Anti-tumoral effects of somatostatin analogs: a lesson from the CLARINET study.

Octreotide and lanreotide, the first-generation somatostatin analogs, successfully control hormone hyperproduction, and related syndromes, in patients with acromegaly and neuroendocrine tumors. However, their anti-tumor effect, rather evident in large number of pituitary adenomas in acromegalic patients, has been hypothesized for a long time in patients with neuroendocrine tumors as well, although a significant tumor shrinkage has rarely been observed. However, the recent publication of the CLARINET study has strengthened the evidence, already emerged with the PROMID trial, that the long-term treatment with the first-generation long-acting somatostatin analogs may exert an anti-tumor activity on G1 and G2 enteropancreatic neuroendocrine tumors, as well. After the publication, majority of international guidelines have updated their algorithms in line with these results and this class of drugs obtained the indication as anti-tumor agents in the majority of patients with neuroendocrine tumors.

Will 68Ga PSMA-radioligands be the only choice for nuclear medicine in prostate cancer in the near future? A clinical update. / ¿Constituirán en el futuro los radioligandos de 68Ga-PSMA la única elección de la Medicina Nuclear para el cáncer de próstata? Actualización clínica.

Prostate Cancer (PCa) represents the most common malignant tumor in men but according to the European Association of Urology (EAU) guidelines, a mass screening for PCa diagnosis should not be performed due to over-diagnosis and over-treatment related problems. An early clinical diagnosis is possible, mainly based on digital rectal examination and Prostatic Specific Agent (PSA) testing. However, the only mandatory test to define the presence of PCa is ultrasound guided-biopsy, obtained on multiple samples, which has also a high prognostic value. In this context, diagnostic imaging plays an important role as confirmed by EAU that in a 2016 update of their guidelines on PCa stated the importance of Positron Emission Tomography (PET) with 11C- or 18F-choline combined with computed tomography (CT) to identify local relapse, lymph node involvement and metastatic spread at all stages. Consequently, in 2017, the European Association of Nuclear Medicine (EANM) together with the Society of Nuclear Medicine and Molecular Imaging (SNMMI) published new guidelines for 68Ga-Prostate Specific Membrane Antigen (PSMA) PET/CT to help physicians in the recommendation, execution and interpretation of PET/CT scans in patients with PCa. Thus, the aim of this 'evidence paper' is to define the current diagnostic algorithm in PCa in order to increase the general level of confidence in approaching such a crucial topic.

Tumor clearance of technetium 99m-sestamibi as a predictor of response to neoadjuvant chemotherapy for locally advanced breast cancer.

PURPOSE: Since we have previously shown that the efflux rate of technetium 99m (99mTc) sestamibi, a transport substrate of P-glycoprotein (Pgp), is directly correlated with Pgp levels in untreated breast carcinoma, we tested whether tumor clearance of 9mTc-sestamibi may be predictive of therapeutic response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS: Thirty-nine patients with stage III disease, median tumor diameter 5.8 cm (range, 3 to 10) were enrolled onto this prospective clinical trial and underwent 99mTc-sestamibi scan before neoadjuvant chemotherapy. Patients were injected intravenously (i.v.) with 740 MBq of 99mTc-sestamibi; a 15-minute dynamic study was performed, and static planar images were obtained at 0.5, 1, 2, and 4 hours. The time to half clearance of 99mTc-sestamibi was calculated in each patient from decay corrected time-activity curves using a monoexponential fitting. Patients were treated with epirubicin 150 mg/m2 i.v. every 2 weeks for three courses and then underwent surgery within 3 weeks from the completion of chemotherapy. Residual tumor was assessed by pathologic examination of mastectomy specimens. RESULTS: Seventeen of 39 patients showed a rapid tumor clearance of 9mTc-sestamibi (time to half clearance [t1/2] < or = 204 minutes) and 15 of these 17 (88%) showed a highly cellular macroscopic residual tumor at histology that indicated lack of tumor response to neoadjuvant chemotherapy. In contrast, only eight of 22 (36%) with prolonged retention of 99mTc-sestamibi (t1/2 > 204 minutes) showed residual macroscopic tumor at histology (Fisher's exact test, P < .01). CONCLUSION: A rapid tumor clearance of 99mTc-sestamibi may predict lack of tumor response to neoadjuvant chemotherapy with drugs affected by the multidrug-resistant phenotype in patients with locally advanced breast carcinoma.

Effects of induced asynchrony on left ventricular diastolic function in patients with coronary artery disease.

