Novel and recurrent BRCA1/BRCA2 germline mutations in patients with breast/ovarian cancer: a series from the south of Tunisia.

BACKGROUND: The incidence of breast cancer (BC) and/or ovarian cancer (OC) is increasing in Tunisia especially in young women and mostly those with family history. However, the spectrum of BRCA mutations remains little explored in Tunisian patients in particular in the southern region. METHODS: We sequenced the entire coding regions of BRCA1and BRCA2 genes using next generation sequencing (NGS) in 134 selected patients with BC and/or OC. RESULTS: Among the 134 patients, 19 (14.17%) carried pathogenic mutations (10 are BRCA1 mutation carriers and 9 are BRCA2 mutation carriers) that are mainly frameshift index (76.9%). Interestingly, 5 out of the 13 variants (38.46%) were found at least twice in unrelated patients, as the c.1310-1313 delAAGA in BRCA2 and the c.5030_5033 delCTAA that has been identified in 4/98 BC patients and in 3/15 OC patients from unrelated families with strong history of cancer. Besides recurrent mutations, 6 variant (4 in BRCA1 and 2 in BRCA2) were not reported previously. Furthermore, 3 unrelated patients carried the VUS c.9976A > T, (K3326*) in BRCA2 exon 27. BRCA carriers correlated significantly with tumor site (p = 0.029) and TNBC cases (p = 0.008). In the groups of patients aged between 31 and 40, and 41-50 years, BRCA1 mutations occurred more frequently in patients with OC than those with BC, and conversely BRCA2 carriers are mostly affected with BC (p = 0.001, and p = 0.044 respectively). CONCLUSIONS: The overall frequency of the BRCA germline mutations was 14.17% in patients with high risk of breast/ovarian cancer. We identified recurrent mutations as the c.1310_1313 delAAGA in BRCA2 gene and the c.5030_5033 delCTAA in BRCA1 gene that were found in 4% and 20% of familial BC and OC respectively. Our data will contribute in the implementation of genetic counseling and testing for families with high-risk of BC and/or OC.

Tuberculosis and non-pulmonary malignancies : study of ten cases.

INTRODUCTION: Tuberculosis (TBC) is a major public health problem with high mortality especially in developing countries. It is associated with a higher risk of developing pulmonary and non-pulmonary malignancies including solid and hematologic cancers. Association between TBC and nonpulmonary malignancies is rarely described in the literature. AIM: To describe the epidemiological, clinical, therapeutic modalities and the evolutive aspects of patients treated for cancer and TBC. METHODS: This is a retrospective study conducted over a period of 19 years (between 1993 and 2012), including 10 patients followed up for cancer and tuberculosis at the department of oncology and the department of infectious disease, CHU Habib Bourguiba Hospital and CHU HediChaker, Sfax, Tunisia. RESULTS: The average age of patients was 55 years old. The sex ratio was 1. The different locations of cancer were represented by the breast (4 cases), the nasopharynx (1 case), the colon (1 case), the kidney (1 case) the gum (1 case), the endometrium (1 case) and the blood (1 case).TBC and cancer were synchronous in 5 cases. Concerning the metachronous presentation that interested 5 patients, the average time betweenthe onset of TBC after cancer diagnosis was 3.5 years. Three of these patients were treated by chemotherapy with radiation therapy. TBClocalization was nodal in 6 cases, spinal one case, nasopharyngeal in one case, peritoneal in one case and urogenital in one case. The diagnosisof TBC was made incidentally in two cases during axillary lymph node dissection. The therapeutic management of cancer was based on surgery,chemotherapy and / or radiotherapy. All patients received anti TBC treatment for at least six months. Surgery was indicated in one case(laminectomy). A complete remission of cancer was observed in 9 patients. Concerning TBC, recovery was observed in 8 patients, 1 patient hada spinal recurrence and 1 patient is being treated. CONCLUSION: Chronic inflammation during TBC can lead to cancer development. The etiopathogenesis of this association is still imperfectly known. Association between TBC and non-pulmonary cancer, although rare, should be always kept in mind in order to handle in time these two diseases in order provide the best chances of recovery for patients.

