ESC position paper on cardiovascular toxicity of cancer treatments: challenges and expectations

The recent position paper of the European Society of Cardiology (ESC) on cardiovascular toxicity of cancer treatments has attracted considerable interest by healthcare professionals, since it is the first concrete help in the difficult task of monitoring and approaching cardiovascular side effects of anticancer treatments. The ESC expert opinion was not intended as a clinical practice guideline; however, it reports major cardiovascular complications grouped into nine categories, addressing current clinical strategies for prevention and mitigation. In this point of view, we discuss key challenges emerging from critical appraisal of the ESC position paper: (1) the wide spectrum of cardiovascular toxicities associated with oncological drugs, focusing on targeted agents, (2) managing strategies in patients with cardiac implantable devices, (3) the underappreciated (but emerging) immune-related cardiovascular toxicities of checkpoint inhibitors, which may also result in severe heart failure and fulminant myocarditis, (4) the evolving role of anticoagulation in oncology, and the evidence supporting (or not) the use of direct-acting oral anticoagulants in cancer-associated thrombosis.     

Clinical Significance of Laboratory-determined Aspirin Poor Responsiveness After Primary Percutaneous Coronary Intervention

Aims

The objective of the present substudy was to examine whether aspirin poor/high responsiveness (APR/AHR) is associated with increased rates of major adverse cardiovascular events (MACE) and serious bleeding after primary percutaneous coronary intervention (PPCI).

Methods

We analyzed 961 consecutive ST-elevation acute myocardial infarction patients who underwent PPCI between February 2008 and June 2011. Multiplate analyser (Dynabite, Munich, Germany) was used for the assessment of platelet reactivity. APR/AHR were defined as the upper/lower quintiles of ASPI values, determined 24 h after aspirin loading. APR patients were tailored using 300 mg maintenance dose for 30 days. The co-primary end points at 30 days were: MACE (death, non-fatal infarction, ischemia-driven target vessel revascularization and ischemic stroke) and serious bleeding according to the BARC classification.

Results

One hundred and 90 patients were classified as APR, and 193 patients as AHR. At admission, compared with aspirin sensitive patients (ASP), patients with APR had more frequently diabetes, anterior infarction and heart failure, while AHR patients had reduced values of creatine kinase, leukocytes, heart rate and systolic blood pressure. Compared with ASP, the rates of 30-day primary end points did not differ neither in APR group including tailored patients (MACE, adjusted OR 1.02, 95%CI 0.47-2.17; serious bleeding, adjusted OR 1.92, 95%CI 0.79-4.63), nor in patients with AHR (MACE, adjusted OR 1.58, 95%CI 0.71-5.51; serious bleeding, adjusted OR 0.69, 95%CI 0.22-2.12).

Conclusions

The majority of APR patients were suitable for tailoring. Neither APR including tailored patients nor AHR were associated with adverse 30-day efficacy or safety clinical outcomes.

     

Role of DNA Methylation on the Expression of the Anthracycline Metabolizing Enzyme AKR7A2 in Human Heart

The intracardiac synthesis of anthracycline alcohol metabolites by aldo–keto reductases (AKRs) contributes to the pathogenesis of anthracycline-related cardiotoxicity. AKR7A2 is the most abundant anthracycline reductase in hearts from donors with and without Down syndrome (DS), and its expression varies between individuals (≈tenfold). We investigated whether DNA methylation impacts AKR7A2 expression in hearts from donors with (n = 11) and without DS (n = 30). Linear models were used to test for associations between methylation status and cardiac AKR7A2 expression. In hearts from donors without DS, DNA methylation status at CpG site ?865 correlated with AKR7A2 mRNA (Pearson’s regression coefficient, r = ?0.4051, P = 0.0264) and AKR7A2 protein expression (r = ?0.5818, P = 0.0071). In heart tissue from donors with DS, DNA methylation status at CpG site ?232 correlated with AKR7A2 protein expression (r = 0.8659, P = 0.0025). Multiple linear regression modeling revealed that methylation at several CpG sites is associated with the synthesis of cardiotoxic daunorubicinol. AKR7A2 methylation status in lymphoblastoid cell lines from donors with and without DS was examined to explore potential parallelisms between cardiac tissue and lymphoid cells. These results suggest that DNA methylation impacts AKR7A2 expression and the synthesis of cardiotoxic daunorubicinol.     

Distraction histogenesis of the maxillofacial region

The changes in the surrounding soft tissues during long bone distraction in orthopedic surgery have been the subject of several reports, studies on changes in the craniofacial region, in which various tissues, including the skin, muscle, tendon, blood vessel, and gingiva are rare. Therefore, there is a need for studies on the soft tissue aspects of bone lengthening of the craniofacial region. The aim of this review was to address this issue by reviewing the literature about the distraction histogenesis of various tissues, including skin, muscle, blood vessel, nerve, and gingiva.     

