Managing children with chronic myeloid leukaemia (CML)

Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long‐term use of treatment, pose specific challenges in this age group, which we are only beginning to understand.     

Pharmacological and dietary prevention for colorectal cancer

Background

Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. People at higher risk are those individuals with a family history of CRC and familial adenomatous polyposis. Prevention and screening are two milestones for this disease. The aim of this study is to evaluate the chemopreventive role of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclooxygenase 2 inhibitors, some micronutrients (folic acid, calcium, selenium, antioxidants) and probiotics.

Discussion

The studies on aspiring reported promising results, but it is debatable whether aspirin should be used as chemoprevention, because of its side effects and because of poor efficacy evident in subjects at high risk. Similar results were reported for other non-aspirin NSAIDs, such as sulindac and celecoxib, which the potential adverse effects limit their use. Selenium role in prevention of various types of cancer as well as in colon adenomas are often inconclusive or controversial. Several studies suggested that calcium may have a possible chemopreventive effect on colon adenomas and CRC, although contrasting results are reported for the latter. A recent meta-analysis including 13 randomized trial suggested that folic acid supplementation had not a chemiopreventive action on CRC. Several studies investigated the association between antioxidants, administered alone or in combination, and CRC risk, both among general and at risk population, but only few of them supported statistically significant results.

Conclusion

The results of this literature review showed an unclear role in CRC prevention of both pharmacological and dietary intervention. Despite several options are available to prevent colon cancer, it is challenging to identify a correct strategy to prevent CRC through pharmacological and dietary intervention due to the long latency of cancer promotion and development. Since some of the drugs investigated may have uncertain individual effects, it can be suggested to potentiate such effects by adding them together.

     

Social disparities,health risk behaviors,and cancer

Background

Overall cancer incidence rates decreased in the most recent time period in both men and women, largely due to improvements in surgical therapeutic approaches (tertiary prevention) and screening programs (secondary prevention), but differences in cancer incidence and survival according to socioeconomic status are documented worldwide. Health risk behaviors, defined as habits or practices that increase an individual’s likelihood of harmful health outcomes, are thought to mediate such inequalities.

Discussion

Obesity has been related with increased cancer incidence and mortality due to imbalance of leptin and adiponectin which are connected to activation of PI3K, MAPK, and STAT3 pathways and decreasing insulin/insulin-like growth factor (IGF)-1 and mTOR signaling via activation of 5 AMP-activated protein kinase (AMPK), respectively. Physical activity has been associated to prevent cancer by the aforementioned obesity-related mechanisms, but also increasing level of circulating vitamin D, which has been related to lower risk of several cancers, and increasing prostaglandin F2a and reducing prostaglandin E2, which are both related with cancer prevention and promotion, respectively. A large number of different substances may induce themselves a direct cytotoxicity and mutagenic action on cells by smoking, whereas alcohol promote immune suppression, the delay of DNA repair, inhibition of the detoxification of carcinogens, the production of acetaldehyde, and the contribution to abnormal DNA methylation. The combined smoking and alcohol drinking habits have been shown to increase cancer risk by smoke action of increasing the acetaldehyde burden following alcohol consumption and alcohol action of enhancing the activation of various procarcinogens contained in tobacco smoke.

Conclusions

Interventions at the social level may be done to increase awareness about cancer risks and promote changing in unhealthy behaviors.

     

Deep transcranial magnetic stimulation as a treatment for psychiatric disorders: A comprehensive review

Deep transcranial magnetic stimulation (TMS) is a technique of neuromodulation and neurostimulation based on the principle of electromagnetic induction of an electric field in the brain. The coil (H-coil) used in deep TMS is able to modulate cortical excitability up to a maximum depth of 6 cm and is therefore able not only to modulate the activity of the cerebral cortex but also the activity of deeper neural circuits. Deep TMS is largely used for the treatment of drug-resistant major depressive disorder (MDD) and is being tested to treat a very wide range of neurological, psychiatric and medical conditions. The aim of this review is to illustrate the biophysical principles of deep TMS, to explain the pathophysiological basis for its utilization in each psychiatric disorder (major depression, autism, bipolar depression, auditory hallucinations, negative symptoms of schizophrenia), to summarize the results presented thus far in the international scientific literature regarding the use of deep TMS in psychiatry, its side effects and its effects on cognitive functions.     