[Tunisian National Protocol for Adult Hodgkin's Lymphoma Treatment: Results of a therapeutic regimen adapted to the 2-cycle CT response, about 444 patients]. / Protocole national Tunisien prospectif de traitement du Lymphome de Hodgkin de l'adulte : résultats d'un schéma thérapeutique adapté à la réponse par tomodensitométrie à 2 cycles, à propos de 444 patients.

OBJECTIVE: In Tunisia, the management of Adult Hodgkin's Lymphoma (HL) has been standardized since 1999. We propose in this study to report the therapeutic results of the national protocol of adult HL treatment (MDH2008). PATIENTS AND METHODS: Our study is prospective multicenter interesting 444 patients followed for HL between July 2008 and June 2013 and treated according to the MDH2008 protocol. The median age of our patients was 30 years. B symptoms were present in 62.8 % of our patients. According to the Ann Arbor classification, our patients were in stages I, II, III and IV in 3 %, 42 %, 26 % and 29 %, respectively. The MDH2008 protocol is based on a strategy adapted to the therapeutic response to 2 cycles of chemotherapy. RESULTS: Response≥75 % to 2 courses of chemotherapy was achieved in 43 % of patients and the response rate at the end of treatment was 92.1 %. Forty-eight patients (11.4 %) had primary failure. In the multi-variant study, bulky mediastinal mass (IMT≥0.35) was an independent predictive factor of primary failure (P: 0.000). Nineteen toxic deaths (4.35 %) were reported. The relapse rate was 7.8 %. Event free survival, relapse-free survival and overall survival at 5years were 75 %, 89 % and 90 %, respectively. Adaptation of the treatment to the 2 cycles response was effective in unfavorable early stages and advanced stages. CONCLUSION: Compared to MDH2002 (second version of Tunisian prospective protocol), the MDH2008 reduced the primary failure rate, the rate of toxic deaths with escalated BEACOPP and the rate of relapse in Tunisian patients.

[Neoadjuvant chemotherapy with concurrent chemoradiotherapy in the treatment of nasopharyngeal cancer: Southern Tunisian experience]. / La chimiothérapie néoadjuvante associée à la chimioradiothérapie concomitante dans le traitement du cancer du nasopharynx : expérience du Sud-Tunisien.

PURPOSE: A retrospective study to evaluate the efficacy and safety of the addition of neoadjuvant chemotherapy to concurrent chemoradiotherapy in the treatment of nasopharyngeal carcinoma. PATIENTS AND METHODS: Data from 62 patients treated for non-metastatic nasopharyngeal carcinoma were analyzed by comparing two groups of patients: a first group of 32 patients treated with 3 cycles of neoadjuvant chemotherapy based on docetaxel, cisplatin and 5-fluoro-uracil every 21 days followed by concurrent chemoradiotherapy (weekly cisplatin 40mg/m2 with radiotherapy 70Gy, 2Gy per session, 5 sessions per week) and a second group of 30 patients treated with the same concurrent chemoradiotherapy. RESULTS: After a median follow-up of 53.5 months, neoadjuvant chemotherapy showed a significant reduction in the rate of a distant metastatic relapses (3.3% vs. 10%, P=0.03). No significant difference in disease-free survival at 5 years (65.6% vs. 68.8%, P=0.46) or overall survival at 5 years (68.8% vs. 73.3%, P=0.46) was noted between the two groups. Induction chemotherapy was associated with febrile neutropenia of 15.6%. During concurrent chemoradiotherapy, hematological complications were greater in the first chemotherapy group (53% vs. 33%). CONCLUSION: Induction chemotherapy by docetaxel, cisplatin and 5-fluoro-uracil is a safe and effective option in the treatment of nasopharyngeal carcinoma. A better definition of high risk of relapse group would optimize the indications of this chemotherapy in the therapeutic arsenal.

