Rendimiento diagnóstico de un nuevo software de aprendizaje profundo para corrección de atenuación en la imagen de perfusión miocárdica utilizando una cámara CZT cardiodedicada. Experiencia en la práctica clínica / Diagnostic performance of a novel deep learning attenuation correction software for MPI using a cardio dedicated CZT camera: Experience in the clinical practice

Objetivo Evaluar el rendimiento diagnóstico de un nuevo software de aprendizaje profundo para corrección de atenuación (SAPCA) en imágenes de perfusión miocárdica (IPM) utilizando una cámara cardiodedicada de cadmio-cinc-telurio (CZT) con correlación con angiografía coronaria (AC) para el diagnóstico de enfermedad arterial coronaria (EAC) en una población de alto riesgo. Métodos Estudio retrospectivo de 300 pacientes (196 varones [65%], edad media de 68 años) desde septiembre de 2014 hasta octubre de 2019. Posteriormente realizaron una IPM, seguida de AC dentro de los 6 meses posteriores a la IPM. La probabilidad media pretest para EAC según los criterios de la Sociedad Europea de Cardiología fue del 37%. La IPM se realizó en una cámara CZT cardio dedicada (D-SPECT® Spectrum Dynamics) usando un protocolo de 2 días, de acuerdo con las guías de la Sociedad Europea de Medicina Nuclear (EANM). La IPM fue evaluada con y sin el SAPCA. Resultados La precisión diagnóstica global de la IPM sin el SAPCA para identificar pacientes con cualquier EAC obstructiva en la AC fue del 87%, sensibilidad del 94%, especificidad del 57%, valor predictivo positivo del 91% y valor predictivo negativo del 64%. Utilizando el SAPCA, la precisión diagnóstica global fue del 90%, la sensibilidad del 91%, la especificidad del 86%, el valor predictivo positivo del 97% y el valor predictivo negativo del 66%. Conclusión El uso del novel SAPCA mejora el rendimiento diagnóstico de la IPM usando la cámara CZT D-SPECT®, especialmente reduciendo el número de resultados falsos positivos al reducir los artefactos (AU)

urpose To evaluate the diagnostic performance of a novel deep learning attenuation correction software (SAPCA) for myocardial perfusion imaging (MPI) using a cadmium-zinc-telluride (CZT) cardio dedicated camera with invasive coronary angiography (ICA) correlation for the diagnosis of coronary artery disease (CAD) in a high-risk population. Methods Retrospective study of 300 patients (196 males [65%], mean age 68 years) from September 2014 to October 2019 undergoing MPI, followed by ICA and evaluated by means of quantitative angiography software, within six months after the MPI. The mean pre-test probability score for coronary disease according to the European Society of Cardiology criteria was 37% for the whole cohort. The MPI was performed in a dedicated CZT cardio camera (D-SPECT® Spectrum Dynamics) with a two-day protocol, according to the European Association of Nuclear Medicine guidelines. MPI was retrospectively evaluated with and without the SAPCA. Results The overall diagnostic accuracy of MPI without SAPCA to identify patients with any obstructive CAD at ICA was 87%, Sensitivity 94%, Specificity 57%, positive predictive value 91% and negative predictive value 64%. Using SAPCA the overall diagnostic accuracy was 90%, sensitivity 91%, specificity 86%, positive predictive value 97% and negative predictive value 66%. Conclusion Use of the novel SAPCA enhances performance of the MPI using the CZT D-SPECT® camera and achieves improved results, especially avoiding artefacts and reducing the number of false positive results (AU)

Rendimiento diagnóstico de diferentes protocolos de estrés cardiaco usados en imagen de perfusión miocárdica para el diagnóstico de enfermedad coronaria usando una cámara de cadmio-zinc-telurio con correlación con angiografía coronaria / Diagnostic performance of different cardiac stress protocols for myocardial perfusion imaging for the diagnosis of coronary artery disease using a cadmium-zinc-telluride camera with invasive coronary angiography correlation

