Prevalence and risk factors of trastuzumab induced cardiotoxicity in Tunisian HER2-positive breast cancer patients.

INTRODUCTION: Cardiotoxicity is the most important side effect of Trastuzumab treatment. The purpose of this study is to evaluate the prevalence of Trastuzumab induced cardiotoxicity and to analyze risk factors associated with this side effect. MATERIALS AND METHODS: A retrospective institutional study was carried out from June 2018 to December 2018 at the department of Medical Oncology of Salah Azaiz institute, Tunis, Tunisia. Demographic, clinical characteristics (menopausal status, breast cancer stage, anthracyclines exposure, comorbidities presence…) and left ventricular ejection function (LVEF) measurements, were collected from patient records. RESULTS: Twenty-three women (20%) had Trastuzumab induced cardiotoxicity.65.2% (N = 15) experienced a decrease in LVEF more than 10% with a decrease below normal value and 34.8% (N = 8) experienced a decrease in LVEF more than 20%. Obesity is a risk factor for the occurrence of Trastuzumab induced cardiotoxicity (adjusted odds ratio (OR) = 2.919 (95% confidence interval (CI) [1.0411-8.186]; p = 0.042). CONCLUSION: Our study highlighted that obesity is associated with a high risk of cardiotoxicity in women treated with Trastuzumab. Therefore, close monitoring of cardiac function is recommended especially for obese women during Trastuzumab administering.

Incidence and risk factors associated with development of oxalipatin-induced acute peripheral neuropathy in colorectal cancer patients.

INTRODUCTION: Oxaliplatin utilized in colorectal neoplasms treatment could induce acute peripheral neuropathy (APN) which is a dreadful and frequent adverse event. The objective of this study is to estimate incidence of APN induced by oxaliplatin cumulative incidence in cancer patients colorectal and to describe the distribution of the APN incidence according to demographic and clinical characteristics, as well as according to oxaliplatin cumulative dose. MATERIAL AND METHODS: This is a prospective descriptive study which took place from June to December 2018 at the Salah Azaiz Institute, Tunis. Demographic data, clinical data and data on oxaliplatin administration were collected from patient interview, medical files and pharmaceutical databases. RESULTS: The APN (grade 1, grade 2 and grade 3) cumulative incidence during the period of six months of follow up was 86% (95% CI [0.7815-0.9132]). While 38.3% (95% CI [0.29-0.48]) of the patients had grade 2 or 3 neuropathy. The search for factors associated with the risk of grade 2 and 3 NAP revealed trend significant association with diabetes (adjusted RR = 5.7 (IC95% [0.9- 37.3]; p = 0.07). Moreover, there was significant association with oxaliplatin cumulative dose (≥421 mg/m2) to increase the risk of APN grade 2 and 3 (adjusted RR = 7.8; [2.7-22.7]; p = 0.0001). Furthermore, significant association with obesity to increase the risk of APN grade 2 and 3 (adjusted RR = 5.3 [1.1- 25.4]; p = 0.04) was found. Among the patients included, 31.1% experienced oxaliplatin dose reduction and in the majority of cases this reduction is due to neurotoxicity (90.9%). CONCLUSION: The high incidence of oxaliplatin-induced APN remains an embarrassing and handicapping side effect. Our study has shown that oxaliplatin cumulative dose (≥421 mg/m2), diabetes and obesity are risk factor for the development of grade 2 and 3 APN.

Patterns of complementary and alternative medicine use among Tunisian cancer patients.

INTRODUCTION: The use of complementary and alternative medicine (CAM) among cancer patients is prevalent worldwide as cancer patient are perpetually seeking for a way to improve their quality of life and to cure their disease. Unfortunately, the majority ignore the danger that can resort when they use CAM currently with conventional therapies. The purpose of this study is to assess prevalence and predictors of CAM use in cancer patients. METHODS: Cross-sectional study using a questionnaire administered to cancer patients, who were attending Salah Azaiz institute, Tunis, Tunisia. The study took place from September to December 2018. RESULTS: In 222 cancer patients, the overall prevalence of CAM use was 40.54%. On univariate analysis, patients who had university education level were less likely to use CAM (p = 0.05). Based on multivariate analysis, CAM users had more likely metastatic tumor (p = 0.047; OR = 1.913).It is reported that the majority of the population used herbal medicine. The most common herbal products consuming by patients, included Ephedra foeminea (51.8%), Annona muricata (12%) and Curcuma longa L. (10.84%).The main source of information was entourage (family, friends, hospital entourage) (74.44%).The majority of CAM users (61.11%) reported to consume CAM currently with conventional therapies. CONCLUSION: This survey revealed a high prevalence of CAM use. The most common type of CAM use is herbal products. Some of the used herbal products are known to interact with conventional anticancer medication. This emphasizes the importance of patients disclosure of CAM use to health professionals in order to avoid herb-medications interactions.

