Integrated PET/CT: current applications and future directions

For the past 5 years, combined positron emission tomography (PET) and computed tomography (CT), or PET/CT, has grown because the PET portion provides information that is very different from that obtainable with other imaging modalities. However, the paucity of anatomic landmarks on PET images makes a consistent "hardware fusion" to anatomic cross-sectional data extremely useful. Clinical experience indicates a single direction: Addition of CT to PET improves specificity foremost, but also sensitivity, and the addition of PET to CT adds sensitivity and specificity in tumor imaging. Thus, PET/CT is a more accurate test than either of its individual components and is probably also better than side-by-side viewing of images from both modalities. The synergistic advantage of adding CT is that the attenuation correction needed for PET can also be derived from the CT data, an advantage not obtainable by integrating PET and magnetic resonance imaging. This makes PET/CT 25%-30% faster than PET alone with standard attenuation-correction methods, leading to higher patient throughput and a more comfortable examination, which typically last 30 minutes or less. Fluorodeoxyglucose (FDG) PET/CT appears to provide relevant information in the staging and therapy monitoring of many tumors, including lung carcinoma, mesothelioma, colorectal cancer, lymphoma, melanoma, and many others, with the notable exception of prostatic cancer. For prostatic cancer, choline derivatives may become useful radiopharmaceuticals. The published literature on the applications of FDG PET/CT in oncology is still limited, but several well-designed studies have demonstrated the benefits of PET/CT.     

Clinical Outcomes in Asymptomatic and Symptomatic Atrial Fibrillation Presentations in GARFIELD-AF: Implications for AF Screening

BackgroundAsymptomatic atrial fibrillation is often detected incidentally. Prognosis and optimal therapy for asymptomatic compared with symptomatic atrial fibrillation is uncertain. This study compares clinical characteristics, treatment, and 2-year outcomes of asymptomatic and symptomatic atrial fibrillation presentations.MethodsGlobal Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF) is a global, prospective, observational study of newly diagnosed atrial fibrillation with ≥1 stroke risk factors (http://www.clinicaltrials.gov, unique identifier: NCT01090362). Patients were characterized by atrial fibrillation-related symptoms at presentation and the CHA₂DS₂-VASc score. Two-year follow-up recorded anticoagulation patterns (vitamin K antagonist, direct oral anticoagulants, parenteral therapy) and outcomes (stroke/systemic embolism, all-cause mortality, and bleeding).ResultsAt presentation, of 52,032 eligible patients, 25.4% were asymptomatic and 74.6% symptomatic. Asymptomatic patients were slightly older (72 vs 70 years), more often male (64.2% vs 52.9%), and more frequently initiated on anticoagulation ± antiplatelets (69.4% vs 66.0%). No difference in events (adjusted hazard ratios, 95% confidence interval) for nonhemorrhagic stroke/systemic embolism (1.19, 0.97-1.45), all-cause mortality (1.06, 0.94-1.20), or bleeding (1.02, 0.87-1.19) was observed. Anticoagulation was associated with comparable reduction in nonhemorrhagic stroke/systemic embolism (0.59, 0.43–0.82 vs 0.78, 0.65–0.93) and all-cause mortality (0.69, 0.59-0.81 vs 0.77, 0.71-0.85) in asymptomatic versus symptomatic, respectively.ConclusionsMajor outcomes do not differ between asymptomatic and symptomatic atrial fibrillation presentations and are comparably reduced by anticoagulation. Opportunistic screening-detected asymptomatic atrial fibrillation likely has the same prognosis as asymptomatic atrial fibrillation at presentation and likely responds similarly to anticoagulation thromboprophylaxis.     

LC-ESI-MS/MS reveals the formation of reactive intermediates in brigatinib metabolism: elucidation of bioactivation pathways

Brigatinib (BGB) is a newly approved anaplastic lymphoma kinase (ALK) inhibitor. On April 28, 2017, BGB was approved by the U.S. FDA for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer. The toxicity profile of BGB includes nausea, fatigue, diarrhea, elevated lipase, dyspnoea, hypertension, hypoxia, pneumonia, elevated amylase, pulmonary embolism, elevated ALT, hyponatraemia and hypophosphatemia. Using LC-MS/MS, we investigated the in vitro phase I metabolism of for BGB in rat liver microsomes (RLMs). In the in vitro metabolism of BGB, iminium reactive intermediates were trapped by potassium cyanide forming a stable complex that can be characterized by LC-MS/MS. Four BGB in vitro phase I metabolites were identified. In vitro phase I metabolic pathways were N-dealkylation, α hydroxylation and α oxidation. Additionally, three iminium reactive metabolites were found and the bioactivation mechanisms were proposed. A piperidine ring was found to be responsible for BGB bioactivation. The presence of these three reactive metabolites may be the main reason for BGB side effects. A literature review showed no previous article reported the in vitro phase I metabolism study of BGB or structural identification of the formed reactive metabolites.