Coronary flow limits right ventricular performance during positive end-expiratory pressure

The effect of positive end-expiratory pressure (PEEP) on right ventricular performance and myocardial blood flow was determined in 16 dogs before and after right coronary artery (RCA) occlusion. Right ventricular ejection fraction (RVEF), end-diastolic volume (EDV) and end-ejection volume were measured by thermodilution. Right ventricular end-ejection pressure-volume relations (RVEEPVR) were determined at baseline and at 20 cm H2O PEEP, both before and after RCA occlusion. In four of the dogs, RVEEPVR were also determined at 10 cm H2O PEEP after RCA occlusion. With intact RCA flow, RVEF declined with PEEP (37 +/- 5 to 19 +/- 6%) with no significant change in EDV (50 +/- 11 to 42 +/- 11 ml) or end-ejection volume (31 +/- 7 to 36 +/- 9 ml). RVEEPVR and right ventricular myocardial blood flow were also unchanged with PEEP. After RCA occlusion, RVEF declined with PEEP (27 +/- 4 to 15 +/- 5%) in association with a significant increase in end-ejection volume (39 +/- 8 to 49 +/- 10 ml), but no change in EDV (53 to 55 ml). In addition, RVEEPVR and myocardial blood flow declined with RCA occlusion, and declined further with 20 cm H2O, but not with 10 cm H2O PEEP, after RCA occlusion. Therefore, in this experimental model, right ventricular performance was adversely affected during PEEP when right coronary blood flow was limited.     

Conversion of the interleukin 1 receptor antagonist into an agonist by site-specific mutagenesis.

Interleukin 1 (IL-1) receptor antagonist (IL-1ra) is a naturally occurring protein that binds to the IL-1 receptor present on T cells, fibroblasts, and other cell types and acts to block IL-1-induced responses. IL-1ra is a pure antagonist and has no agonist activity in in vitro or in vivo systems. By site-specific mutagenesis, an analog of IL-1ra was created that contained a substitution of a single amino acid, Lys-145----Asp. This analog, IL-1ra K145D, exhibited partial agonist activity in the D10.G4.1 cell proliferation assay. The newly acquired agonist activity could not be neutralized by antisera to IL-1 alpha or IL-1 beta, but it could be blocked by a monoclonal antibody to the T-cell IL-1 receptor. The analog also showed agonist activity as assayed by increased prostaglandin E2 synthesis from CHO cells expressing recombinant mouse IL-1 receptor. These results with IL-1ra K145D demonstrate the importance of the region surrounding the corresponding Asp-145 residue in IL-1 beta for triggering the biological response to IL-1.     

Evaluation of four comorbidity indices and Charlson comorbidity index adjustment for colorectal cancer patients

Introduction

Cancer survival is related not only to primary malignancy but also to concomitant nonmalignant diseases. The aim of this study was to investigate the prognostic capacity of four comorbidity indices [the Charlson comorbidity index (CCI), the Elixhauser method, the National Institute on Aging (NIA) and National Cancer Institute (NCI) comorbidity index, and the Adult Comorbidity Evaluation-27 (ACE-27)] for both cancer-related and all-cause mortality among colorectal cancer patients. A modified version of the CCI adapted for colorectal cancer patients was also built.

Methods

The study population comprised 468 cases of colorectal cancer diagnosed between 1 January 2000 and 31 December 2010 at a community hospital. Data were prospectively collected and abstracted from patients’ clinical records. Kaplan-Meier method and multivariate logistic regression models were performed for survival and risk of death analysis.

Results

Only moderate or severe renal disease [hazard ratio (HR) 2.71, 95 % confidence interval (CI) 1.11–6.63] and AIDS (HR 3.27, 95 % CI 1.23–8.68) were independently associated with cancer-specific mortality, with a population attributable risk of 5.18 and 4.36 %, respectively. For each index, the highest comorbidity burden was significantly associated with poorer overall survival (NIA/NCI: HR 2.14, 95 % CI 1.14–4.01; Elixhauser: HR 1.98, 95 % CI 1.09–1.42; ACE-27: HR 1.78, 95 % CI 1.07–1.23; CCI: HR 1.68, 95 % CI 1.05–1.42) and cancer-specific survival. The modified version of the CCI resulted in a higher predictive power compared with other indices studied (cancer-specific mortality HR?=?2.37, 95 % CI 1.37–4.08).

Conclusions

The comorbidity assessment tools provided better prognostic prevision of prospective outcome of colorectal cancer patients than single comorbid conditions.