Objetivo Evaluar el rendimiento diagnóstico de tres protocolos diferentes de estrés cardiaco utilizados en imagen de perfusión miocárdica (IPM), usando una cámara de cadmio-zinc-telurio (CZT) en correlación con angiografía coronaria (AC) para el diagnóstico de enfermedad arterial coronaria (EAC) en una población de alto riesgo. Métodos Estudio retrospectivo realizado en 263 pacientes (96 mujeres y 167 varones, edad media 68 años), de los cuales 119 realizaron una prueba de estrés con bicicleta (PEB), 113 una prueba de estrés farmacológica (PEF) y 31 una combinación de ambas (PEC), entre septiembre de 2014 y diciembre de 2018. Posteriormente realizaron una IPM, seguida de AC dentro de los seis meses posteriores a la IPM. La probabilidad preprueba media para EAC según los criterios de la Sociedad Europea de Cardiología fue de 36%. La IPM se realizó en una cámara CZT cardio dedicada (D-SPECT Spectrum Dynamics) con un protocolo de dos días, de acuerdo con las guías de la Asociación Europea de Medicina Nuclear (EANM). Resultados No se observaron diferencias significativas entre los diferentes protocolos de estrés en términos de precisión diagnóstica (PEB 85%, PEF 88%, PEC 84%). La exactitud diagnóstica general de IPM para identificar pacientes con cualquier EAC obstructiva en AC fue de 86%, sensibilidad de 93%, especificidad de 54%, VPP de 90% y VPN de 63%. Conclusión La cámara CZT D-SPECT logra resultados generales satisfactorios en el diagnóstico de la EAC, sin encontrar diferencias significativas en el rendimiento diagnóstico cuando la prueba de esfuerzo se realizó como PEB, PEF o PEC. (AU)

Purpose To evaluate the diagnostic performance of three different cardiac stress protocols for myocardial perfusion imaging (MPI) using a cadmium-zinc-telluride (CZT) camera with invasive coronary angiography (ICA) correlation for the diagnosis of coronary artery disease in a high risk population. Methods Retrospective study of 263 patients (96 women and 167 males, mean age 68 years) from which 119 patients performed a bicycle stress test (BST), 113 pharmacological stress test (PST) and 31 a combination of the two (CST) between September 2014 and December 2018. The patients then underwent myocardial perfusion imaging (MPI), followed by ICA and evaluated by means of quantitative angiography software, within six months after the MPI. The mean pre-test probability score for coronary disease according to the European Society of Cardiology criteria was 36% for the whole population. The MPI was performed in a dedicated CZT cardio camera (D-SPECT Spectrum Dynamics) with a two-day protocol, according to the European Association of Nuclear Medicine guidelines. Results No significant difference was observed between the three stress protocols in terms of diagnostic accuracy (BST 85%, PST 88% and CST 84%). The overall diagnostic accuracy of MPI to identify patients with any obstructive CAD at ICA was 86%, Sensitivity 93%, Specificity 54%, PPV 90% and NPV 63%. Conclusion The CZT D-SPECT camera achieves overall satisfactory results in the diagnosis of CAD, observing no significant differences in the diagnostic performance when the stress test was performed as a BST, PST or CST (AU)

Long term outcome after treatment of de novo coronary artery lesions using three different drug coated balloons.

OBJECTIVE: To evaluate the long-term efficacy of three currently available drug coated balloons (DCB) for the treatment of de-novo coronary lesions. METHODS: This was a retrospective analysis of prospectively collected data from the Swedish Coronary Angiography and Angioplasty Registry. Between 2009 and 2017, three currently available DCB brands used in the treatment of de novo lesions were included. Outcomes were clinically driven restenosis and target lesion thrombosis (TLT) (per device) and major adverse cardiac events (MACE) including death, myocardial infarction or target vessel revascularization (per patient) at 4 years. Multivariable Cox regression models were used to adjust for differences. RESULTS: We included 6715 lesions treated with DCBs, 4483 SeQuent® Please (S-DCB), 1071 IN.PACT Falcon (I-DCB) and 1161 Pantera® Lux (P-DCB), in 5670 patients. The mean DCB diameter was 2.4 mm. Bailout stenting occurred in 6.7% of lesions. Angiographic success was 98.5%. The overall cumulative rate of restenosis was 5.5% (299 events). The risk for reported restenosis did not significantly differ between I-DCB vs S-DCB, adjusted hazard ratio (aHR) 0.96; 95% confidence interval (CI) 0.69-1.34, P-DCB vs S-DCB aHR 0.88; 95% CI 0.63-1.23 and I-DCB vs P-DCB aHR 1.10; 95% CI 0.72-1.68. The cumulative risk for TLT was 0.8% in all three DCBs. The risk for MACE or individual components of MACE did not differ between the three patient-groups. CONCLUSION: In de novo coronary lesions, we found comparable long-term efficacy with three currently available DCB brands. DCB angioplasty was feasible with low risk for long-term restenosis and TLT.