OBJECTIVES: This study was designed to increase asynchrony with sequential atrioventricular (AV) pacing and to study its effects on left ventricular isovolumetric relaxation, rapid filling and stiffness. BACKGROUND: Left ventricular nonuniformity is a major determinant of diastolic function. METHODS: Thirteen patients with coronary artery disease were studied by simultaneous equilibrium radionuclide angiography and cardiac catheterization during atrial and AV pacing. Ejection fraction and peak filling rate were measured by radionuclide angiography. Regional analysis was obtained by analyzing time-activity curves of four left ventricular sectors; systolic and diastolic asynchrony were evaluated as the coefficient of variation of time to end-systole and, respectively, time to peak filling rate in the four sectors. Cardiac index and left ventricular pressure were measured with high fidelity catheters at cardiac catheterization. The time constant of isovolumetric relaxation was derived from left ventricular pressure. Pressure-volume loops were assembled and constants of chamber stiffness were computed. RESULTS: Atrioventricular pacing led to a decrease in cardiac index (3.7 +/- 0.9 to 3.3 +/- 0.8 liters/min per m2, p = 0.01) and peak filling rate (352 +/- 125 to 287 +/- 141 ml/s, p = 0.03; 2.4 +/- 0.8 to 2.0 +/- 0.8 end-diastolic counts/s, p = 0.02; 4 +/- 1.3 to 3.2 +/- 1.0 stroke counts/s, p = 0.008). The time constant of isovolumetric relaxation increased (57 +/- 10 to 64 +/- 12 ms, p = 0.04) and the global diastolic pressure-volume relation shifted upward. CONCLUSIONS: Atrioventricular pacing induces left ventricular asynchrony, which is associated with a slower rate of isovolumetric relaxation. The isovolumetric relaxation lasts after the filling phase has begun, thereby reducing the rate of rapid filling.

Early detection of encephalitis with (18)F-FDG PET/CT.

Encephalitis is a relatively rare condition for which making an accurate diagnosis can be challenging. In fact, clinical features are not specific and structural imaging can be normal in a considerable number of cases. However, an early diagnosis is important as many forms of treatment are effective if started promptly. Even though recent guidelines do not recommend (18)F-FDG PET/CT for patients with suspected encephalitis, the case presented suggests that (18)F-FDG PET/CT may play a relevant role for the early diagnosis of this clinical condition.

Performance comparison of two resolution modeling PET reconstruction algorithms in terms of physical figures of merit used in quantitative imaging.

PURPOSE: Resolution modeling (RM) of PET systems has been introduced in iterative reconstruction algorithms for oncologic PET. The RM recovers the loss of resolution and reduces the associated partial volume effect. While these methods improved the observer performance, particularly in the detection of small and faint lesions, their impact on quantification accuracy still requires thorough investigation. The aim of this study was to characterize the performances of the RM algorithms under controlled conditions simulating a typical (18)F-FDG oncologic study, using an anthropomorphic phantom and selected physical figures of merit, used for image quantification. METHODS: Measurements were performed on Biograph HiREZ (B_HiREZ) and Discovery 710 (D_710) PET/CT scanners and reconstructions were performed using the standard iterative reconstructions and the RM algorithms associated to each scanner: TrueX and SharpIR, respectively. RESULTS: RM determined a significant improvement in contrast recovery for small targets (≤17 mm diameter) only for the D_710 scanner. The maximum standardized uptake value (SUVmax) increased when RM was applied using both scanners. The SUVmax of small targets was on average lower with the B_HiREZ than with the D_710. Sharp IR improved the accuracy of SUVmax determination, whilst TrueX showed an overestimation of SUVmax for sphere dimensions greater than 22 mm. The goodness of fit of adaptive threshold algorithms worsened significantly when RM algorithms were employed for both scanners. CONCLUSIONS: Differences in general quantitative performance were observed for the PET scanners analyzed. Segmentation of PET images using adaptive threshold algorithms should not be undertaken in conjunction with RM reconstructions.

Moyamoya disease in Italian monozygotic twins.

We report white monozygotic twins with moyamoya disease (MMD) (adult ischemic type). Both had cerebral angiography, MRI, magnetic resonance angiography, SPECT, EEG, human leukocyte antigen (HLA) typing, evaluation of thrombophilia, and immunologic and karyotype analysis. The clinical features and HLA phenotypes described in Asian monozygotic twins with MMD were not found in our patients. However, genetic analysis revealed a homozygous state for C-->T (Ala-->Val substitution) in position 677 of the methylenetetrahydrofolate reductase-encoding gene.

Left ventricular diastolic function in systemic sclerosis: assessment by radionuclide angiography.

