A kinetics-based approach to amyloid PET semi-quantification.

PURPOSE: To develop and validate a semi-quantification method (time-delayed ratio, TDr) applied to amyloid PET scans, based on tracer kinetics information. METHODS: The TDr method requires two static scans per subject: one early (~ 0-10 min after the injection) and one late (typically 50-70 min or 90-100 min after the injection, depending on the tracer). High perfusion regions are delineated on the early scan and applied onto the late scan. A SUVr-like ratio is calculated between the average intensities in the high perfusion regions and the late scan hotspot. TDr was applied to a naturalistic multicenter dataset of 143 subjects acquired with [18F]florbetapir. TDr values are compared to visual evaluation, cortical-cerebellar SUVr, and to the geometrical semi-quantification method ELBA. All three methods are gauged versus the heterogeneity of the dataset. RESULTS: TDr shows excellent agreement with respect to the binary visual assessment (AUC = 0.99) and significantly correlates with both validated semi-quantification methods, reaching a Pearson correlation coefficient of 0.86 with respect to ELBA. CONCLUSIONS: TDr is an alternative approach to previously validated ones (SUVr and ELBA). It requires minimal image processing; it is independent on predefined regions of interest and does not require MR registration. Besides, it takes advantage on the availability of early scans which are becoming common practice while imposing a negligible added patient discomfort.

Prognostic Value of 18F-Fluorocholine PET Parameters in Metastatic Castrate-Resistant Prostate Cancer Patients Treated with Docetaxel.

Background and Aim: The availability of new treatments for metastatic castrate-resistant prostate cancer (mCRPC) patients increases the need for reliable biomarkers to help clinicians to choose the better sequence strategy. The aim of the present retrospective and observational work is to investigate the prognostic value of 18F-fluorocholine (18F-FCH) positron emission tomography (PET) parameters in mCRPC. Materials and Methods: Between March 2013 and August 2016, 29 patients with mCRPC were included. They all received three-weekly docetaxel after androgen deprivation therapy, and they underwent 18F-FCH PET/computed tomography (CT) before and after the therapy. Semi-quantitative indices such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) with partial volume effect (PVC-SUV) correction, metabolically active tumour volume (MATV), and total lesion activity (TLA) with partial volume effect (PVC-TLA) correction were measured both in pre-treatment and post-treatment 18F-FCH PET/CT scans for each lesion. Whole-body indices were calculated as sum of values measured for each lesion (SSUVmax, SPVC-SUV, SMATV, and STLA). Progression-free survival (PFS) and overall survival (OS) were considered as clinical endpoints. Univariate and multivariate hazard ratios for whole-body 18F-FCH PET indices were performed, and p < 0.05 was considered as significant. Results: Cox regression analysis showed a statistically significant correlation between PFS, SMATV, and STLA. No correlations between OS and 18F-FCH PET parameters were defined probably due to the small sample size. Conclusions: Semi-quantitative indices such as SMATV and STLA at baseline have a prognostic role in patients treated with docetaxel for mCRPC, suggesting a potential role of 18F-FCH PET/CT imaging in clinical decision-making.

Iodine-131 metaiodobenzylguanidine (I-131 MIBG) diagnosis and therapy of pheochromocytoma and paraganglioma: current problems, critical issues and presentation of a sample case.

Iodine-131 metaiodobenzylguanidine (I-131 MIBG) has been used for the diagnosis and treatment of malignant pheochromocytomas (PHEO) and paragangliomas (PGL) since 1980's. Despite increasing amount of experience with iodine-131 (I-131) MIBG therapy, many important questions still exist. In this article, we will discuss the current problems learned from clinical experience in diagnosis and therapy of PHEO/PGL with I-131 MIBG, and present a sample case to emphasize the critical aspects for an optimal treatment strategy.

Treatment with tandem [(90)Y]DOTA-TATE and [(177)Lu] DOTA-TATE of neuroendocrine tumors refractory to conventional therapy: preliminary results.

AIM: Neuroendocrine tumors over-express somatostatin receptors and literature data have demonstrated the efficacy of the peptide receptor radionuclide therapy with somatostatin analogues labelled with high activities of b-emitting radioisotopes, such as (90)Y and (177)Lu. Yttrium-90 is a pure high energy b-emitter while (177)Lu is a b/g emitter of medium energy. We decided to evaluate an original tandem treatment based on administration of radiolabeled [DOTA(0),Tyr(3)]octreotate (DOTA-TATE) alternating (177)Lu and 90Y. Aim of this study was to evaluate the feasibility, the efficacy and the toxicity of this treatment in neuroendocrine tumors expressing somatostatin receptors relapsed or refractory to conventional therapies. METHODS: Patients were treated with four therapeutic cycles alternating [(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). Dosimetric evaluation after administration of [(177)Lu]DOTA-TATE allows to calculate the absorbed doses in healthy organs. Blood samples were collected at 5 min, 1, 6, 24, 48, 72, 96 h and scintigraphy was performed once a day for four days after administration. Toxicity was evaluated considering hematological parameters and renal toxicity was evaluated also by the glomerular filtration rate (GFR). Efficacy related with RECIST criteria. RESULTS: Up to now 26 patients entered the study and 16 patients completed all cycles. Treatment was well tolerated with no adverse event registered. No damage to healthy organs was revealed in accordance with the calculated absorbed doses. We had a partial response in 10/15 patients evaluated three months after the fourth treatment. CONCLUSIONS: Up to now only a few patients participated in and concluded this study; preliminary results are encouraging and indicate the feasibility of the study.

