Efficacy of cetuximab and panitumumab in oral squamous cell carcinoma cell lines: Prognostic value of MAGE-A subgroups for treatment success

BackgroundOver-expression of epidermal growth factor receptor (EGFR) has been observed in a variety of epithelial tumours. The selective inhibition of the associated signalling pathway using monoclonal antibodies appears to be a promising therapeutic target. Individual differences in response rates, particularly against highly selective chemotherapeutic agents, underline the need for further research of the molecular basis of this process. Previously described resistance mechanisms are not able to explain all refractory responses. Several subgroups of the melanoma-associated antigens (MAGE) tumour antigens were described in connection with regulatory functions relating to the cell cycle and chemosensitivity.MethodsIn the present study, five cell lines of human squamous cell carcinomas were treated with cetuximab and panitumumab (0.01–100 μg/ml) over a period of 24 or 48 h. The efficacy of the agents used was measured dynamically using real-time cell analysis (RTCA). Subsequently, the expression levels of MAGE-A1, -A5, -A8, -A9, -A11 and -A12 were determined by RT-qPCR. A correlation between chemosensitivity and MAGE-A expression was investigated.ResultsThe tumour cell lines exhibited a very low overall response to the chemotherapy drugs. Only one cell line showed a cytostatic effect after treatment with cetuximab and panitumumab. This effect, however, was significant only for panitumumab. The expression of MAGE-A12 was significantly associated with greater efficacy of panitumumab. The expression of MAGE-A5 and -A8 was associated with poorer response rates after panitumumab treatment. Due to an insignificant effect of cetuximab on the number of viable cells, no correlation with the MAGE-A levels was observed.ConclusionFor the first time, these results show a correlation between the efficacies of EGFR inhibitors and various MAGE-A subgroups in the treatment of HNSCC. Determining the MAGE-A status could help to improve the success of anti-tumour drug therapy. In addition, evaluating MAGE-A levels might be an important tool in the development of patient-specific treatment protocols.     

Higher frequency of cagA EPIYA-C Phosphorylation Sites in H. pylori strains from first-degree relatives of gastric cancer patients

ABSTRACT: BACKGROUND: To evaluate the prevalence of more virulent H. pylori genotypes in relatives of gastric cancer patients and in patients without family histories of gastric cancer. METHODS: We evaluated prospectively the prevalence of the infection by more virulent H. pylori strains in 60 relatives of gastric cancer patients comparing the results with those obtained from 49 patients without family histories of gastric cancer. H. pylori status was determined by the urease test, histology and presence of H. pylori ureA. The cytotoxin associated gene (cagA), the cagA-EPIYA and vacuolating cytotoxin gene (vacA) were typed by PCR and the cagA EPIYA typing was confirmed by sequencing. RESULTS: The gastric cancer relatives were significant and independently more frequently colonized by H. pylori strains with higher numbers of CagA-EPIYA-C segments (OR = 4.23, 95%CI = 1.53--11.69) and with the most virulent s1m1 vacA genotype (OR = 2.80, 95%CI = 1.04--7.51). Higher numbers of EPIYA-C segments were associated with increased gastric corpus inflammation, foveolar hyperplasia and atrophy. Infection by s1m1 vacA genotype was associated with increased antral and corpus gastritis. CONCLUSIONS: We demonstrated that relatives of gastric cancer patients are more frequently colonized by the most virulent H. pylori cagA and vacA genotypes, which may contribute to increase the risk of gastric cancer.     

Relationships between reduced heart rate variability and pre-clinical cardiovascular disease in patients with type 2 diabetes

Aims

Reduced heart rate variability (HRV), an early sign of diabetic cardiovascular autonomic neuropathy (CAN), is associated with worse cardiovascular outcomes. The objective was to evaluate relationships between HRV parameters and three pre-clinical cardiovascular disease markers (left ventricular hypertrophy [LVH], aortic stiffness and carotid atherosclerosis) in type 2 diabetes.

