Focused echocardiography in cardio-oncology

Transthoracic echocardiography (TTE) is the cornerstone of imaging in patients with a malignancy in all stages of their treatment—before, during, and after the completion of it—to identify most of the cardiotoxic complications. However, the restricted time and resources of cardio-oncology services and the high volume of oncological patients and survivors on the other hand limit the access of this population to this modality. Focused Echo in Cardio-Oncology (FECO) in proportion to other focused cardiac protocols is proposed as a valuable tool after the initial standard complete TTE to: (a) identify the potential toxicity expected by the specific cancer therapy applied; (b) assess sequentially the pre-existing abnormality, if any, in relation to therapy; (c) assess the effect of any cardio-protective intervention; (d) identify any cardiac origin of patient complaints during or after therapy; (e) assess cardiac function in asymptomatic patients who develop significant changes in cardiac biomarkers during cancer therapy. Four different protocols of FECO are proposed according to the type of cardiotoxicity anticipated: FECOm (in patients on chemotherapeutics that cause myocardial dysfunction), FECOv (in patients at risk of valvular heart disease), FECOpd (in patients at risk of pericardial disease), and FECOph (in patients at risk of pulmonary hypertension). The application of FECO protocols is aimed to ensure accuracy, reliability, and effectiveness in the early identification of cardiovascular complications, improving quality of life, and being at the same time cost-effective.     

Improving Glucose Homeostasis after Parathyroidectomy for Normocalcemic Primary Hyperparathyroidism with Co-Existing Prediabetes

We have previously described increased fasting plasma glucose levels in patients with normocalcemic primary hyperparathyroidism (NPHPT) and co-existing prediabetes, compared to prediabetes per se. This study evaluated the effect of parathyroidectomy (PTx) (Group A), versus conservative follow-up (Group B), in a small cohort of patients with co-existing NPHPT and prediabetes. Sixteen patients were categorized in each group. Glycemic parameters (levels of fasting glucose (fGlu), glycosylated hemoglobin (HbA1c), and fasting insulin (fIns)), the homeostasis model assessment for estimating insulin secretion (HOMA-B) and resistance (HOMA-IR), and a 75-g oral glucose tolerance test were evaluated at baseline and after 32 weeks for both groups. Measurements at baseline were not significantly different between Groups A and B, respectively: fGlu (119.4 ± 2.8 vs. 118.2 ± 1.8 mg/dL, p = 0.451), HbA_1c (5.84 ± 0.3 %vs. 5.86 ± 0.4%, p = 0.411), HOMA-IR (3.1 ± 1.2 vs. 2.9 ± 0.2, p = 0.213), HOMA-B (112.9 ± 31.8 vs. 116.9 ± 21.0%, p = 0.312), fIns (11.0 ± 2.3 vs. 12.8 ± 1.4 μIU/mL, p = 0.731), and 2-h post-load glucose concentrations (163.2 ± 3.2 vs. 167.2 ± 3.2 mg/dL, p = 0.371). fGlu levels demonstrated a positive correlation with PTH concentrations for both groups (Group A, rho = 0.374, p = 0.005, and Group B, rho = 0.359, p = 0.008). At the end of follow-up, Group A demonstrated significant improvements after PTx compared to the baseline: fGlu ((119.4 ± 2.8 vs. 111.2 ± 1.9 mg/dL, p = 0.021) (−8.2 ± 0.6 mg/dL)), and 2-h post-load glucose concentrations ((163.2 ± 3.2 vs. 144.4 ± 3.2 mg/dL, p = 0.041), (−18.8 ± 0.3 mg/dL)). For Group B, results demonstrated non-significant differences: fGlu ((118.2 ± 1.8 vs. 117.6 ± 2.3 mg/dL, p = 0.031), (−0.6 ± 0.2 mg/dL)), and 2-h post-load glucose concentrations ((167.2 ± 2.7 vs. 176.2 ± 3.2 mg/dL, p = 0.781), (+9.0 ± 0.8 mg/dL)). We conclude that PTx for individuals with NPHPT and prediabetes may improve their glucose homeostasis when compared with conservative follow-up, after 8 months of follow-up.     

A carcinosarcoma/sarcomatoid carcinoma arising in a urinary bladder diverticulum

We describe an invasive polypoid carcinosarcoma/sarcomatoid carcinoma arising within a urinary bladder diverticulum in a 65-year-old patient with synchronous, moderately differentiated prostatic adenocarcinoma. Histologically, the diverticular tumor exhibits an admixture of different morphologic components, including invasive high-grade urothelial carcinoma, malignant glandular structures in a cellular background of malignant spindle cells, and areas formed exclusively by spindle and pleomorphic cells. There was full-thickness involvement of the diverticulum with extension of the tumor into the perivesical fat and ipsilateral seminal vesicle. In view of the early invasive behavior of carcinosarcoma/sarcomatoid carcinoma combined with the paucity of the muscular layer in the diverticulum wall, a graver prognosis was expected for this aggressive tumor that occurred in this unusual site.     

Emerging antibodies for the treatment of pancreatic cancer

Introduction: Pancreatic ductal adenocarcinoma cancer (PDAC) is the fourth leading cause of cancer death worldwide. Recently, two chemotherapy regimens have proven to improve median overall survival in comparison with gemcitabine. Based on better understanding of tumor molecular biology and of the role of tumor microenvironment, monoclonal antibodies (mAbs) could be an interesting and new type of targeted treatment of PDAC.

Areas covered: Preclinical and clinical trials have evaluated the efficacy of several mAbs in pancreatic cancer treatment. This review will underline the most important targeted pathways by mAbs involved in this disease, including EGFR, HER-2, IGF-1 R, VEGF/VEGFR, NOTCH, WNT and immune checkpoints.