An exceptional evolution of primary peritoneal serous carcinoma.

Primary peritoneal serous carcinoma (PPSC) is a rare malignancy of the peritoneum. Clinically and histopathologically, PPSC is similar to serous ovarian papillary carcinoma. Brain metastases (BM) from PPSC are exceedingly rare. We report here a new case of BM two years after complete remission from a PPSC, to make aware physicians about this entity. This case is exceptional; firstly given the rarity of this entity and secondly due to the good response after radiotherapy then systemic chemotherapy with Carboplatin and Paclitaxel.

Ewing's sarcoma of the cranial vault: a case report.

Ewing's sarcoma is a malignant tumor that mainly affects young patients. It represents 10% of primary malignant tumors of the bone and 3% of malignant tumors of the child. Cranial localization is extremely rare representing less than 1% of all the localizations. We report a case of a 10-year-old girl who presented with an intracranial hypertension syndrome with left parietal mass of progressive installation. The X-ray skull showed a lytic lesion with irregular margins involving the left parietal bone. Brain magnetic resonance imaging revealed extensive parietal bone destruction involving both the inner and outer tables. The girl was operated in emergency. Histological examination concluded to Ewing's Sarcoma. The resection was incomplete (R1). The girl received induction's chemotherapy. The cerebral scanner evaluation showed no abnormalities. Then, she received consolidation's chemotherapy with concomitant local radiation therapy. Currently, the girl is in complete remission with a seven-month decline.

A Review of Ewing Sarcoma Treatment: Is it Still a Subject of Debate?

BACKGROUND: The Ewing sarcoma (ES) represents 10 to 15% malignant bone tumors and 40 to 45% pediatric malignant bone tumors. The aim of this review is to clarify the therapeutic results and prognostic factors of this entity. METHODS: A systematic review of the literature was performed. Studies focused on the management of ES were considered for inclusion. RESULT: ES represents a model of multidisciplinary approach. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between the pediatric and medical oncologists. The overall 5- year survival of Ewing localized tumors was 70% versus 30% in metastatic ES. CONCLUSION: The treatment of ES includes neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The role of high-dose chemotherapy is still debated.

Cardiac metastases: 4 cases report.

Cardiac metastases are rare. They are found in one to 10% of autopsies of patients withmalignant neoplasm. Adenocarcinoma represents the most common histologicaltype. The most common neoplasms that metastasize to the heart are lung andbreast cancers, melanoma, mesothelioma and lymphoma. However, Cardiacinvolvement is unusual in Hepatic, cutaneous and gastric cancer. We reportedthese three primary localizations in our cases.

CpG methylation of APC promoter 1A in sporadic and familial breast cancer patients.

Tumour suppressor gene (TSG) silencing through promoter hypermethylation plays an important role in cancer initiation. The aim of this study was to assess the extent of methylation of APC gene promoter in 91 sporadic and 44 familial cases of Tunisian patients with breast cancer (BC) in. The frequency of APC promoter methylation is somewhat similar for sporadic and familial breast cancer cases, (52.1%, and 54.5% respectively). For sporadic breast cancer patients, there was a significant correlation of APC promoter hypermethylation with TNM stage (p = 0.024) and 3-year survival (p = 0.025). Regarding the hormonal status (HR), we found significant association between negativity to PR and unmethylated APC (p= 0.005) while ER and Her2/neu are not correlated. Moreover, unmethylated APC promoter is more frequent in tumours expressing at least one out the 3 proteins compared to triple negative cases (p= 0.053). On the other hand, aberrant methylation of APC was associated with tumour size (p = 0.036), lymph node (p = 0.028), distant metastasis (p = 0.031), and 3-year survival (p = 0.046) in the group of patients with familial breast cancer. Moreover, patients with sporadic breast cancer displaying the unmethylated profile have a significant prolonged overall survival compared to those with the methylated pattern of APC promoter (p log rank = 0.008). Epigenetic change at the CpG islands in the APC promoter was associated with the silence of its transcript and the loss of protein expression suggesting that this event is the main mechanism regulating the APC expression in breast cancer. In conclusion, our data showed that the loss of APC through aberrant methylation is associated with the aggressive behavior of both sporadic and familial breast cancer in Tunisian patients.

