A clinical phase II study of a non-anthracycline sequential combination of cisplatin-vinorelbine followed by docetaxel as first-line treatment in metastatic breast cancer

BACKGROUND: We tested a sequential combination regimen using cisplatin and vinorelbine (PVn) followed by docetaxel as first-line chemotherapy in a phase II clinical trial in metastatic breast cancer (MBC). PATIENTS AND METHODS: Thirty-five patients were enrolled. Cisplatin 80 mg/m(2) was given on day 1 and vinorelbine 30 mg/m(2) on days 1 and 8 every 3 weeks for 4 cycles. Responding patients received docetaxel 75 mg/m(2) every 21 days for a maximum of 4 cycles. Three patients were excluded from analysis because of death unrelated to treatment. RESULTS: After a median follow-up of 14 months, 32 patients completed the study. The overall response rate was 53.1%. Complete remission was seen in 5 patients (15.6%), partial response in 12 (37.5%), stable disease in 6 (18.75%), and progressive disease in 9 patients (28.1%). Median time to disease progression was 8 months (range 1-24). At 24 months, 12 (37.5%) patients were alive. A total of 183 cycles were administered. Febrile neutropenia was observed in 4 patients (2.2%). Grade II nephrotoxicity occurred in 12 cycles (6.5%) and grade III vomiting in 31/183 cycles (16.9%). DISCUSSION: PVn is a feasible non-anthracycline option as first-line chemotherapy in patients with metastatic breast cancer and has acceptable toxicity. The sequential addition of 4 cycles of docetaxel following 4 cycles of PVn did not improve the overall response rate and results.     

A genome wide SNP genotyping study in the Tunisian population: specific reporting on a subset of common breast cancer risk loci

Background

Breast cancer is the most common cancer in women worldwide. Around 50% of breast cancer familial risk has been so far explained by known susceptibility alleles with variable levels of risk and prevalence. The vast majority of these breast cancer associated variations reported to date are from populations of European ancestry. In spite of its heterogeneity and genetic wealth, North-African populations have not been studied by the HapMap and the 1000Genomes projects. Thus, very little is known about the genetic architecture of these populations.

Methods

This study aimed to investigate a subset of common breast cancer loci in the general Tunisian population and to compare their genetic composition to those of other ethnic groups. We undertook a genome-wide haplotype study by genotyping 135 Tunisian subjects using the Affymetrix 6.0-Array. We compared Tunisian allele frequencies and linkage disequilibrium patterns to those of HapMap populations and we performed a comprehensive assessment of the functional effects of several selected variants.

Results

Haplotype analyses showed that at risk haplotypes on 2p24, 4q21, 6q25, 9q31, 10q26, 11p15, 11q13 and 14q32 loci are considerably frequent in the Tunisian population (>?20%). Allele frequency comparison showed that the frequency of rs13329835 is significantly different between Tunisian and all other HapMap populations. LD-blocks and Principle Component Analysis revealed that the genetic characteristics of breast cancer variants in the Tunisian, and so probably the North-African populations, are more similar to those of Europeans than Africans.Using eQTl analysis, we characterized rs9911630 as the most strongly expression-associated SNP that seems to affect the expression levels of BRCA1 and two long non coding RNAs (NBR2 and LINC008854). Additional in-silico analysis also suggested a potential functional significance of this variant.

Conclusions

We illustrated the utility of combining haplotype analysis in diverse ethnic groups with functional analysis to explore breast cancer genetic architecture in Tunisia. Results presented in this study provide the first report on a large number of common breast cancer genetic polymorphisms in the Tunisian population which may establish a baseline database to guide future association studies in North Africa.

     

Effects of barium graded doses on redox status,membrane bound ATPases and histomorphological aspect of the liver in adult rats

Nowadays, liver diseases constitute a major health problem in the world. The objective of the present study was to elucidate the hepatotoxicity induced by barium chloride (BaCl₂) administered at graded doses in order to evaluate redox state and membrane-bound ATPases in the liver of adult rats. Our results showed, after 21 days of treatment with barium at doses 67 150 and 300?ppm, an increase in hepatic biomarkers such as AST, ALT and GGT activities and in bilirubin and albumin levels. A significant increase in MDA, LOOHs, H₂O₂, AOPP and PCO levels in liver of treated rats with graded doses of BaCl₂ was also observed suggesting the implication of oxidative stress with a significant relation between dose and response. Moreover, LDH activity increased in plasma and decreased in liver of all treated groups. Antioxidant activities of glutathione peroxidase and catalase decreased, especially with the highest dose of barium, indicating a failure of antioxidant system defense. Additionally, the activities of Na⁺K⁺-ATPase and Mg²⁺-ATPase significantly decreased in all treated groups. Our biochemical findings were supported by histological observations. These results highlight the subchronic hepatotoxicity of barium.     