Immune responses to the 105AD7 human anti-idiotypic vaccine after intensive chemotherapy, for osteosarcoma.

105AD7 is a human monoclonal antibody that mimics the complement regulatory protein, CD55, overexpressed by many solid tumours including osteosarcoma. This study was designed to assess the toxicity and efficacy of this vaccine in a young age group of patients within 1-6 months of myleosuppressive chemotherapy. Out of 28, 20 (71%, 95% CI 51-87%) patients showed a significant T-cell proliferation response in vitro to the 105AD7 protein but not to human IgG. Furthermore, 13 out of 22 (59%, 95% CI 36-79%) patients showed antigen-specific gammaIFN secretion (range 20-370 U/ml). Nine out of 28 (32%, 95% CI 16-52%) patients made weak antibody responses to CD55. This study showed that 105AD7 was well tolerated in younger patients with osteosarcoma. In addition, two patients with possible clinical responses were given compassionate permission to continue immunisation quarterly for 2 years. They both remain alive and disease free 5.8 and 6.5 years from original diagnosis of osteosarcoma and showed no adverse effects of repeated immunisation. In conclusion, the majority of patients showed measurable T helper responses when vaccination was commenced within a 6-month window of intensive chemotherapy with no clinically significant toxicity. Future clinical trials incorporating immune stimulation strategies should include early introduction of vaccines during the highest risk period for relapse.

A phase I trial of amsalog (CI-921) administered by intravenous infusion using a 5-day schedule.

PURPOSE: Amsalog, a derivative of 9-aminoacridine, is an inhibitor of topoisomerase II. Early studies of intravenous amsalog administered either once weekly, or daily for 3 days repeated every 3 weeks, showed that myelosuppression is the dose-limiting toxicity (DLT). Phase II studies showed only limited activity in breast, head and neck, and non-small-cell lung cancer. The activity of other topoisomerase inhibitors is schedule-dependent. We therefore performed a phase I study to evaluate the use of amsalog on a more prolonged schedule. METHODS: A group of 19 patients with refractory malignancies were treated in six cohorts using 2-h infusions of amsalog daily for 5 days, repeated every 3 weeks. RESULTS: Myelosuppression was seen as DLT at 200 mg/m2 per day. Other toxicities included nausea and vomiting, fatigue, and, when administered via a peripheral venous line, severe phlebitis necessitating administration via an indwelling central venous catheter for doses greater than 100 mg/m2. Pharmacokinetic studies showed a linear relationship between Cmax and AUC, and dose. The terminal half-life was 2 h, consistent with previous studies. CONCLUSION: We conclude that amsalog can be safely given on a 5-day schedule every 3 weeks at doses up to 200 mg/m2. The dose recommended for further studies is 180 mg/m2 per day for 5 days repeated every 3 weeks. However, in view of the phlebitis, which necessitated the use of central venous catheters for administration, other routes of administration, for example oral formulations, should be explored.

Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee.

PURPOSE: D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. METHODS: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of D-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. RESULTS: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (Cmax) for D-limonene ranged from 10.8+/-6.7 to 20.5+/-11.2 microM. Predominant circulating metabolites were perillic acid (Cmax 20.7+/-13.2 to 71+/-29.3 microM), dihydroperillic acid (Cmax 16.6+/-7.9 to 28.1+/-3.1 microM), limonene-1,2-diol (Cmax 10.1+/-8 to 20.7+/-8.6 microM), uroterpenol (Cmax 14.3+/-1.5 to 45.1+/-1.8 microM), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of D-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. CONCLUSIONS: D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

Increased dihydropyridine-sensitive calcium channels in rat brain may underlie ethanol physical dependence.