Primary Gingival Melanoma: An Important Entity.

Primary melanoma of the mandibular gingiva is extremely rare. It is often misinterpreted as a benign pigmented process. The prognosis of this entity is very poor. We report here the first case of primary gingival melanoma described in the Tunisian literature about a 55-year-old smoker having cerebral and pulmonary metastases from gingival melanoma at diagnosis. Our patient underwent brain radiotherapy at a dose of 18 Gy in three sessions but he died with a decline of 3 months before starting systemic therapy. Therefore, each new case should be illustrated to make clinicians aware about the importance of the early diagnosis to improve the poor diagnosis of this entity.

A Comparative Study of Breast Cancer Screening by Age Across 10000 Tunisian Women.

INTRODUCTION: We propose in this study to analyze the results obtained in the experience of Dar El Amal by comparing the two age groups 45-49 years versus over 50 years. This experience of Dar Al Amal was started in Sfax (Tunisia) in 2004. The project had included women over a period of six and a half years. The target population was all women over the age of 45 years. RESULTS: In the period of the study, 10 000 women had at least one mammography within the first round in Dar El Amal. The average age was 51.56 years. The recall rate was more important in women aged 45-49 years compared with those over 50 years with a statistically significant relationship (p=0.013). Tests classified ACR0 and ACR3 predominated in women aged between 45 and 49 years with a statistically significant relationship. The positive predictive value (PPV) of mammography was better in those over 50 years (p=0.012). CONCLUSION: The majority of countries in the world opt for screening from the age of 50 years. Women under 50 years are not routinely concerned, but they have more right to a targeted and appropriate screening.

Fracture at catheter of totally implantable venous access port with migration into the right pulmonary artery: A serious complication.

Totally implantable venous access port has become an essential prerequisite for many chemotherapy protocols in solid tumors and hematological malignancies. However, we should be aware of its complications such as: venous thrombosis, extravasations, dislocation, obstruction, catheter leakage, and local or systemic infections. Among those complications, a dislodged broken catheter is rare and dangerous. We report a new case with review of literature to make oncologists aware about this entity and the necessity of monitoring by chest radiography. Percutaneous endovascular retrieval of a dislodged Port-A catheter (portacath) is both safe and effective. However, there are potential risks of valve damage and fatal tachycardia during retrieval of a fractured Port-A catheter. Physicians should be aware of these complications.

The Difficulties in the Management of Breast Cancer and Pregnancy.

INTRODUCTION: Breast cancer and pregnancy is rare. It is defined by the discovery of breast cancer during pregnancy or within one year after delivery. Throughout this study, we analyzed the characteristics of this entity with review of the literature. MATERIALS AND METHODS: We report through a retrospective study of breast cancer in pregnant women, a series of 11 cases collected at the oncology department in Sfax between 1994 and 2012. RESULT: The average age of our patients at diagnosis was 35 years. The average term of pregnancy was 22 weeks. Nine cases were diagnosed during pregnancy. The pregnancy outcome was well with babies in a good health, in 10 cases. The prognosis was excellent with complete remission after a mean follow of 39 months in 7 cases (2years-9years). CONCLUSION: The diagnosis of breast cancer in pregnant women is often delayed because of physiological changes of pregnancy and the young age which explain the poor prognosis of this entity. The prognosis was excellent in our series compared to the literature.

CpG methylation of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) and P53 mutation pattern in sporadic colorectal cancer.

