Sinus node dysfunction in catecholaminergic polymorphic ventricular tachycardia: Risk factor and potential therapeutic target?

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited heart rhythm disorder characterized by the occurrence of potentially life-threatening polymorphic ventricular tachyarrhythmias in conditions of physical or emotional stress. The underlying cause is a dysregulation in intracellular Ca handling due to mutations in the sarcoplasmic reticulum Ca release unit. Recent experimental work suggests that sinus bradycardia, which is sometimes observed in CPVT patients, may be another primary defect caused by CPVT mutations. Herein, we review the pathophysiology of CPVT and discuss the role of sinus node dysfunction as a modulator of arrhythmia risk and potential therapeutic target.     

Assessment of patient's pain-related behavior at physical examination may allow diagnosis of recent osteoporotic vertebral fracture

Background contextAlthough innumerable studies have analyzed the multiple aspects of osteoporotic vertebral fractures, no study has focused on the clinical features related to spine pain in patients with recent osteoporotic vertebral compression fractures (VCFs).PurposeTo determine whether the assessment of pain-related behavior (P-RB) of patients with osteoporotic VCFs of recent onset may allow the fracture to be strongly suspected, or even diagnosed, at physical examination.Study designPain-related behavior of elderly patients attending an outpatient spine clinic was evaluated on the basis of six consecutive movements made on the examining table.Patient sampleFifty-six patients complaining only of lumbar or thoracic pain. The fractured patients (FPs), representing the fracture group (FG), were the 19 who had a recent VCF, whereas the control group (CG) consisted of the remaining 37 patients.MethodsAssessment of P-RB was based on six parameters: grimacing, sighing, clenching or blocking eyelids, gaping or strongly tightening the lips, need for help to take positions, and extreme difficulty to turn in the prone position. A score of 1 or a decimal was assigned to each parameter, the final score to each patient being 0 to 6. Three types of injury, acute (I), subacute (II), or chronic (III), were identified on the basis of the time elapsed from the probable occurrence of the fracture. The diagnosis of recent fracture was based on magnetic resonance images. Patients were videotaped during their movements. An examiner, unaware of the clinical history and diagnosis, gave a P-RB score to all patients and indicated whether they had to be placed in FG or CG, and also their presumable type of fracture. Subsequently, a DVD with the videotapes of all patients was given to three independent examiners, not specifically expert of spine conditions, who were asked to make the same evaluations as the first examiner.ResultsThe mean scores for P-RB given by the first examiner were 4.6 to FG and 0.7 to CG (p<.01). He identified as FPs 89% of those who were in FG. The type of fracture was indicated correctly in 88% of patients identified as FPs. The mean scores for the three types of fracture ranged from 5.4 (Type I) to 3.3 (Type III) (p<.001). The mean scores for P-RB given by the independent examiners to FG and CG were similar to those of the first examiner. The rates of correctness in identifying the type of fracture in patients indicated as FPs varied from 87% to 80%. The mean scores assigned to the patients included in the three types of fracture ranged from 5.4 to 2.8.ConclusionsPain-related behavior evaluation of patients with osteoporotic VCF during their movements on the examining table may allow to suspect, or even diagnose, the presence of a fracture, particularly in the initial 4 to 6 weeks after the occurrence. Even orthopedic surgeons not particularly familiar with spine care may be able to suspect the injury during physical examination.     

Fibrous Dysplasia of the Maxilla: Diagnostic Reliability of the Study Image. Literature Review

Objective Fibrous dysplasia (FD) is a benign bone disorder in facial bones. This study evaluates the possibility of diagnosing fibrous dysplasia on imaging alone, without biopsy of the lesion, which is often burdensome for the patient. Materials and Methods The authors bring their experience of four cases of bone lesions of the maxillofacial region and present a review of published studies. The imaging techniques evaluated are computed tomography (CT) and magnetic resonance imaging (MRI) with and without contrast. Results The literature review demonstrates that it is impossible to make diagnosis of fibrous dysplasia exclusively by imaging. Radiographic images often show a ground-glass appearance, which is characteristic but not pathognomonic of fibrous dysplasia. Conclusion Although CT and MRI images may in many cases suggest a diagnosis of fibrous dysplasia, histological examination or follow-up imaging should follow.     

Notch signaling deregulation in multiple myeloma: A rational molecular target

Despite recent therapeutic advances, multiple myeloma (MM) is still an incurable neoplasia due to intrinsic or acquired resistance to therapy. Myeloma cell localization in the bone marrow milieu allows direct interactions between tumor cells and non-tumor bone marrow cells which promote neoplastic cell growth, survival, bone disease, acquisition of drug resistance and consequent relapse. Twenty percent of MM patients are at high-risk of treatment failure as defined by tumor markers or presentation as plasma cell leukemia. Cumulative evidences indicate a key role of Notch signaling in multiple myeloma onset and progression. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, in MM cell Notch signaling is aberrantly activated due to an increased expression of Notch receptors and ligands; notably, this also results in the activation of Notch signaling in surrounding stromal cells which contributes to myeloma cell proliferation, survival and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance. Here we review the last findings on the mechanisms and the effects of Notch signaling dysregulation in MM and provide a rationale for a therapeutic strategy aiming at inhibiting Notch signaling, along with a complete overview on the currently available Notch-directed approaches.     