Physical and chemical stability of cytarabine in polypropylene syringes.

BACKGROUND: Cytarabine is widely used to treat leukemia and lymphoma. Currently, Cyrabol®, powder for injection, is one of the specialties marketed in Tunisia. However, no stability data when diluted with 0.9% NaCl are available. The aim of this study is to evaluate the physical and chemical stability of cytarabine (Cyrabol®) solution after dilution in 0.9% NaCl (1 mg/mL, 5 mg/mL and 10 mg/mL) in polypropylene syringes under different storage conditions. METHODS: Cytarabine solutions (1 mg/mL, 5 mg/mL and 10 mg/mL) in 0.9% NaCl were prepared in polypropylene syringes and stored for 28 days under different conditions. Cytarabine preparations in glass containers were prepared as a control to detect any adsorption. Chemical stability was assessed by a stability-indicating high-performance liquid chromatography method. The stability-indicating capacity of the method was proved by forced degradation tests. Linearity, precision and limit of detection and quantification were performed according to the International Conference on Harmonisation recommendations. Physical stability was checked by visual inspection. RESULTS: The method was proven to be a validated stability-indicating assay. At 2-8°C, all tested solutions were chemically stable for 28 days. However, at 25°C, the main degradation product gradually increased during the study and the chemical stability of 1 mg/mL, 5 mg/mL and 10 mg/mL solutions was 14 days, 8 days and 5 days, respectively. Similar results were observed in the glass containers. CONCLUSION: The highest physical and chemical stability of cytarabine diluted in 0.9% NaCl in polypropylene syringes was observed at 2-8°C. At 25°C, better stability was found in the 1 mg/mL solution compared with those at higher concentrations (5 mg/mL and 10 mg/mL).

Toxicity, risk factors and management of cisplatin-induced toxicity: A prospective study.

BACKGROUND AND PROPOSE: Cisplatin is a cytotoxic drug that triggers several toxicities. However, nephrotoxicity and ototoxicity remain major clinical limitations. The aim of our study was to evaluate the incidence of chemotherapy toxicity induced by cisplatin and to analyze the influence of risk factors in the Tunisian population. METHODS: We performed a prospective descriptive study in a period of four months. Patients were eligible if they had pathologically confirmed malignancies and treated with cisplatin-regimen chemotherapy. Nephrotoxicity and digestive toxicity were graded according to the World Health Organization toxicity scale and ototoxicity was scored clinically according to the Common Terminology Criteria for Adverse Events (CTCAE). Multivariate logistic regression analysis was performed to evaluate the influence of clinical variables on cisplatin-induced toxicity. RESULTS: A total of 150 patients were included. Forty-four percent of patients developed cisplatin-regimen toxicity: 15% developed cisplatin-induced nephrotoxicity, 9% cisplatin-induced ototoxicity and 27% digestive toxicity. In the multivariate analysis, age >65 years (OR= 6.129, p = 0.010), metastatic cancer (OR = 0.171, p = 0.007) and cumulative dose (OR= 1.004 mg/m2; p = 0.042) were strong predisposing factors for CDDP-induced nephrotoxicity. The cumulative dose was an independent prognostic indicator for digestive toxicity (OR = 0.997, p = 0.002). CONCLUSION: In our study, age >65 years and metastatic cancer were risk factors for cisplatin-induced nephrotoxicities. We also found the correlation between cumulative dose and nephrotoxicity or digestive toxicity.

A new case of 8q22.1 microdeletion restricts the critical region for Nablus mask-like facial syndrome.

Microdeletions of 8q21.3-8q22.1 have been identified in all patients with Nablus mask-like facial syndrome (NMLFS). A recent report of a patient without this specific phenotype presented a 1.6 Mb deletion in this region that partially overlapped with previously reported 8q21.3 microdeletions, thus restricting critical region for this syndrome. We report on another case of an 8q21.3 deletion revealed by array comparative genome hybridization (aCGH) in a 4-year-old child with global developmental delay, autism, microcephaly, but without Nablus phenotype. The size of the interstitial deletion was estimated to span 5.2 Mb. By combining the data from previous reports on 8q21.3-8q22.1 deletions and our case, we were able to narrow the critical region of Nablus syndrome to 0.5 Mb. The deleted region includes FAM92A1, which seems to be a potential candidate gene in NMLFS.

FANCA Gene Mutations in North African Fanconi Anemia Patients.