Redifferentiating agents in non-radioiodine avid cancer.

Thyroid cancer is the most common malignant cancer of the endocrine system. Treatment for well differentiated forms include surgery and radioactive iodine ablation. When cancer cells exhibit a less differentiated phenotype they may no longer be able to accumulate iodine, making 131-I administration ineffective. Recent studies have demonstrated the important role of therapeutic agents that have redifferentiating potential, leading to reactivation and expression of thyrocyte-specific genes, including those responsible for iodine uptake. This review will discuss the results of the most recent studies on drugs with redifferentiating properties and their application in patients with radioiodine refractory thyroid cancer.

Individualized dosimetry in the management of metastatic differentiated thyroid cancer.

AIM: This paper analyzes the available data on the dosimetric approach and describes the use of dosimetry in the Division of Nuclear Medicine of the National Cancer Institute in Milan. Dosimetry is rarely performed when planning radio-iodine activity, although most of the available guidelines do mention this possibility, without giving any well defined indication. Aim of the present research was to validate the usefulness of dosimetry in the management of metastatic thyroid cancer. Benua (1962) set the limit of blood absorbed dose at 2 Gy to avoid hematological toxicity. Maxon (1983) determined at 80 Gy the dose to achieve complete destruction of a metastatic lesion. Dorn (2003) combined red marrow and lesion dosimetry showing that high activity administrations with less that 3 Gy to the red marrow are a safe and more effective with respect to fixed activities administrations. Lee (2008) reported 50% responses with high activity administrations based on blood dosimetry, in 47 patients which were unsuccessfully previously treated with fixed activities. Sgouros (2005) and Song (2006) introduced key parameters as Biological Effective Dose and Uniform Equivalent Dose in order to describe the effects of continuous low dose rate irradiation and non uniform activity uptake, typical of nuclear medicine treatments. METHODS: Red marrow and lesion dosimetry (planar view) were performed during the treatment, without changing the fixed activity schema. RESULTS: This experience demonstrate first of all, that dosimetry is feasible in the clinical routine, and that it can provide the clinician with important information, no matter its often quoted limited numerical accuracy. A total of 17/20 lesion doses below 80 Gy have been detected. Three/17 (doses between 40 and 80 Gy) disappeared in the follow-up scintigram. Two/17 were undetectable at computed tomography or nuclear magnetic resonance. These data suggest that repetition of treatment on a lesion drastically reduces its uptake, with a loss of therapeutic efficacy along the sequence of fixed activity administrations. CONCLUSIONS: The usefulness of dosimetry should not be assessed only on the basis of patient survival or therapeutic efficacy; the possibility to avoid useless treatments should also be considered. According to the authors, individualized dosimetry could improve the management of metastatic differentiated thyroid cancer. Even post-therapeutic dosimetry, as performed at this institution, has a significant impact on clinical decision-making. The question for the future is how to include dosimetry into the patient management framework.

Predictability of medical students' performance at the Aga Khan University from admission test scores, interview ratings and systems of education.

INTRODUCTION: Performance in an admission test and carefully conducted, structured interview provides a uniform basis for the assessment of applicants prepared in different systems of education for admission to an institute of higher professional learning. We studied the predictability of the system of education followed by the students prior to entrance into the Medical College, the admission test scores, and interview ratings on performance after five trimesters at the Aga Khan University Medical College. METHOD: A cohort of 374 medical students who were admitted during 1989--1994, were considered. The associations between the admission test score, interview ratings, system of education, and the scores obtained for anatomy, physiology, biochemistry and community health sciences examinations held after five trimesters were analysed using appropriate statistical procedures. RESULTS: Interview ratings were associated with the scores in Physiology but not other subjects. The chief finding of this study was the association between the system of education and performance in both the admission test and the examination after five trimesters. Students who followed the British school curricula for 13 years scored significantly higher than those who followed the 12 years of the Pakistani system. When controlled for the admission test score, the difference in mean scores of the two groups was still evident for two subjects; community health sciences and physiology. CONCLUSION: We believe that the evidence indicates differences in learning methods inculcated by the system of education prior to entry into the Medical College, notwithstanding the 1-year difference in duration of education.

Bronchodilator response in pulmonary disease at two different states of respiratory mechanics.