Methods

In a cross-sectional study, 313 patients with type 2 diabetes performed 24-h Holter monitoring, carotid ultrasonography (intima-media thickness and plaques measurements), aortic pulse wave velocity measurement and echocardiography (left ventricular mass index [LVMI] measurement). Time-domain HRV parameters were the standard deviation of all normal RR intervals (SDNN), the standard deviation of the averaged normal RR intervals for all 5 min segments (SDANN), the root mean square of differences between adjacent R-R intervals (rMSSD), and the percentage of adjacent R-R intervals that varied by >50 ms (pNN50). Multivariate linear and logistic regressions assessed associations between HRV parameters and the three markers of pre-clinical cardiovascular disease.

Results

Patients with reduced HRV had longer diabetes duration, greater prevalences of microvascular complications, lower physical fitness, and higher heart rate, glycated hemoglobin, albuminuria and LVMI than patients with normal HRV. On multivariate regressions, after adjustments for several confounders, reduced SDNN and SDANN were independently associated with LVH and aortic stiffness. No HRV parameter was associated with carotid atherosclerosis.

Conclusions

Two reduced HRV parameters, SDNN and SDANN, which reflect cardiovascular autonomic imbalance, were associated with LVH and aortic stiffness, markers of pre-clinical cardiovascular disease. These findings may offer insights into physiopathological mechanisms linking CAN to worse cardiovascular prognosis.     

Management of suspected infectious diarrhoea by English GPs: are they right?

Background

The criteria used when GPs submit stool specimens for microbiological investigation are unknown.

Aim

To determine what criteria GPs use to send stool specimens, and if they are consistent with national guidance, and whether GPs would prescribe an antibiotic before they receive a result.

Design and setting

Questionnaire survey of 974 GPs in 172 surgeries in England.

Method

GPs were sent a questionnaire (23 questions) based on national guidance.

Results

Questionnaires were returned by 90% (154/172) of surgeries and 49% (477/968) of GPs. GPs reported sending stool specimens in about 50% of cases of suspected infectious diarrhoea, most commonly because of individual symptoms, rather than public health implications. Fewer considered sampling with antibiotic-associated diarrhoea post hospitalisation, or children with acute, painful, bloody diarrhoea; only 14% mentioned outbreaks as a reason. Nearly one-half of GPs reported they would consider antibiotics in suspected cases of Escherichia coli O157, which is contraindicated. Only 23% of GPs would send the recommended three specimens for ova, cysts, and parasites (OCP) examination. Although 89% of GPs gave some verbal advice on how to collect stool specimens, only 2% of GPs gave patients any written instructions.

Conclusion

GPs need more education to address gaps in knowledge about the risks and diagnosis of different infections in suspected infectious diarrhoea, especially Clostridium difficile post-antibiotics, E. coli O157, and requesting OCPs. Advice on reports, tick boxes, or links to guidance on electronic request forms may facilitate this.     

Overview of reviews: Mechanical interventions for the treatment and management of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by a progressive and non‐reversible airflow limitation and symptoms of breathlessness, sputum production and cough. COPD is the fourth most common cause of mortality worldwide and represents a significant social and economic burden. As such, effective strategies that might be employed to treat COPD and manage symptoms need to be investigated. This overview aimed to summarize the existing evidence available in the Cochrane Library regarding the use of mechanical interventions used for the treatment and management of COPD. Systematic reviews that included adult participants with diagnosed COPD who received a mechanical intervention were included. Five reviews were included, and due to the heterogeneity of these reviews, direct and indirect comparisons of the effects of the intervention were not possible. Instead, data of the effectiveness of each intervention were extracted and summarized in tables and discussed as a narrative summary. Interventions included non‐invasive positive pressure ventilation (NPPV), positive airway pressure (PEP) devices and neuromuscular electrical stimulation (NMES). Evidence regarding the effectiveness of NPPV was limited, and available data do not support the use of NPPV for patients with stable COPD. NPPV might, however, be of benefit as a weaning strategy for intubated patients and for patients experiencing respiratory failure; however, more research is required. Although PEP devices are considered as a safe airway clearance technique, data do not reveal a clear clinical benefit to their use. NMES is also regarded as safe for patients with COPD, and might also be beneficial in improving exercise tolerance and improving quality of life for patients with COPD.