Populations in North Africa (NA) are characterized by a high rate of consanguinity. Consequently, the proportion of founder mutations might be higher than expected and could be a major cause for the high prevalence of recessive genetic disorders like Fanconi anemia (FA). We report clinical, cytogenetic, and molecular characterization of FANCA in 29 North African FA patients from Tunisia, Libya, and Algeria. Cytogenetic tests revealed high rates of spontaneous chromosome breakages for all patients except two of them. FANCA molecular analysis was performed using three different molecular approaches which allowed us to identify causal mutations as homozygous or compound heterozygous forms. It included a nonsense mutation (c.2749C > T; p.Arg917Ter), one reported missense mutation (c.1304G > A; p.Arg435His), a novel missense variant (c.1258G > A; p.Asp409Glu), and the FANCA most common reported mutation (c.3788_3790delTCT; p.Phe1263del). Furthermore, three founder mutations were identified in 86.7% of the 22 Tunisian patients: (1) a deletion of exon 15, in 36.4% patients (8/22); (2), a deletion of exons 4 and 5 in 23% (5/22) and (3) an intronic mutation c.2222 + 166G > A, in 27.3% (6/22). Despite the relatively small number of patients studied, our results depict the mutational landscape of FA among NA populations and it should be taken into consideration for appropriate genetic counseling.

A Survey of Aedes (Diptera: Culicidae) Mosquitoes in Tunisia and the Potential Role of Aedes detritus and Aedes caspius in the Transmission of Zika Virus.

The present study aimed to update the list of Aedes mosquito species occurring in Tunisia and to test the vector competence of Aedes (Ochlerotatus) caspius (Pallas) and Ae. (Ochlerotatus) detritus (Haliday), the locally most abundant and widespread species, to transmit Zika virus (ZIKV). In 2017-2018, mosquito larvae were collected from 39 different larval habitats in seven bioclimatic zones of Tunisia. The salinity and pH of each breeding site were measured. The survey revealed the presence of 10 Aedes species in Tunisia: Ae. (Stegomyia) albopictus (Skuse), Ae. (Ochlerotatus) berlandi (Séguy), Ae. caspius, Ae. detritus, Ae. (Finlaya) echinus (Edwards), Ae. (Finlaya) geniculatus (Olivier), Ae. (Acartomyia) mariae (Sergent and Sergent), Ae. (Ochlerotatus) pulcritarsis (Rondani), Ae. (Aedimorphus) vexans (Meigen), and Ae. (Fredwardsius) vittatus (Bigot). Of these 10 species, Ae. caspius and Ae. detritus were the most abundant in Tunisia. Aedes detritus and Ae. caspius larvae were reared until the imago stage under insectary conditions to test autogeny. The study showed that Ae. detritus is autogenous and stenogamous and Ae. caspius, anautogenous and eurygamous. Finally, the collected strains of these two species were experimentally infected with the Asian genotype of ZIKV, originally isolated from a patient in April 2014 in New Caledonia, to test their vector competence. Neither of these species was able to transmit ZIKV at 7 and 14 d postexposure. Further investigations are needed to test the competence of other Tunisian mosquito species that may be associated with ZIKV transmission.

Potential of Aedes albopictus to cause the emergence of arboviruses in Morocco.

In 2015, the mosquito Aedes albopictus was detected in Rabat, Morocco. This invasive species can be involved in the transmission of more than 25 arboviruses. It is known that each combination of mosquito population and virus genotype leads to a specific interaction that can shape the outcome of infection. Testing the vector competence of local mosquitoes is therefore a prerequisite to assess the risks of emergence. A field-collected strain of Ae. albopictus from Morocco was experimentally infected with dengue (DENV), chikungunya (CHIKV), zika (ZIKV) and yellow fever (YFV) viruses. We found that this species can highly transmit CHIKV and to a lesser extent, DENV, ZIKV and YFV. Viruses can be detected in mosquito saliva at day 3 (CHIKV), day 14 (DENV and YFV), and day 21 (ZIKV) post-infection. These results suggest that the local transmission of these four arboviruses by Ae. albopictus newly introduced in Morocco is a likely scenario. Trial registration: ClinicalTrials.gov APAFIS#6573-201606l412077987v2.

Chromosomal abnormalities in 163 Tunisian couples with recurrent miscarriages.