It would be convenient to be able to measure airway responsiveness to bronchodilator drugs with a sequential use of oscilloresistometry and spirometry, which may allow the comparison of the response to bronchodilator at two different states of respiratory mechanics i.e., resting tidal breathing at functional residual capacity (FRC) versus forced expiratory manoeuvre from total lung capacity to residual volume. The evaluation of airway resistance and forced expiratory volume at 1 s (FEV1) may thus assist in the interpretation of bronchial responsiveness tests (BRT) to pick up responders among non-responders to administered bronchodilator. Such a concept was verified in 54 patients with respiratory disease before and 10 min after inhalation of 200 micrograms of salbutamol. Within 10 min following salbutamol challenge the increase for forced vital capacity (FVC), FEV1 and peak expiratory flow rate (PEFR) was 23, 27 and 39% in 27 asthmatic patients of group A (p < 0.005). On the other hand, 27 patients with chronic obstructive pulmonary disease in group B did not show any significant change in FEV1 and PEFR (p > 0.05). However, they showed a decrease in airway resistance of 30% (p < 0.005) during normal tidal breathing at FRC. Twenty-two normal controls in group C showed values of airway resistance and expiratory flow rates to be within the normal range and the response to administered salbutamol inhalation was not significant (p > 0.05). It may be concluded that the airway responsiveness to bronchodilators using only FEV1 as an index of BRT should be interpreted with caution in non-responders because they may not be able to tolerate the mechanical challenge in the form of an FCV manoeuvre but show a significant decrease in airway resistance during resting tidal breathing at FRC.

Factors associated with elevated serum cholesterol levels in well-to-do Pakistani schoolchildren.

Cholesterol (CH) and triglyceride (TG) levels were determined in blood drawn after an overnight fast from 388 school children aged 5-19 years from private schools in Karachi. The mean CH levels ranged from 4.4 to 4.6 mmol l-1 (170.1 to 177.9 mg dl-1) for boys and 4.4 to 4.8 mmol l-1 (170.1 to 185.6 mg dl-1) for girls. The range of TG levels was 1.0 to 1.2 mmol l-1 (88.6 to 106.3 mg dl-1) and 0.9 to 1.1 mmol l-1 (79.7 to 97.4 mg dl-1) for boys and girls respectively. Sixty-two per cent of the girls and 54% of the boys had cholesterol values greater than or equal to 4.4 mmol l-1 (170 mg dl-1), a level at which dietary intervention is recommended for children. Thirty-two per cent of all the children had triglyceride levels above the 90th percentile of the levels for similar age groups in North America. The mean cholesterol intake was 469 mg/day for girls and 518 mg/day for boys. Overweight and inactivity were associated with raised serum cholesterol levels. Forty per cent of the girls and 25% of the boys reported a strong family history of hypercholesterolaemia and/or heart disease. The results show that the prevalence of hypercholesterolaemia is high in well-to-do Pakistani school children and factors which can be modified to lower serum cholesterol levels are identified.

Mechanisms of fixed coupled ventricular ectopic complexes.

Mechanisms of fixed coupled ventricular ectopic complexes (VECs) were studied in the monitoring ECGs of 7 patients with the aid of a special purpose computer. Over 80% of the 4500 fixed coupled VECs studied had coupling intervals restricted to a range of 120 ms. The actual coupling interval varied between subjects. No special part of diastole exhibited the property of fixation. In five patients there was evidence of parasystole despite the fixed coupling. In two of these the ectopic period was clearly different from the sinus period. In the other three a difference was evident between inter-ectopic and sinus intervals, but the ectopic period could not be determined due to absence of short inter-ectopic intervals. Absence of some intervals was due to exit block or consistent coincidence of ectopic stimuli with ventricular refractoriness. In all five patients the inter-ectopic intervals showed progressive adjustment so as to become equal to a multiple of the sinus period. The coupling interval, which indicated the preferred phase relationship of the two rhythms, was altered by small changes in the sinus period. These adjustments were greater manifestations of the synchronising effects, already described, of sinus rhythm on a ventricular parasystolic rhythm. By contrast the VECs of two other patients exhibited very different characteristics. In one, the VECs restricted to 40 ms after the T wave in early diastole were probably due to ventricular re-excitation. In the other, runs of idioventricular rhythm and VECs in late diastole were due to an escape pacemaker rhythm.

Coupling interval, exit block, and periodicity of ventricular parasystolic rhythm.

The electrocardiograms in this study of parasystolic rhythm were tape recorded and then analysed with a special purpose hybrid computer. The rate of appearance of specific inter-ectopic intervals was shown to change significantly with small changes in either the sinus or parasystolic pacemaker period. Natural changes in the period of the ectopic pacemakers were observed over several hours. Changes amounting to 14% within 10 min and 18% overall were observed in one patient, and a gradual lengthening of 10% over 3 h in another. A previously undescribed form of exit block has been discovered in one patient where the block remained active for a given time only after propagation from the parasystolic focus. Different interectopic intervals were shown to contribute to specific and restricted coupling interval locations in diastole. Hence this form of exit block, by preventing some inter-ectopic intervals from propagating, limited the locations in diastole in which parasystolic ectopic complexes could appear. In this case later diastolic complexes were inhibited and hence fusion complexes were completely absent. Parasystolic rhythm, with and without the exit block described, was simulated successfully by a digital computer. The simulations aided our understanding of the clinical data.