The effect of cannabis on oxidative stress and neurodegeneration induced by intrastriatal rotenone injection in rats

We investigated the effect of cannabis treatment on the development of oxidative stress and nigrostriatal cell injury induced by intrastriatal rotenone injection in rats. Rotenone was injected into the right striatum at a concentration of 5 mM (3 μl/rat). The control rats received the vehicle (DMSO). Subsequently, the effect of Cannabis sativa extract treatment on rotenone toxicity was evaluated. Starting on the second day of rotenone injection, rats were treated with C. sativa extract (5, 10, or 15 mg/kg) (expressed as Δ⁹-tetrahydrocannabinol) subcutaneously (s.c.) once daily for 30 days. Biochemical markers of oxidative stress, malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, paraoxonase 1 (PON1) activity, catalase activity, as well as tumor necrosis factor alpha (TNF-α), were determined in different brain areas after 30 days of rotenone treatment. Histopathology and immunohistochemical expression of tyrosine hydroxylase (TH), capase 3, and inducible nitric oxide synthase (iNOS) were also performed. Results showed that intrastriatal injection of rotenone resulted in increased brain oxidative stress in the cerebral cortex, striatum, hippocampus, midbrain, and cerebellum. MDA increased by 41.4–70 %, nitric oxide increased by 48.3–77.5 %, while GSH decreased by 25.0–34.2 %. PON1 and catalase activities decreased by 43.0–60.8 % and by 14.2–36 %, respectively, in these areas. Striatal TNF-α increased by 638.9 % of control value after rotenone injection. Rotenone induced motor deficits (decreased rearing activity). Rotenone caused marked nigrostriatal neurodegeneration, decreased TH immunoreactivity, and increased both iNOS and caspase 3 immunoreactivities in the striatum. Cannabis decreased brain oxidative stress and nitric oxide release induced by intrastriatal rotenone in several brain areas. Cannabis also decreased the elevated TNF-α in the striatum. Cannabis did not protect against the immunohistochemical changes in the striatum and substantia nigra or against neuronal degeneration induced by rotenone treatment. Collectively, these results indicated that the administration of cannabis did not protect against nigrostriatal damage caused by intrastriatal rotenone.     

Multimodal neuroimaging in humans at 9.4 T: a technological breakthrough towards an advanced metabolic imaging scanner

The aim of this paper is twofold: firstly, to explore the potential of simultaneously acquiring multimodal MR–PET–EEG data in a human 9.4 T scanner to provide a platform for metabolic brain imaging. Secondly, to demonstrate that the three modalities are complementary, with MRI providing excellent structural and functional imaging, PET providing quantitative molecular imaging, and EEG providing superior temporal resolution. A 9.4 T MRI scanner equipped with a PET insert and a commercially available EEG device was used to acquire in vivo proton-based images, spectra, and sodium- and oxygen-based images with MRI, EEG signals from a human subject in a static 9.4 T magnetic field, and demonstrate hybrid MR–PET capability in a rat model. High-resolution images of the in vivo human brain with an isotropic resolution of 0.5 mm and post-mortem brain images of the cerebellum with an isotropic resolution of 320 µm are presented. A ¹H spectrum was also acquired from 2 × 2 × 2 mm voxel in the brain allowing 12 metabolites to be identified. Imaging based on sodium and oxygen is demonstrated with isotropic resolutions of 2 and 5 mm, respectively. Auditory evoked potentials measured in a static field of 9.4 T are shown. Finally, hybrid MR–PET capability at 9.4 T in the human scanner is demonstrated in a rat model. Initial progress on the road to 9.4 T multimodal MR–PET–EEG is illustrated. Ultra-high resolution structural imaging, high-resolution images of the sodium distribution and proof-of-principle ¹⁷O data are clearly demonstrated. Further, simultaneous MR–PET data are presented without artefacts and EEG data successfully corrected for the cardioballistic artefact at 9.4 T are presented.     