Four phase I BGB metabolites and three cyano adducts for BGB were detected using LC-MS/MS. The piperidine ring was found to be responsible for BGB bioactivation and the bioactivation pathways are proposed.     

Evaluation of Ozone Application in Dental Unit Water Lines Contaminated with Pathogenic Acanthamoeba

Background: In this study morphological and molecular characterization of Acanthamoeba strains, isolated from dental unit waterlines (DUWLs) were surveyed and the levels of disinfection achievable in vitro by the application of ozone disinfectant to DUWLs were evaluate. Methods: Water samples were collected from air-water syringes, cup fillers and tap water before and at the end of the working day. They were cultured on non-nutrient agar (NNA) plates. Species identification was carried out with a PCR assay based on sequence analysis of the 18S rRNA gene. The cellular response to ozone was tested on Acanthamoeba cyst with different doses at different contact time in vitro twice. Results: Prevalence rates for Acanthamoeba contamination were 100, 100 and 72% for air-water syringes, cup fillers and tap water, respectively. The morphological analysis revealed the presence of A. castellanii, A. griffin, A. hatchitti and A. lenticulata. Phylogenetic analysis of the sequences showed the four strains to be closely related to a sequence type (T3, T4, T5 and T11). Acanthamoeba cells were stained with trypan blue, which revealed killed of Acanthamoeba instantaneously after 10 minutes in ozonized water. There was no growth of Acanthamoeba occurred after ozone treatment in water bottles for 5 minutes with a flow rate of 500 mg/hour. Conclusion : Ozone can play an important role in controlling the problem of contamination of DUWLs as a potent disinfectant.Key Words: Acanthamoeba spp., Dental units water lines, PCR, Ozone     

Prognostic Impact of Serum Growth Differentiation Factor 15 Level in Acute Myeloid Leukemia Patients

Growth differentiation factor 15 (GDF15) plays an important role in cancer pathophysiology and prognosis. However, limited studies analyzed its level and prognostic value in acute myeloid leukemia (AML) patients. This study included 56 adult AML patients. Serum GDF15 level was measured at diagnosis in all patients by enzyme-linked immunosorbent assay. Remission and survival statuses were assessed at 90 days following treatment. GDF15 level was significantly higher in patients than in controls (P < 0.001). GDF15 level correlated positively with age (P < 0.001), hemoglobin level (P = 0.027), and platelet count (P = 0.024). High GDF15 above the median level was associated with inferior OS (P = 0.044) together with high platelet count (P = 0.006) and high bone marrow blast percent (P = 0.038). There was no statistically significant difference between patients with GDF15 above and below the median level regarding DFS (P = 0.881). On multivariate analysis for OS, GDF15 level was an independent risk factor (P = 0.047). In conclusion, serum GDF15 level is significantly elevated in AML patients and high GDF15 level is associated with inferior OS.     

Depression,Dietary Habits,and Cardiovascular Events Among Women with Suspected Myocardial Ischemia

Background

Dietary habits and depression are associated with cardiovascular disease risk. Patients with depression often report poor eating habits, and dietary factors may help explain commonly observed associations between depression and cardiovascular disease.

MethodS

From 1996 to 2000, 936 women were enrolled in the Women's Ischemia Syndrome Evaluation at 4 US academic medical centers at the time of clinically indicated coronary angiography and then assessed (median follow-up, 5.9 years) for adverse outcomes (cardiovascular disease death, heart failure, myocardial infarction, stroke). Participants completed a protocol including coronary angiography (coronary artery disease severity) and depression assessments (Beck Depression Inventory scores, antidepressant use, and depression treatment history). A subset of 201 women (mean age, 58.5 years; standard deviation, 11.4) further completed the Food Frequency Questionnaire for Adults (1998 Block). We extracted daily fiber intake and daily servings of fruit and vegetables as measures of dietary habits.