Recurrent miscarriage (RM) is defined as three or more consecutive pregnancy losses before 24 weeks of gestation. Parental chromosomal abnormalities represent an important etiology of RM. The aim of the present study was to identify the distribution of chromosome abnormalities among Tunisian couples with RM referred to the Department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia) during the last five years. Standard cytogenetic analysis was carried out in a total of 163 couples presenting with two or more spontaneous abortions. Karyotypes were analyzed by R-banding. We identified 14 chromosomal abnormalities including autosomal reciprocal translocation, Robertsonian translocation, inversion, mosaic aneuploidy and heteromorphysm. The overall prevalence of chromosomal abnormalities was 8.5% in our cohort. This finding underlies the importance of cytogenetic investigations in the routine management of RM.

Cytogenetic abnormalities in Tunisian women with premature ovarian failure.

To identify the distribution of chromosome abnormalities among Tunisian women with premature ovarian failure (POF) referred to the department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia), standard cytogenetic analysis was carried out in a total of 100 women younger than 40 affected with premature ovarian failure. We identified 18 chromosomal abnormalities, including seven X-numerical anomalies in mosaic and non-mosaic state (45,X; 47,XXX), four sex reversal, three X-structural abnormalities (terminal deletion and isochromosomes), one autosomal translocation and one supernumerary marker. The overall prevalence of chromosomal abnormalities was 18% in our cohort. X chromosome aneuploidy was the most frequent aberration. This finding confirms the essential role of X chromosome in ovarian function and underlies the importance of cytogenetic investigations in the routine management of POF.

Prevalence of Y chromosome microdeletions in infertile Tunisian men.

Yq microdeletions are the leading genetic cause of male infertility and its detection in clinically relevant for appropriate genetic counseling. The objective of this study was to determine the frequency of Y microdeletion in a group of Tunisian infertile men and to compare the prevalence of these abnormalities with other countries and other Tunisian reported series. Totally, 105 Tunisian idiopathic infertile men (74 azoospermic and 31 severe oligozoospermic) were screened for the presence of Y chromosome microdeletions. The screening of Yq microdeletions was performed by two multiplex PCRs using six STS markers recommended by the EAA/EMQN. No microdeletions were detected in the men with severe oligozoospermia. In the azoospermic group, 2/74 (2.7%) patients showed Y chromosome microdeletions. Both had complete deletion of the AZFc region. No microdeletion was identified in the AZFa region or in the AZFb region. The estimated frequency of Y chromosome microdeletions in the present survey was similar to some other reports but lower than that of previous reports in Tunisian populations.

Chromosomal evaluation in a group of Tunisian patients with non-obstructive azoospermia and severe oligozoospermia attending a Tunisian cytogenetic department.

Male infertility is the cause in half of all childless partnerships. Numerous factors contribute to male infertility, including chromosomal aberrations and gene defects. Few data exist regarding the association of these chromosomal aberrations with male infertility in Arab and North African populations. We therefore aimed to evaluate the frequency of chromosomal aberrations in a sample of 476 infertile men with non-obstructive azoospermia (n=328) or severe oligozoospermia (n=148) referred for routine cytogenetic analysis to the department of cytogenetics of the Pasteur Institute of Tunis. The overall incidence of chromosomal abnormalities was about 10.9%. Out of the 52 patients with abnormal cytogenetic findings, sex chromosome abnormalities were observed in 42 (80.7%) including Klinefelter syndrome in 37 (71%). Structural chromosome abnormalities involving autosomes (19.2%) and sex chromosomes were detected in 11 infertile men. Abnormal findings were more prevalent in the azoospermia group (14.02%) than in the severe oligozoospermia group (4.05%). The high frequency of chromosomal alterations in our series highlights the need for efficient genetic testing in infertile men, as results may help to determine the prognosis, as well as the choice of an assisted reproduction technique. Moreover, a genetic investigation could minimize the risk of transmitting genetic abnormalities to future generations.

Differentiation of Fanconi anemia and aplastic anemia using mitomycin C test in Tunisia.

Fanconi anemia (FA) is a recessive chromosomal instability syndrome that is clinically characterized by multiple symptoms. Chromosome breakage hypersensitivity to alkylating agents is the gold standard test for FA diagnosis. In this study, we provide a detailed laboratory protocol for accurate assessment of FA diagnosis based on mitomycin C (MMC) test. Induced chromosomal breakage study was successful in 171 out of 205 aplastic anemia (AA) patients. According to the sensitivity of MMC at 50 ng/ml, 38 patients (22.22%) were diagnosed as affected and 132 patients (77.17%) as unaffected. Somatic mosaicism was suspected in an 11-year-old patient with a FA phenotype. Twenty-six siblings of FA patients were also evaluated and five of them (19.23%) were diagnosed as FA. From this study, a standard protocol for diagnosis of FA was developed. It is routinely used as a diagnostic test of FA in Tunisia.