The aim of this study was to assess left ventricular function in subjects with systemic sclerosis. Twenty-four women with systemic sclerosis (mean age 48 +/- 11 yr) and 14 age- and sex-matched normal subjects were studied by radionuclide angiography performed at rest with a temporal resolution of 20 msec/frame. Left ventricular volume curves were generated and indices of systolic and diastolic function were computed. Left ventricular diastolic asynchrony was evaluated by dividing the left ventricle into five regions and then computing the time-to-peak filling rate for each region. After excluding the valvular region, the coefficient of variation of this index was obtained. The isovolumic relaxation period was prolonged in systemic sclerosis patients in comparison to normal subjects (127 +/- 39 msec versus 87 +/- 44 msec, p less than 0.05). Moreover, 38% of the systemic sclerosis patients had a subnormal peak filling rate. Left ventricular diastolic asynchrony was increased in the systemic sclerosis group, as expressed by a higher coefficient of variation of the regional time to peak filling rate (27.9% +/- 11.5% versus 14.5% +/- 8.6%, p less than 0.05). Our results indicate an impaired relaxation and an increased diastolic asynchrony in patients with systemic sclerosis.

Evaluation of left ventricular asynchrony by radionuclide angiography: comparison of phase and sector analysis.

UNLABELLED: The aim of this study was to assess the optimal method to evaluate asynchrony in equilibrium radionuclide angiography (RNA). METHODS: We studied 20 patients (14 males and 6 females, age range 25-60 yr) with RNA during atrial and sequential atrioventricular (AV) pacing, which increased left ventricular (LV) asynchrony. Both studies were performed at the same heart rate. Asynchrony was assessed either on phase images, by computing the standard deviation of the phase distribution (SD-P) and by sector analysis. Systolic and diastolic asynchrony were evaluated as the coefficient of variation of time to end systole (CV-TES) and time to peak filling rate (CV-TPFR) in four sectors. In addition, phase values were computed on time-activity curves from the same sectors, and their standard deviation (SD-Psec) was computed. RESULTS: During atrial pacing SD-P was 32.3 degrees +/- 6.7 degrees and did not change during AV pacing (32.1 degrees +/- 5.6 degrees, p = n.s.). Both CV-TES and CV-TPFR had a significant increase during AV pacing (from 7.7% +/- 3.9% to 11.5% +/- 6.4%, p < 0.01, and from 8.4 degrees +/- 5.8 degrees to 12.9 degrees +/- 6.7 degrees, p < 0.001). AV pacing led to a significant increase in SD-Psec (from 6.3 degrees +/- 4.0 degrees to 12.6 degrees +/- 9.7 degrees, p < 0.05). Moreover, reproducibility was assessed in 15 additional age-matched patients. The results of the reproducibility study indicate a better repeatability for CV-TES and CV-TPFR. CONCLUSIONS: The findings of this study suggest that sector analysis with calculation of indices of LV systolic and diastolic asynchrony is better suited for quantitation of LV temporal nonuniformity.

Fractional retention of technetium-99m-sestamibi as an index of P-glycoprotein expression in untreated breast cancer patients.

UNLABELLED: The multidrug-resistant phenotype is characterized by the reduced intracellular retention of several structurally and functionally unrelated cytotoxic compounds due to the energy-dependent pump activity of P-glycoprotein (Pgp). Because 99mTc-sestamibi is a suitable transport substrate of Pgp, we tested whether the time-dependent fractional retention of this tracer could be used as an index of Pgp expression in untreated breast carcinomas. METHODS: Twenty-seven patients with histologically confirmed breast carcinoma were intravenously injected with 740 MBq (20 mCi) of 99mTc-sestamibi, and static planar images of the breast were obtained at 10, 60 and 240 min. The fractional retention of 99mTc-sestamibi was then calculated as the ratios between 60 and 10 min (R60/10) and between 240 and 10 min (R240/10) of decay-corrected counts/pixel registered in the region of interest drawn around the tumor. Surgically excised tumors were then obtained from each patient, and Pgp levels were determined using 125I-labeled MRK16 monoclonal antibody and in vitro quantitative autoradiography. RESULTS: The fractional retention of 99mTc-sestamibi at 60 and 240 min was significantly higher in tumors with low Pgp levels (Group I, n = 18) as compared to that measured in tumors with high Pgp expression (Group II, n = 9) (p < 0.001). In particular, R60/10 values were 0.86 and 0.59 in breast carcinomas of Groups I and II, respectively, whereas the values of R240/10 were 0.56 and 0.25 in low- and high-Pgp-expressing tumors, respectively. CONCLUSION: The determination of fractional retention of 99mTc-sestamibi may be used as a simple functional test for Pgp expression in untreated breast cancer. A preliminary estimate of the sensitivity and the specificity of the test indicates its potential use in clinical practice to identify patients with a high probability of developing multidrug resistance.