Ethanol physical dependence can be viewed as a state of latent hyperexcitability in brain which is exposed on withdrawal of the drug. This hyperexcitability may reflect an increased sensitivity to Ca2+ of central neurones. Dihydropyridine (DHP) binding sites which represent a subtype of neuronal Ca2+-channel, are increased in brains from ethanol-dependent rats as are functional effects of the DHP Ca2+-channel activator, BAYK8644. These effects are reversed by DHP Ca2+ inhibitors, which also prevent the ethanol physical withdrawal syndrome. These results suggest that an increase in DHP-sensitive Ca2+-channels on central neurons may represent the molecular basis for ethanol physical dependence.

Altered characteristics of catecholamine release from rat cortical slices and bovine adrenal chromaffin cells in culture after chronic exposure to ethanol and the effect of the dihydropyridine drugs on these systems.

The depolarisation-induced release of dopamine from control rat striatal slices is inhibited by ethanol in vitro. The same parameter is enhanced in preparations from ethanol-treated rats. Under conditions of superfusion with normal physiological solutions we were unable to see similar results in noradrenaline (NA) release from cortical slices. Since we believed altered intracellular Ca2+ metabolism might underlie changes induced by ethanol in dopamine neurones, we superfused cortical slices with low K+ solutions which raise intracellular Ca2+. Under these conditions, ethanol in vitro inhibited depolarisation-induced NA release in control preparations. In preparations from ethanol tolerant animals, ethanol enhanced depolarisation-induced release. In cultures of adrenal chromaffin cells, similar alterations in coupling between Ca2+ and catecholamine release can be seen. Some of these changes may be a consequence of increased functional activity of dihydropyridine-sensitive Ca2+ channels.

Flavonoid impairment of neutrophil response.

Flavonoids are a class of phenolic plant pigments which impair the oxidative burst of neutrophils to an extent dependent on their hydrophobicity. The distribution of quercetin and of morin in nitrogen-cavitated neutrophils paralleled their respective hydrophobic characteristics and respiratory burst inhibition. While both flavonoids were localized primarily in the specific granule membrane of neutrophils, the amount of quercetin was considerably greater than that of morin. We here demonstrate inhibition of the initial stimulation response, depolarization of the membrane potential as monitored by fluorescence of the membrane probe diS-C3-(5), and of the respiratory burst, monitored by following the destruction of diS-C3-(5), a reaction mediated by the H2O2 produced in the burst. The flavonoids kaempferol, morin, quercetin, or fisetin were preincubated with human neutrophils at a concentration of 100 microM per 2 X 10(6) cells/ml for 2-3 min and subsequently stimulated with 1 microgram/ml of the tumor promoter phorbol myristate acetate (PMA) or with 60 micrograms/ml of immune complex. The effect of each compound differed, i.e. depolarization was enhanced by some and inhibited by others, while H2O2 generation was inhibited by each, supporting our previous findings that membrane potential depolarization and the respiratory burst are dissociable events. Concentration-response experiments, performed at flavonoid concentrations between 12.5 and 500 microM to determine the IC50 values of these compounds for depolarization and burst activation, indicated that none of the flavonoids affected the resting potential, while all perturbed the stimulus-coupled response, the direction and extent of the perturbation depending upon the stimulus, and the function assessed. These data show that the effects of flavonoids on human neutrophils are complex and suggest several sites of action depending upon the flavonoid's subcellular distribution and pathway of stimulation.

Alterations in Ca2+-dependent and Ca2+-independent release of catecholamines in preparations of rat brain produced by ethanol treatment in vivo.

Compared to preparations from control animals, superfused striatal slice preparations from brains of rats treated chronically with ethanol released a significantly greater fraction of stored [3H] dopamine on depolarisation in 40 mM K+. Similarly, the electrically-evoked release of [3H]-norepinephrine from cortical slices and of [3H]-dopamine from striatal slices is also increased, although with this mechanism of depolarisation the change is significant only in the case of [3H] norepinephrine release. In contrast to this tendency to enhancement of Ca2+-dependent depolarisation-induced release, a reduced fraction of stored [3H]-catecholamines was released from these preparations by the indirect sympathomimetics tyramine and (+)-amphetamine. The catecholamine release induced by these indirect sympathomimetics is largely independent of external Ca2+ and the results are interpreted as suggesting that chronic alcohol treatment changes the distribution of catecholamine neurotransmitters between storage pools in the nerve terminal which do or do not require Ca2+ entry for release.