Can cyclin-dependent kinase 4/6 inhibitors convert inoperable breast cancer relapse to operability? A case report

BACKGROUND Pathological complete response(pCR) is rare in hormone receptor-positive(HR+)HER2-negative breast cancer(BC) treated with either endocrine therapy(ET) or chemotherapy. Radical resection of locoregional relapse, although potentially curative in some cases, is challenging when the tumor invades critical structures.The oral cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with ET has obtained a significant increase in objective response rates and progression-free survival in patients with advanced BC and is now being evaluated in the neoadjuvant setting. We present a clinical case of a patient with an inoperable locoregional relapse of HR+ HER2-negative BC who experienced p CR after treatment with palbociclib.CASE SUMMARY We report the clinical case of a 60-year-old patient who presented with an inoperable locoregional relapse of HR+, HER2-negative BC 10 years after the diagnosis of the primary tumor. During a routine follow-up visit, breast magnetic resonance imaging and positron emission tomography/computed tomography revealed a 4-cm lesion in the right subclavicular region, infiltrating the chest wall and extending to the subclavian vessels, but without bone or visceral involvement. Treatment was begun with palbociclib plus letrozole, converting the disease to operability over a period of 6 mo. Surgery was performed and a p CR achieved. Of note, during treatment the patient experienced a very uncommon toxicity characterized by burning tongue and glossodynia associated with dysgeusia, paresthesia, dysesthesia, and xerostomia. A reduction in the dose of palbociclib did not provide relief and treatment with the inhibitor was thus discontinued, resolving the tongue symptoms. Laboratory exams were unremarkable. Given that this was a late relapse, the tumor was classified asendocrine-sensitive, a condition associated with high sensitivity to palbociclib.CONCLUSION This case highlights the potential of the cyclin-dependent kinase 4/6 inhibitor plus ET combination to achieve pCR in locoregional relapse of BC, enabling surgical resection of a lesion initially considered inoperable.     

Nestin and vimentin colocalization affects the subcellular location of glucocorticoid receptor in cutaneous melanoma

Aims: Nestin (a neuronal stem cell/progenitor cell marker of central nervous system development), vimentin (which is ubiquitously expressed in mesenchymal cells), and the glucocorticoid receptor (GR, which is involved in the immune response, cell proliferation, and apoptosis) have been shown to interact in embryonic and undifferentiated tissues in modulating cell proliferation. The aim of this study was to analyse nestin, vimentin and GR expression in tumour tissue (melanoma), and their association with clinicopathological variables, to evaluate any effect on tumour progression. Methods and results: Immunohistochemistry, double‐label immunofluorescence and confocal laser scanning microscopy were performed on biopsy specimens of cutaneous melanoma from 81 patients. Fisher’s and Pearson’s tests showed a correlation between nestin, vimentin and subcellular GR location (P = 0.008). Their concomitant expression also correlated with Clark level and thickness (P = 0.02 and P = 0.029, respectively). Kaplan–Meier analysis revealed a poorer outcome for stage III and IV patients with associated expression of nestin, vimentin and cytoplasmic GR in tumour tissue (P = 0.02). Conclusions: These results suggest the presence in melanoma of growth mechanisms involving nestin, vimentin, and GR, similarly to that occurring in embryonic and undifferentiated cells, and may help in understanding tumour biology to provide a molecular basis for clinical therapies.     

Reward bias and lateralization in gambling behavior: behavioral activation system and alpha band analysis

The present research explored the main factors that can influence subjects’ choices in the case of decisions. In order to elucidate the individual differences that influence the decisional processes, making their strategies more or less advantageous, we tested the effect of a reward sensitivity in the behavioral activation system (BAS-Reward) constructed on the ability to distinguish between high- and low-risk decisions. Secondly, the lateralization effect, related to increased activation of the left (BAS-related) hemisphere, was explored. Thirty-one subjects were tested using the Iowa Gambling Task, and the BAS-Reward measure was applied to distinguish between high-BAS and low-BAS groups. Behavioral responses (gain/loss options) and alpha-band modulation were considered. It was found that high-BAS group increased their tendency to opt in favor of the immediate reward (loss strategy) rather than the long-term option (win strategy). Secondly, high-BAS subjects showed an increased left-hemisphere activation in response to losing (with immediate reward) choices in comparison with low-BAS subjects. A “reward bias” effect was supposed to explain both the bad strategy and the unbalanced hemispheric activation for high-BAS and more risk-taking subjects.     

Twenty-five-gauge vitrectomy versus 23-gauge vitrectomy in the management of macular diseases: a comparative analysis through a Health Technology Assessment model

Small-gauge vitreoretinal techniques have been shown to be safe and effective in the management of a wide spectrum of vitreoretinal diseases. However, the costs of the new technologies may represent a critical issue for national health systems. The aim of the study is to plan a Health Technology Assessment (HTA) by performing a comparative analysis between the 23- and 25-gauge techniques in the management of macular diseases (epiretinal membranes, macular holes, vitreo-macular traction syndrome). In this prospective study, 45–80-year-old patients undergoing vitrectomy surgery for macular disease were enrolled at the Torino Eye Hospital. In the HTA model we assessed the safety, clinical effectiveness, and cost and financial evaluation of 23-gauge compared with 25-gauge vitrectomies. Fifty patients entered the study; 14 patients underwent 23-gauge vitrectomy and 36 underwent 25-gauge vitrectomy. There was no statistically significant difference in post-operative visual acuity at 1 year between the two groups. No cases of retinal detachment or endophtalmitis were registered at 1-year follow-up. The 23-gauge technique was slightly more expensive than the 25-gauge: the total surgical costs were EUR1217.70 versus EUR1164.84 (p = 0.351). We provide a financial comparison between new vitreoretinal procedures recently introduced in the market and reimbursed by the Italian National Health System and we also stimulate a critical debate about the expensive technocratic model of medicine.