Frequency encoding for simultaneous display of multimodality images.

UNLABELLED: An original method for simultaneous display of functional and anatomic images, based on frequency encoding (FE), merges color PET with T1-weighted MR brain images, and grayscale PET with multispectral color MR images. A comparison with two other methods reported in the literature for image fusion (averaging and intensity modulation techniques) was performed. METHODS: For FE, the Fourier transform of the merged image was obtained summing the low frequencies of the PET image and the high frequencies of the MR image. For image averaging, the merged image was obtained as a weighted average of the intensities of the two images to be merged. For intensity modulation, the red, green and blue components of the color image were multiplied on a pixel-by-pixel basis by the grayscale image. A comparison of the performances of the three techniques was made by three independent observers assessing the conspicuity of specific MRI and PET information in the merged images. For evaluation purposes, images from seven patients and a computer-simulated MRI/PET phantom were used. Data were compared with a chi-square test applied to ranks. RESULTS: For the depiction of MRI and PET information when merging color PET and T1-weighted MR images, FE was rated superior to intensity modulation and averaging techniques in a significant number of comparisons. For merging grayscale PET with multispectral color MR images, FE and intensity modulation were rated superior to image averaging in terms of both MRI and PET information. CONCLUSION: The data suggest that improved simultaneous evaluation of MRI and PET information can be achieved with a method based on FE.

Assessment of left ventricular diastolic function: comparison of contrast ventriculography and equilibrium radionuclide angiography.

Twenty-two patients with coronary artery disease were studied first by radionuclide angiography (RNA) and then by contrast ventriculography. Cardiac medications were discontinued at least 72 hr before study. The patients were studied during atrial pacing at heart rates close to their spontaneous sinus rhythm. Contrast ventriculography was performed at 50 frames/sec in the 30 degrees right anterior oblique projection using 40 ml of a nonionic contrast medium (iopamidol) at a flow rate of 10-12 ml/sec. The contours of the left ventricular silhouette at contrast ventriculography were traced, frame by frame, on a graphic table with a digitizing penlight. Equilibrium 99mTc RNA was performed in the best septal 45 degrees left anterior oblique projection, acquiring 150,000 cts/frame, at 50 frames/sec and with a 5% gate tolerance. Time-activity curves from both end-diastolic and end-systolic ROIs were built and interpolated. Both RNA and contrast ventriculography volume curves were filtered with Fourier five harmonics. A close relationship was found between RNA and contrast ventriculography measurements of peak filling rate normalized to end-diastolic cps (r = 0.87, p less than 0.001) and stroke count (r = 0.87, p less than 0.001), ejection fraction (r = 0.94, p less than 0.001). Thus, in patients with coronary artery disease, LV filling can be accurately assessed using RNA.

Effects of intravenous verapamil on left ventricular relaxation and filling in stable angina pectoris.

Left ventricular (LV) diastolic function is often impaired in coronary artery disease (CAD). To assess whether verapamil could improve LV diastolic properties, 12 patients with CAD undergoing right- and left-sided cardiac catheterization, as well as simultaneous radionuclide angiography, were studied before and during intravenous administration of verapamil (0.1 mg/kg as a bolus followed by 0.007 mg/kg/min). The heart rate was kept constant by atrial pacing in both studies. LV pressure-volume relations were obtained. Verapamil decreased LV systolic pressure (130 +/- 22 to 117 +/- 16 mm Hg, p less than 0.01) and the end-systolic pressure/volume ratio (2.4 +/- 1.3 to 1.6 +/- 0.5 mm Hg/ml, p less than 0.05), and increased LV end-diastolic (13 +/- 4 to 16 +/- 4 mm Hg, p less than 0.02) and pulmonary capillary pressures (10 +/- 5 to 12 +/- 5 mm Hg, p less than 0.005). Despite such negative inotropic effects, cardiac index increased (3.4 +/- 0.7 to 3.9 +/- 0.6 liters/min/m2, p less than 0.02). The time constant of isovolumic relaxation shortened (63 +/- 14 to 47 +/- 9 ms, p less than 0.02); peak filling rate increased (370 +/- 155 to 519 +/- 184 ml/s, p less than 0.001; 2.6 +/- 1.1 to 3.3 +/- 0.9 end-diastolic counts/s, p less than 0.02; and 4.1 +/- 1.6 to 5.5 +/- 1.5 stroke counts/s, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

White matter lesion detection in multiple sclerosis: improved interobserver concordance with multispectral MRI display.

