection, therefore, two separate injections are needed to differentiate scar from ischemia with this tracer. The injections can be given on the same day (one-day protocol) or on separate days (two-day protocol). As part of a Phase II clinical study, a one-day protocol was compared with a two-day protocol. METHODS: Fifty-five patients with suspected coronary artery disease were studied according to the following protocol: on the first day at rest, anterior, left lateral, left anterior oblique 40 degrees and 70 degrees images were acquired 30 min after injection of 8 mCi of tetrofosmin for 5 min each. Two days later, exercise and rest images were acquired on the same day. At peak exercise, 8 mCi of tetrofosmin were injected and 30 min later the same four standard planar images were recorded as on Day one. Four hours after the exercise injection, 24 mCi of tetrofosmin were injected at rest and imaging was repeated 30 min later. Qualitative comparisons between the one- and two-day protocols were performed in 50 patients in whom all data were available following blinded evaluation of images by three readers. RESULTS: All three readers reported identical results for the 26 patients. A difference in extent or location between the observers was found in seven patients, differences between normal and abnormal in eight patients, while discrepancies between ischemia and necrosis were noted in four patients. In five patients, an ischemic area was found according to the one-day protocol, but according to the data of the two-day protocol, this area was judged to be necrotic. One observer reported the opposite in one patient. These discrepancies between the reversibility of defects were restricted to the inferior wall. Comparison with 201Tl data showed no systematic pattern of variation. CONCLUSION: Tetrofosmin can be used in a one-day protocol. However, in planar imaging, the inferior wall should be reported with caution.

Myocardial kinetics of potassium-38 in humans and comparison with copper-62-PTSM.

UNLABELLED: The aim of this study was to define the kinetics of 38K and its suitability to evaluate myocardial blood flow at rest and during pharmacological vasodilation in normal subjects. Potassium-38's kinetic characteristics were also compared to those of a 62Cu-pyruvaldehyde bis(n4-methyl-thio-semicarbazone) copper (II) (PTSM) flow tracer. METHODS: Potassium-38 and 62Cu-PTSM were injected at rest and after pharmacological vasodilation in six healthy volunteers. Dynamic PET acquisition was performed over 20 min and myocardial tracer retention calculated. Homogeneity of regional myocardial tracer distribution was also evaluated. RESULTS: High image quality of the heart was observed at rest and after dipyridamole with both tracers. Potassium-38 demonstrated prolonged myocardial retention with minimal lung and liver accumulation. In contrast to 38K, 62Cu-PTSM demonstrated high liver uptake which may hinder observation of the inferior wall of the myocardium. Copper-62-PTSM dipyridamole-to-rest retention ratio was 1.49. CONCLUSIONS: Potassium-38 and 62Cu-PTSM display suitable kinetics for the qualitative evaluation of blood flow and flow reserve in the human heart. Compared to 62Cu-PTSM, potassium-38, which does not show high liver uptake, may more accurately estimate blood flow in the inferior wall of the heart. However, accurate quantification of myocardial blood flow using 38K or 62Cu-PTSM retention appears to be limited to decreasing retention fraction at hyperhemic states.

Characterization of technetium-99m-L,L-ECD for brain perfusion imaging, Part 2: Biodistribution and brain imaging in humans.

The safety, biodistribution and kinetics of a new perfusion imaging agent [99mTc-L,L]-ethyl cysteinate dimer (ECD) was evaluated in normal volunteers. Technetium-99m-L,L-ECD is a neutral, lipophilic complex, which is radiochemically pure and stable. Twelve healthy adults were injected with 25-30 mCi of 99mTc-L,L-ECD and imaged periodically for up to 24 hr. Planar imaging showed rapid brain uptake with a peak concentration of 4.9% injected dose and very slow brain washout (approximately 6% per hour during the first 6 hr). Repeat or dynamic tomographic imaging of the brain using either a rotating gamma camera or a multidetector system was performed up to 6 hr postinjection. The distribution of 99mTc-L,L-ECD in the brain did not change and was similar to the pattern seen with other perfusion agents. Background facial areas and lungs cleared rapidly. Peak blood activity was below 10% injected dose at all times and 99mTc-L,L-ECD cleared rapidly through the kidneys. Vital signs, blood and urine chemistries were normal in all volunteers and no adverse reactions were noted. These results suggest that 99mTc-L,L-ECD should be useful for routine assessment of cerebral perfusion in humans.

Biodistribution, dosimetry, and clinical evaluation of technetium-99m ethyl cysteinate dimer in normal subjects and in patients with chronic cerebral infarction.