Expert opinion: Despite the promising results of preclinical and phase I trials, the addition of mAbs to standard chemotherapy or in association with other target agents seems not to confirm these results in the following phase II and III trials in pancreatic cancer patients. However, an improved patient selection before treatment based on molecular characteristics in association with reliable predictive biomarkers can identified more efficacious treatment approaches, minimizing toxicity profile of these drugs.     

Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells

In addition to their role as regulators of leukocyte migration and activation, chemokines and their receptors also function in angiogenesis, growth regulation, and HIV-1 pathogenesis--effects that involve the action of chemokines on nonhematopoietic cells. To determine whether chemokine receptors are expressed in human colonic epithelium, HT-29 cells were examined by RT-PCR for the expression of the chemokine receptors for lymphotactin, fractalkine, CCR1-10, and CXCR1-5. The only receptor consistently detected was CXCR4 (fusin/LESTR), although HT-29 cells did not express mRNA for its ligand, stromal cell-derived factor (SDF-1alpha). Flow cytometric analysis with anti-CXCR4 antibody indicated that the CXCR4 protein was expressed on the surface of roughly half of HT-29 cells. CXCR4 was also expressed in colonic epithelial cells in vivo as shown by immunohistochemistry on biopsies from normal and inflamed human colonic mucosa. The mRNA for SDF-1alpha and other CC and CXC chemokines was present in normal colonic biopsies. The CXCR4 receptor in HT-29 cells was functionally coupled, as demonstrated by the elevation in [Ca2+]i, which occurred in response to 25 nM SDF-1alpha and by the SDF-1alpha-induced upregulation of ICAM-1 mRNA. Sodium butyrate downregulated CXCR4 expression and induced differentiation of HT-29 cells, suggesting a role for CXCR4 in maintenance and renewal of the colonic epithelium. This receptor, which also serves as a coreceptor for HIV, may mediate viral infection of colonic epithelial cells.     

Nerve echogenicity and intranerve CSA variability in high-resolution nerve ultrasound (HRUS) in chronic inflammatory demyelinating polyneuropathy (CIDP)

Journal of Neurology - HRUS is increasingly being used in the diagnosis and evaluation of autoimmune neuropathies such as CIDP. Recently, studies focused not only on changes of nerves size, but...     

Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes

Objectives

Our aime was to study the short- and long-term effects of ketogenic diet on the disease course and disease-related outcomes in patients with pyruvate dehydrogenase complex deficiency, the metabolic factors implicated in treatment outcomes, and potential safety and compliance issues.

Methods

Pediatric patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with ketogenic diet were evaluated. Study assessments at specific time points included developmental and neurocognitive testing, patient log books, and investigator and parental questionnaires. A systematic literature review was also performed.

Results

Nineteen patients were assessed, the majority having prenatal disease onset. Patients were treated with ketogenic diet for a median of 2.9 years. All patients alive at the time of data registration at a median age of 6 years. The treatment had a positive effect mainly in the areas of epilepsy, ataxia, sleep disturbance, speech/language development, social functioning, and frequency of hospitalizations. It was also safe—except in one patient who discontinued because of acute pancreatitis. The median plasma concentration of ketone bodies (3-hydroxybutyric acid) was 3.3 mmol/l. Poor dietary compliance was associated with relapsing ataxia and stagnation of motor and neurocognitive development. Results of neurocognitive testing are reported for 12 of 19 patients.

Conclusion

Ketogenic diet was an effective and safe treatment for the majority of patients. Treatment effect was mainly determined by disease phenotype and attainment and maintenance of ketosis.

     

Role of serotonin 5-HT2A and 5-HT2C receptors on brain stimulation reward and the reward-facilitating effect of cocaine

Rationale

The serotonin 5-HT_2A and 5-HT_2C receptors, which are found in abundance in the mesolimbocortical dopaminergic system, appear to modulate the behavioral effects of cocaine.

Objectives

The present series of studies set out to investigate the role of 5-HT_2A and 5-HT_2C receptors on brain reward and on the reward-facilitating effect of cocaine and localize the neural substrates within the mesolimbocortical dopaminergic system that are responsible for these effects.

Methods

Male Sprague-Dawley rats were implanted with stimulating electrodes and bilateral cannulae for the experiments involving microinjections and were trained to respond to electrical stimulation. In the first study, we examined the effects of systemic administration of selective 5-HT_2A and 5-HT_2C receptor agonists (TCB-2 and WAY-161503) and antagonists (R-96544 and SB-242084) on intracranial self-stimulation (ICSS). In the second study, we examined the effectiveness of TCB-2, WAY-161503, R-96544, and SB-242084 in blocking the reward-facilitating effect of cocaine. In the third study, we examined the effects of intra-medial prefrontal cortex (mPFC), intra-nucleus accumbens (NAC), and intra-ventral tegmental area (VTA) injection of WAY-161503 on the reward-facilitating effect of cocaine.

Results

Acute systemic administration of TCB-2 and WAY-161503 increased ICSS threshold. Systemic WAY-161503 attenuated the reward-facilitating effect of cocaine. This effect was reversed by pretreatment with SB-242084. Intracranial microinjections of WAY-161503 into the mPFC and the NAC shell/core, but not the VTA, attenuated the reward-facilitating effect of cocaine.

Conclusion

These data indicate that 5-HT_2C receptors within the mPFC and the NAC modulate the reinforcing effects of cocaine and provide evidence that 5-HT_2C receptor agonists could be a possible drug discovery target for the treatment of psychostimulant addiction.