Results

In separate Cox regression models adjusted for age, smoking, and coronary artery disease severity, Beck Depression Inventory scores (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.01-1.10), antidepressant use (HR, 2.4; 95% CI, 1.01-5.9), and a history of treatment for depression (HR, 2.4; 95% CI, 1.1-5.3) were adversely associated with time to cardiovascular disease outcomes. Fiber intake (HR, 0.87; 95% CI, 0.78-0.97) and fruit and vegetable consumption (HR, 0.36; 95% CI, 0.19-0.70) were associated with a decreased time to cardiovascular disease event risk. In models including dietary habits and depression, fiber intake and fruit and vegetable consumption remained associated with time to cardiovascular disease outcomes, whereas depression relationships were reduced by 10% to 20% and nonsignificant.

Conclusions

Among women with suspected myocardial ischemia, we observed consistent relationships among depression, dietary habits, and time to cardiovascular disease events. Dietary habits partly explained these relationships. These results suggest that dietary habits should be included in future efforts to identify mechanisms linking depression to cardiovascular disease.     

Approach to the difficult transseptal: diathermy facilitated left atrial access

Percutaneous transseptal left atrial (LA) access is increasingly becoming a routine procedure in the electrophysiology and cardiac catheterisation laboratories. Our aim was to review an unselected large series of this procedure performed over a period of five years. We clinically characterised difficult cases and presented a method of safe and expeditious LA access. Overall, 543 transseptal punctures were performed. Of those, 10 were classified as difficult, with failure to access the LA in three or more attempts. In all 10 cases, surgical electrocautery was successfully used to facilitate needle puncture of the septum. All patients subsequently underwent an uncomplicated procedure. In conclusion, we describe a method to trouble-shoot the difficult transseptal access procedure, outlining the clinical characteristics, echocardiographic features and special precautions that need to be considered when utilising this method.     

In silico and in vitro metabolism of ribociclib: a mass spectrometric approach to bioactivation pathway elucidation and metabolite profiling

Ribociclib (RBC, Kisqali®) is a highly selective CDK4/6 inhibitor that has been approved for breast cancer therapy. Initially, prediction of susceptible sites of metabolism and reactivity pathways were performed by the StarDrop WhichP450™ module and the Xenosite web predictor tool, respectively. Later, in vitro metabolites and adducts of RBC were characterized from rat liver microsomes using LC-MS/MS. Subsequently, in silico data was used as a guide for the in vitro work. Finally, in silico toxicity assessment of RBC metabolites was carried out using DEREK software and structural modification was proposed to reduce their side effects and to validate the bioactivation pathway theory using the StarDrop DEREK module. In vitro phase I metabolic profiling of RBC was performed utilizing rat liver microsomes (RLMs). Generation of reactive metabolites was investigated using potassium cyanide (KCN) as a trapping nucleophile for the transient and reactive iminium intermediates to form a stable cyano adduct that can be identified and characterized using mass spectrometry. Nine phase I metabolites and one cyano adduct of RBC were characterized. The proposed metabolic pathways involved in generation of these metabolites are hydroxylation, oxidation and reduction. The reactive intermediate generation mechanism of RBC may provide an explanation of its adverse reactions. Aryl piperazine is considered a structural alert for toxicity as proposed by the DEREK report. We propose that the generation of only one reactive metabolite of RBC in a very small concentration is due to the decreased reactivity of the piperazine ring compared to previous reports of similar drugs. Docking analysis was performed for RBC and its proposed derivatives at the active site of the human CDK6 enzyme. Methyl-RBC exhibited the best ADMET and docking analysis and fewer side effects compared to RBC and fluoro-RBC. Further drug discovery studies can be conducted taking into account this concept allowing the development of new drugs with enhanced safety profiles that were confirmed by using StarDrop software. To the best of our knowledge, this is the first literature report of RBCin vitro metabolic profiling and structural characterization and toxicological properties of the generated metabolites.

Nine phase I metabolites and one product of KCN trapping of RBC were characterized. Aryl piperazine is considered a structural alert for toxicity as proposed by the DEREK report. Methyl-RBC exhibited less toxicity and more binding affinity to CDK6.