Technetium-99m ethyl cysteinate dimer (ECD) has high initial cerebral uptake with slow clearance in nonhuman primates suggesting ideal characteristics for single photon emission computer tomography (SPECT) imaging. We evaluated the biodistribution, dosimetry and scintigraphic pattern of [99mTc]ECD in normal subjects and the accuracy of SPECT imaging in patients with chronic cerebral infarction. Sixteen normal subjects were injected with approximately 10 mCi of [99mTc]ECD. Anterior and posterior single-pass whole-body images were obtained at multiple times after injection. Blood clearance of the radiotracer was rapid, falling to 10.0 +/- 6.6% and 4.9 +/- 1.1% of the injected dose at 2 and 60 min, respectively. Brain uptake was 6.4 +/- 2.1% of the injected dose 5 min after injection. The critical organ was the urinary bladder. Technetium-99m ECD SPECT was performed with a rotating gamma camera in ten of the 16 normal subjects and 34 patients with clinical and CT evidence of chronic stroke. Thirty-three of the thirty-four patients had focal [99mTc]ECD abnormalities on SPECT (97.1%) based on visual inspection of the SPECT images. In summary, we obtained high quality SPECT images as a result of the optimal physical and biologic characteristics of the tracer. Technetium-99m ECD SPECT shows promise for the evaluation of patients with stroke.

Comparison of myocardial perfusion imaging with technetium-99m tetrofosmin versus thallium-201 in coronary artery disease.

Technetium-99m (Tc-99m) tetrofosmin, a new myocardial perfusion imaging agent, was evaluated at exercise and rest in 50 patients with documented coronary artery disease to determine myocardial kinetics, redistribution and ideal imaging time. Planar imaging was performed at 5, 30, 60, 90, 120 and 240 minutes after an injection of Tc-99m tetrofosmin (8 to 10 mCi) at peak graded ergometric exercise. Reinjection (24 to 30 mCi) was performed at rest, 4 hours after the stress injection and also on a separate day, and imaging was repeated. All patients underwent thallium-201 (Tl-201) exercise and redistribution (4-hour) imaging. Perfusion defect to normal, and heart to lung ratios were calculated for exercise Tc-99m tetrofosmin images at each time point. The mean +/- SD defect to normal ratios were 0.75 +/- 0.10, 0.75 +/- 0.10, 0.74 +/- 0.09, 0.73 +/- 0.10, 0.73 +/- 0.10 and 0.72 +/- 0.10 at 5, 30, 60, 90, 120 and 240 minutes, respectively (p = NS), suggesting absence of redistribution. There was a significant increase in lung uptake of Tl-201 during exercise (p < 0.05), but not with Tc-99m tetrofosmin (p = NS). Washout of Tc-99m tetrofosmin was calculated in a subset of patients (n = 23). Rapid background clearance enabled postexercise diagnostic imaging as early as 5 minutes after injection. Myocardial retention curves after rest injection suggested that the optimal time for imaging was approximately 30 minutes later. Slow myocardial washout (4%/hour after exercise and 0.6%/hour after rest injection) enabled diagnostic images to be obtained up to 4 hours after each study.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of thromboendarterectomy in association with coronary artery bypass grafting.

Thromboendarterectomy is sometimes performed in association with coronary artery bypass graft surgery (CABG). Right coronary arteries and severely narrowed coronary arteries mainly undergo thromboendarterectomy, but perioperative acute myocardial infarctions (AMI) are possible complications. One hundred seventy-six consecutive patients with rest and stress thallium-201 scintigraphy and angiography were studied before and after surgery. To compare patients with and without thromboendarterectomy, 48 patients who had undergone thromboendarterectomy and whose characteristics matched closely those of patients who had not were selected. Twenty patients had previous AMI before CABG in each group. Analysis accounted for the severity of vessel lesion (complete or incomplete) and for the patency of the graft and of the native coronary artery. In these 96 patients, graft patency was lower than in the overall group and similar among patients with and without thromboendarterectomy among the 56 patients without previous AMI. In patients with previous AMI and thromboendarterectomy, however, reperfusion was achieved more often through the native vessel than through the graft. New AMI or residual ischemia occurred in 32% of the areas undergoing thromboendarterectomy and in only 5% of the standard grafts (p less than 0.001). Best results were obtained in patients with incomplete occlusion after AMI. Patients without previous AMI had worse results. Thus, thromboendarterectomy can yield 64 to 75% good results in selected subgroups when CABG is otherwise impossible, but should be avoided in mildly or moderately stenotic arteries perfusing noninfarcted myocardium.

Stress thallium-201 myocardial scintigraphy for the detection of individual coronary arterial lesions in patients with and without previous myocardial infarction.