The ubiquitin-proteasome system plays an essential regulatory role in various cellular processes. Besides its involvement in normal cellular functions, the alteration of proteasomal activity contributes to the pathological states of several clinical disorders, including cancer. Aberrant methylation of the CpG islands has been reported as an alternative way to inactivate gene expression involved in the ubiquitination process and thus protein degradation in tumor tissues. In this study, we aimed to determine the CpG methylation pattern of the UCHL1 promoter, as well as the mutation spectrum and the expression pattern of P53 in sporadic colorectal cancer (CRC) from Tunisian patients. We found that UCHL1 was methylated in 68.57 % and correlated significantly with lymph node metastasis (P = 0.029) and transcriptional silencing in tumor tissues (P = 0.013). Mutation screening of exons 5-9 of P53 showed that 42.85 % of cases harbor somatic mutation and are positively correlated with the methylated pattern of UCHL1 (P = 0.001). Furthermore, cytoplasmic accumulation of P53 was strongly associated with the unmethylated UCHL1 profile (P = 0.006), supporting the relationship between these two proteins in CRC.

Predictive Factors of Febrile Neutropenia Induced by Anticancer Chemotherapy in the South of Tunisia.

INTRODUCTION: Febrile Neutropenia (FN) secondary to chemotherapy is the most common and the earliest hematological complication. The aim of this work is to study the predictive factors of FN. Materiel and Methods: This is a retrospective study including 186 episodes of FN induced by chemotherapy treated in the department of oncology at Sfax in southern Tunisia during the period between 1 January 2006 and 31 December 2010. RESULT: The mean age of patients was 40 years. One hundred and seventeen patients had solid tumors (86.02%), 18 patients (13.23%) had hematological malignancies and one patient was treated for hypo pharyngeal cancer and aplastic Anemia. Chemotherapy was indicated for curative purpose in 94 cases and palliative purpose in 92 cases. One hundred and four patients (76.5%) had a single episode of FN and 32 (23.5%) had at least two episodes. The average time of febrile neutropenia was 11 days. CONCLUSION: Personal history of FN, poor performance status, chemotherapy regimen and the stage of the disease increased the risk of FN, with a statistically significant difference. Other factors such as hematological malignancies, the age over 65 years and concurrent chemo radiotherapy were not retained in our series.

Tunisian adult's Hodgkin lymphoma Study Group.

The Tunisian adult's Hodgkin lymphoma (HL) Study Group was created in 1999. It aimed to improve the management of this curable hematologic malignancy by standardizing the diagnosis, assessment of disease, treatment management and therapeutic evaluation in different Tunisian centers (Hematology, oncology and radiotherapy).Since 1998, four versions of the prospective national protocol for treating adult Hodgkin lymphoma have succeeded (MDH99, MDH2002, MDH2008, MDH2015). Each version was based on the results of the previous version and analyzed according to new data from the literature. Due to this national study group, the number of patients lost to follow decreased significantly (30% before the creation of the group and only 3% for patients treated with MDH2008), the complete and uncertain response rates have improved (75% before the creation of the group and 92% in patients treated with MDH2008) with dramatically improved rates of overall survival from 57% to 90%. On the other hand there was an improvement of toxic death rate (13% of toxic deaths in MDH2002 to 4.37% in the MDH2008) with a decrease of the respective rate of primary failure and relapse by 17% and 12.5% in MDH2002 against the 11.4% and 7.8% in the MDH2008. This resulted in an improvement in overall survival (90%) and event-free survival at 5 years (75%). Now with the introduction of positron emission tomography in Tunisia, we hope yet to finalize the assessment of response and thus better adapt the treatment of this disease. Our objective remains the improvement of event-free survival rate to reach 80%.

Primary pulmonary myoepithelial carcinoma in a child: An ambiguous entity.

Primary myoepithelial carcinoma (MC) of the lung is exceedingly rare. We report here, to the best of our knowledge, the first pediatric case having primitive pulmonary MC. The originality of our case was the disappearance of the pulmonary opacity spontaneously, without any treatment. The difficulties in our case were the diagnosis of this rare entity and its subsequent treatment. In fact, given the rarity of these tumors, recommendations regarding chemotherapy or radiation, were difficult to formulate.