Structural and functional substrates of tetanus toxin in an animal model of temporal lobe epilepsy

The effects of tetanus toxin (TeNT) both in the spinal cord, in clinical tetanus, and in the brain, in experimental focal epilepsy, suggest disruption of inhibitory synapses. TeNT is a zinc protease with selectivity for Vesicle Associated Membrane Protein (VAMP; previously synaptobrevin), with a reported selectivity for VAMP2 in rats. We found spatially heterogeneous expression of VAMP1 and VAMP2 in the hippocampus. Inhibitory terminals in stratum pyramidale expressed significantly more VAMP1 than VAMP2, while glutamatergic terminals in stratum radiatum expressed significantly more VAMP2 than VAMP1. Intrahippocampal injection of TeNT at doses that induce epileptic foci cleaved both isoforms in tissue around the injection site. The cleavage was modest at 2 days after injection and more substantial and extensive at 8 and 16 days. Whole-cell recordings from CA1 pyramidal cells close to the injection site, made 8–16 days after injection, showed that TeNT decreases spontaneous EPSC frequency to 38 % of control and VAMP2 immunoreactive axon terminals to 37 %. In contrast, TeNT almost completely abolished both spontaneous and evoked IPSCs while decreasing VAMP1 axon terminals to 45 %. We conclude that due to the functional selectivity of the toxin to the relative sparing of excitatory synaptic transmission shifts the network to pathogenically excitable state causing epilepsy.     

Development and first data of a customized short tracheal cannula based on digital data

Purpose

At the moment, there is an inadequate margin fit of commercially available stoma buttons. The aim of the present study was to develop a customized short tracheal cannula based on digital data. Furthermore, the applied material has to be evaluated considering germ colonization and appropriate cleaning procedures.

Methods

Computed tomographies of 53 patients who underwent laryngectomy were surveyed. Based on the digital data, a customized short tracheal cannula was created and manufactured from silicone. The new cannula was incorporated in ten patients and worn for 4 weeks. A clinical examination of an otolaryngologist and subjective assessment of the patients were carried out. Furthermore, microbiological test considering germ colonization was performed.

Results

The customized short tracheal cannula could be incorporated in all patients. The clinical results showed no irritation or mucosal lesions. The subjective individual evaluation by the patients was promising. The proposals for improvement could be considered. The microbiological examination revealed a higher contamination of the silicone compared to the silver cannulas. Both chemical and mechanical decontamination showed sufficient results.

Conclusion

A workflow for development and manufacturing of a customized short tracheal cannula from digital data could be established. The cannula is compatible to standard equipment and routine cleaning procedures. Clinical studies are required to evaluate the potential benefit for patients.

     

Accurate estimate of pancreatic T2* values: how to deal with fat infiltration

Purpose

We examined different approaches aimed to deal with the signal fluctuation of pancreatic T2* values due to fat infiltration in order to obtain accurate estimates of iron overload.

Methods

Pancreatic T2* values were assessed in 20 patients (13 females, 37.24 ± 9.12 years) enrolled in the Myocardial Iron Overload in Thalassemia network without and with the application of fat suppression-FS (T2*-NoFS and T2*-FS). T2* values were assessed in three different ways: (1) from the immediate fit (original T2*); (2) discarding the echoes until the achievement of a good visual concordance between the signal and the model (final_vis T2*); (3) eliminating the echoes until the achievement of a fitting error (known) <5% (final_thres T2*).

Results

For the T2*-NoFS sequence the original T2* values were significantly higher than the final_vis T2* values (difference:4.8 ± 6.1 ms; P < 0.0001) and the final_thres T2* values (difference:4.3 ± 6.1 ms; P = 0.006). For the T2*-FS sequence the original T2* values were comparable to final_vis and final_thres T2* values. The original T2*-FS values were significantly different from the original T2*-NoFS values. The final_vis T2*-FS values were comparable to the final_vis T2*-NoFS values and the final_thresh T2*-FS values were comparable to the final_thresh T2*-NoFS values. For both T2*-FS and T2*-NoFS sequences, the final_thres T2* values were not significantly different from the final_vis T2* values and no bias was present.

Conclusions

In the clinical practice, an accurate pancreatic iron overload assessment should be done by applying FS and, when needed, by discarding the TEs until the fitting error goes below 5%.

     

Juvenile Ossifying Fibroma of the Maxilla: A Case Report

Ossifying fibroma is a benign neoplasm of the bone, usually involving the posterior tooth bearing area of the mandible, predominantly seen in females in 2nd–4th decade of life with 5:1 prediliction. Fibro-osseous lesions other than FD seem to arise from the periodontal membrane. These lesions are usually asymptomatic, well defined clinically and radiologically amenable for enucleation. Fibro-osseous lesions of the jaws, including Juvenile Ossifying Fibroma (JOF), pose diagnostic and therapeutic difficulties due to their clinical, radiological and histological variability. Ossifying fibromas which appear as fast growing mass between 5 and 15 years of age, radiologically well bordered, and consistent with ossifying fibroma histologically, are referred as juvenile (aggressive) ossifying fibroma. We report a case of JOF of left side of the maxilla in an 11 year old girl which is an uncommon site of occurrence.