The value of stress thallium-201 scintigraphy for detecting individual coronary arterial stenoses was analyzed in 141 patients with angiographically proved coronary artery disease, 101 with and 40 without a previous myocardial infarction. In patients without infarction, the sensitivity for detecting greater than 50 percent narrowing in the left anterior descending, the right and the left circumflex coronary artery was 66, 53 and 24 percent, respectively. In those with a previous infarction, the sensitivity for demonstrating disease in the artery corresponding to the site of infarction was 100 percent for the left anterior descending, 79 percent for the right and 63 percent for the left circumflex coronary artery. In patients with a prior anterior infarction, concomitant right or left circumflex coronary arterial lesions were detected in only 1 of 12 cases, whereas in those with previous inferior or inferolateral infarction, the sensitivity for left anterior descending coronary artery disease was 69 percent. Because of the reasonably high sensitivity for detecting left anterior descending arterial disease, irrespective of the presence and location of previous infarction, myocardial scintigraphy was useful in identifying multivessel disease in patients with a previous inferior infarction. However, because of its relative insensitivity for right or left circumflex coronary artery disease, scintigraphy proved to be a poor predictor of multivessel disease in patients with a prior anterior infarction and in patients without previous myocardial infarction.

Use of technetium-99m sestamibi to determine the size of the myocardial area perfused by a coronary artery.

The value of the new radionuclide tracer, technetium-99m (Tc-99m) sestamibi, to demonstrate myocardial perfusion in areas supplied by specific coronary arteries was evaluated in patients injected with the agent during cardiac catheterization. Tc-99m sestamibi differs from thallium-201 in its physical characteristics (photon energy 140 keV), half-life (6 hours) and lack of significant redistribution, allowing its administration during an episode of chest pain or ischemia occurring outside the nuclear medicine laboratory with later imaging to visualize the distribution. In 13 patients Tc-99m sestamibi was administered intravenously during balloon-occlusion angioplasty. In 11 of 13 patients, defects of the single photon emission computed tomography images corresponded to the area made ischemic during angioplasty. In the remaining 2 patients, abundant collateral flow was present and no defects were seen. In a second study, 15 patients had Tc-99m sestamibi selectively injected into a coronary artery during angiography. Later imaging identified the area supplied by the artery injected. Tc-99m sestamibi imaging can detect perfusion defects associated with short episodes of ischemia, and the area supplied by the different coronary arteries.

Effect of spinal cord stimulation on regional myocardial perfusion assessed by positron emission tomography.

Spinal cord stimulation (SCS) can relieve symptoms in patients with severe angina pectoris refractory to conventional medical or surgical therapy. This symptomatic improvement may result from decreased myocardial ischemia. To test this hypothesis, positron emission tomography (PET) and potassium-38 as a flow tracer were used in 8 patients for the quantitative evaluation of regional myocardial perfusion at rest and after exercise, before and during SCS. Potassium uptake was evaluated as myocardial clearance (flow times net extraction) in ml/min/100 g. Tomographic segments were categorized as nonaffected and affected on the basis of the absence or presence of arterial stenosis on coronary angiography and on the basis of thallium scintigraphic data. In nonaffected segments, before SCS, regional myocardial clearance significantly increased from rest (28 +/- 4) to exercise (47 +/- 13 clearance units; p less than 0.004). A similar increase occurred after SCS. In affected segments, before SCS, regional myocardial clearance barely increased (p = 0.065) from rest (26 +/- 6) to exercise (33 less than or equal to 12). In comparison, after SCS, the resting regional myocardial clearance was slightly elevated (29 +/- 8) reflecting an increased double product, but did not increase (p = 0.192) with exercise (34 +/- 12). However, the magnitude and duration of ST-segment depression decreased during treatment with SCS. Anginal pain occurred in all patients during control exercise, but was attenuated in all but one with SCS. These results indicate that SCS improves exercise-induced angina and electrocardiographic signs of ischemia but this influence does not appear to be mediated by changes in regional myocardial perfusion.

Monitoring ventricular function at rest and during exercise with a nonimaging nuclear detector.

A portable nonimaging device, the nuclear stethoscope, for measuring beat to beat ventricular time-activity curves in normal people and patients with heart disease, both at rest and during exercise, is being developed and evaluated. The latest device has several operating modes that facilitate left ventricular and background localization, measurement of transit times and automatic calculation and display of left ventricular ejection fraction. The correlation coefficient of left ventricular ejection fraction obtained with the device and with a camera-computer system was 0.92 in 35 subjects. During bicycle exercise the ejection fraction in 15 normal persons increased from 44 to 64 percent (P less than 0.001), whereas among 12 patients with heart disease it was unchanged in 5 and decreased in 7.