An assessment of the detectability of white matter lesions and of concordance between observers with different levels of MRI reading experience was performed with comparative evaluation of spin-echo MRI images and of corresponding "multispectral" maps in 16 patients with definite multiple sclerosis (MS). Multispectral maps were obtained by means of a recently described post-processing technique based on the simultaneous display of MRI parameters and a standardized colour scale with red, green and blue coding for relaxation rates R1 and R2 and proton density, respectively. Spin-echo images on films and multispectral maps displayed on a personal computer were randomly rated at 2-month intervals. Interobserver concordance (k-test) was assessed among three readers with different levels of MRI experience (an experienced neuroradiologist, a radiology resident and a neurologist). For multispectral maps we found increased interobserver concordance with the experienced neuroradiologist (multispectral vs conventional images; k = 0.77 vs 0.66 for the radiology resident and 0.66 vs 0.56 for the neurologist), an increased number of detected lesions and decreased reading time. Multispectral maps permit easy detection of MS lesions and may improve interobserver concordance compared with conventional spinecho studies.

Assessment of left ventricular regional function by radionuclide angiography: effects of number of sectors on repeatability.

Twenty patients were studied by equilibrium radionuclide angiography (RNA) twice in the same day in order to assess the repeatability of quantitative measurements of left ventricular (LV) regional function by using a sector analysis method. RNA was performed in the best septal 45 degrees left anterior oblique projection, acquiring 150,000 counts/frame, at 20 msec/frame with 5% gate tolerance. LV regional analysis was performed using a computer algorithm written by the authors running on Digital PDP 11/34 machine. The algorithm after having identified the center of gravity of the LV, divided it into 4, 5 and 6 equiangular sectors. In the 5, and 6 sector analysis, the region including the mitral and aortic valves was excluded from subsequent analysis. In each sector Ejection Fraction (EF) and Peak Filling Rate (PFR) were computed. In addition, the Time to End Systole (TES) and Time to Peak Filling Rate were also assessed for each region. The coefficient of variation of the regional values of TES (CV-TES) and regional TPFR (CV-TPFR) were then computed and considered as indices of LV systolic (CV-TES) and diastolic (CV-TPFR) asynchrony. Repeatability was firstly assessed by linear regression analysis between the 2 RNA studies. Our data show a high correlation coefficient on regional values of EF and PFR (R: > 0.92). Moreover, the differences in a given parameter between the 2 studies were plotted against their mean value, and the coefficient of repeatability (CR) was calculated as twice the standard deviation of the differences. No significant differences were found between EF and PFR regional values in the 2 RNA studies (EF coefficient of repeatability: < 0.18; PFR coefficient of repeatability: < 0.8). A low value of coefficient of repeatability was found also for CV-TES (< 17) and for CV-TPFR (< 18). In conclusion LV regional analysis is a repeatable method of analysis, and the number of regions does not affect the repeatability.

Assessment of scanner performance and normalization of estimated relaxation rate values.

The purpose of this study was to develop and test a method for the assessment of Magnetic Resonance (MR) scanner performance suitable for routine brain MR studies and for normalization of calculated relaxation times. We hypothesized that regular monitoring of machine performance changes could provide a helpful normalization tool for calculating tissue MR parameters, thus contributing to support their use for longitudinal and comparative studies of both normal and diseased tissues. The method is based on the acquisition of phantom images during routine brain studies with standard spin-echo sequences. MR phantom and brain tissue parameters were used to assess the influence of machine related changes on relaxation parameter estimates. Experimental results showed that scanner performance may affect relaxation rate estimates. Phantom and in vivo results indicate that the correction method yields a reduction in variability of estimated phantom R1 values up to 29% and of R1 for different brain structures up to 17%. These findings support the validity of using brain coil phantoms for routine system monitoring and correction of tissue relaxation rates.

Scintigraphic detection of multidrug resistance in cancer.

One of the most extensively studied mechanisms of drug resistance involves the drug efflux pump P-glycoprotein (Pgp). The availability of radiolabeled substrates of Pgp such as 99mTc-MIBI and analogous 99mTc-labeled agents allows the clinical assessment of Pgp function in cancer patients. The consistency of the results from different institutions and trials strongly support the clinical application of this imaging technique for individual tailoring of chemotherapeutic regimens and for designing clinical trials with Pgp modulators.