Origin of a signal intensity loss artifact in fat-saturation MR imaging

Artifactual water signal intensity loss can be observed on fat-saturation magnetic resonance (MR) images of inhomogeneous regions such as the thorax. Magnetic effects of air inclusions on fat-saturation pulses were investigated as the possible origin of this artifact. Computer simulation results agreed well with observed production of water saturation by means of nominal fat suppression in MR imaging of phantoms and a representative clinical example.     

Synthesis of oxadiazoline and quinazolinone derivatives and their biological evaluation as nitric oxide synthase inhibitors

The synthesis of two new families of compounds with oxadiazoline and quinazolinone structures and their in vitro biological evaluation as inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS) are described. These derivatives have been obtained from cyclization of substituted benzohydrazides with acid anhydrides followed by reduction, using different synthetic procedures. Their structures were confirmed by high-resolution mass spectroscopy and ¹H and ¹³C nuclear magnetic resonance data. In general, the assayed compounds show better inhibition values of nNOS than of iNOS, being 7d the most active derivative with a quinazolinone scaffold, and 6t the best oxadiazoline one and the best nNOS inhibitor of all tested compounds. The structure–activity relationships are discussed in terms of the effects of the substituents on both 2- and 3-positions of the heterocyclic rings.     

Toxicity of Fe<Subscript>3</Subscript>O<Subscript>4</Subscript> nanoparticles on oxidative stress status,stromal enzymes and mitochondrial respiration and swelling of <Emphasis Type="Italic">Oryctolagus cuniculus</Emphasis> brain cortex

Fe₃O₄ nanoparticles are the most widely used metal oxide nanoparticles especially, in biomedical applications. Although, nanoparticles can enter to the different organs, little is known so far on the neurotoxic potential and oxidative stress of Fe₃O₄. Here the understanding of the effect of Fe₃O₄ nanoparticles on the general Redox state of rabbit brain and the effect on mitochondrial swelling and respiration were assessed. Fe₃O₄ resulted in increase of brain markers, lipid peroxidation, protein and ROS formation. Mitochondrial enzymes and swelling were elevated with decreased respiration level. Caspase 3 activity and TNF-α level were also increased. Finally, our study suggested that the mitochondrial disease and dysfunction with elevated oxidative stress in rabbit brain treated with 200 and 300 μg/kg per Os is the original of neurotoxicity and maybe the original cause of neurodegenerative disease.     

Pediatric respiratory tract diseases: Chronological trends and perspectives

Background

The aim of this study was to describe the epidemiological profile of childhood respiratory tract diseases (RTD) in the region of Sfax, Tunisia, and to evaluate their trends over a 13 year period.

Methods

We conducted a retrospective study of all children hospitalized with RTD aged under 14 years. We collected data from the regional morbidity register of the university hospital of Sfax from 2003 to 2015.

Results

A total of 10 797 RTD patients were enrolled from 49 880 pediatric hospitalizations (21.7%). A male predominance was noted (60%). The median age was 8 months (IQR, 2–36 months). Acute bronchitis (AB) accounted for 53.8%, followed by asthma (15%), pneumonia (14%) and acute upper respiratory infection (AURI; 7.2%). The hospital incidence rate (HIR) of RTD was 34/10 000 inhabitants/year. It was 18.2; 5.07; 4.7 and 2.4/10 000 inhabitants for AB, asthma, pneumonia and AURI, respectively. We noted a significant increase in the HIR of RTD with an annual percentage change (APC) of 10.94% (P < 0.001); in the HIR of AB (APC, 5.27%; P < 0.001); and in asthma HIR (APC, 11.2%; P < 0.001). Otherwise, a significant decrease in AURI HIR was observed (APC, –8.8%; P < 0.001). AB lethality rate increased significantly, with an APC of 7.4% (P < 0.001). Projected trends analysis up to 2024 showed a significant rise in AB and in asthma, while AURI would significantly decrease.

Conclusions

RTD continues to be a serious health problem over time in terms of morbidity and mortality. Preventive and curative strategies are needed urgently.