A phase 2, single-arm trial evaluating 131I-PSMA-1095 targeted radioligand therapy for metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains uniformly lethal. Prostate specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in prostate cancer. 131I-PSMA-1095 (also known as 131I-MIP-1095) is a PSMA-targeted radioligand which selectively delivers therapeutic radiation to cancer cells and the tumor microenvironment. METHODS: We conducted a single-arm, phase 2 trial to assess efficacy and tolerability of 131I-PSMA-1095 in mCRPC patients who had exhausted all lines of approved therapy. All patients underwent 18F-DCFPyL PET and 18F-FDG PET to determine PSMA-positive tumor volume, and patients with >50% PSMA-positive tumor volume were treated with up to four doses of 131I-PSMA-1095. The primary endpoint was the response rate of prostate specific antigen (PSA). Secondary endpoints included rates of radiographic response and adverse events. Overall and radiographic progression-free survival were also analyzed. RESULTS: Eleven patients were screened for inclusion and nine patients received 131I-PSMA-1095. The median baseline PSA was 162 µg/l, and six patients demonstrated a >50% PSA decrease. One patient demonstrated a confirmed radiographic response. Median overall survival was 10.3 months, and median progression-free survival was 5.4 months. Four patients experienced adverse events of grade 3 or higher, the most frequent being thrombocytopenia and anemia. CONCLUSION: 131I-PSMA-1095 is highly active against heavily-pretreated PSMA-positive mCRPC, significantly decreasing tumor burden as measured by PSA. Adverse events, mainly hematologic toxicity, were not infrequent, likely related to off-target irradiation. This hematologic toxicity, as well as a higher logistical burden associated with use, could represent relative disadvantages of 131I-PSMA-1095 compared to 177Lu-PSMA-617.

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma: a multicentre retrospective cohort study.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) are indicated for metastatic urothelial cancer (mUC), but predictive and prognostic factors are lacking. We investigated clinical variables associated with ICI outcomes. METHODS: We performed a multicentre retrospective cohort study of 135 patients who received ICI for mUC, 2016-2021, at three Canadian centres. Clinical characteristics, body mass index (BMI), metastatic sites, neutrophil-to-lymphocyte ratio (NLR), response and survival were abstracted from chart review. RESULTS: We identified 135 patients and 62% had received ICI as a second-line or later treatment for mUC. A BMI ≥25 was significantly correlated to a higher overall response rate (ORR) (45.4% vs 16.3%, p value=0.020). Patients with BMI ≥30 experienced longer median overall survival (OS) of 24.8 vs 14.4 for 25≤BMI<30 and 8.5 months for BMI <25 (p value=0.012). The ORR was lower in the presence of bone metastases (16% vs 41%, p value=0.006) and liver metastases (16% vs 39%, p value=0.013). Metastatic lymph nodes were correlated with higher ORR (40% vs 20%, p value=0.032). The median OS for bone metastases was 7.3 versus 18 months (p value <0.001). Patients with liver metastases had a median OS of 8.6 versus 15 months (p value=0.006). No difference for lymph nodes metastases (13.5 vs 12.7 months, p value=0.175) was found. NLR ≥4 had worse OS (8.2 vs 17.7 months, p value=0.0001). In multivariate analysis, BMI ≥30, bone metastases, NLR ≥4, performance status ≥2 and line of ICI ≥2 were independent factors for OS. CONCLUSIONS: Our data identified BMI and bone metastases as novel clinical biomarkers that were independently associated with ICI outcomes in mUC. External and prospective validation are warranted.

Genetic testing for hereditary cancer syndromes in Tunisian patients: Impact on health system.

INTRODUCTION: Cancer management in Africa faces diverse challenges due to limited resources, health system challenges, and other matters. Identifying hereditary cancer syndromic cases is crucial to improve clinical management and preventive care in these settings. This study aims to explore the clinicopathological features and genetic factors associated with hereditary cancer in Tunisia, a North African country with a rising cancer burden MATERIALS AND METHODS: Clinicopathological features and personal/family history of cancer were explored in 521 patients. Genetic analysis using Sanger and next-generation sequencing was performed for a set of patients RESULTS: Hereditary breast and ovarian cancer syndrome was the most frequent cluster in which 36 BRCA mutations were identified. We described a subgroup of patients with likely ''breast cancer-only syndrome'' among this cluster. Two cases of Li-Fraumeni syndrome with distinct TP53 mutations namely c.638G>A and c.733G>A have been identified. Genetic investigation also allowed the identification of a new BLM homozygous mutation (c.3254dupT) in one patient with multiple primary cancers. Phenotype-genotype correlation suggests the diagnosis of Bloom syndrome. A recurrent MUTYH mutation (c.1143_1144dup) was identified in three patients with different phenotypes CONCLUSION: Our study calls for comprehensive genetic education and the implementation of genetic screening in Tunisia and other African countries health systems, to reduce the burden of hereditary diseases and improve cancer outcomes in resource-stratified settings.

Uncovering the clinical relevance of unclassified variants in DNA repair genes: a focus on BRCA negative Tunisian cancer families.

Introduction: Recent advances in sequencing technologies have significantly increased our capability to acquire large amounts of genetic data. However, the clinical relevance of the generated data continues to be challenging particularly with the identification of Variants of Uncertain Significance (VUSs) whose pathogenicity remains unclear. In the current report, we aim to evaluate the clinical relevance and the pathogenicity of VUSs in DNA repair genes among Tunisian breast cancer families. Methods: A total of 67 unsolved breast cancer cases have been investigated. The pathogenicity of VUSs identified within 26 DNA repair genes was assessed using different in silico prediction tools including SIFT, PolyPhen2, Align-GVGD and VarSEAK. Effects on the 3D structure were evaluated using the stability predictor DynaMut and molecular dynamics simulation with NAMD. Family segregation analysis was also performed. Results: Among a total of 37 VUSs identified, 11 variants are likely deleterious affecting ATM, BLM, CHEK2, ERCC3, FANCC, FANCG, MSH2, PMS2 and RAD50 genes. The BLM variant, c.3254dupT, is novel and seems to be associated with increased risk of breast, endometrial and colon cancer. Moreover, c.6115G>A in ATM and c.592+3A>T in CHEK2 were of keen interest identified in families with multiple breast cancer cases and their familial cosegregation with disease has been also confirmed. In addition, functional in silico analyses revealed that the ATM variant may lead to protein immobilization and rigidification thus decreasing its activity. We have also shown that FANCC and FANCG variants may lead to protein destabilization and alteration of the structure compactness which may affect FANCC and FANCG protein activity. Conclusion: Our findings revealed that VUSs in DNA repair genes might be associated with increased cancer risk and highlight the need for variant reclassification for better disease management. This will help to improve the genetic diagnosis and therapeutic strategies of cancer patients not only in Tunisia but also in neighboring countries.

Association between epidemiological and clinico-pathological features of breast cancer with prognosis, family history, Ki-67 proliferation index and survival in Tunisian breast cancer patients.

Breast cancer has different epidemio-clinical characteristics in Middle East and North-African populations compared to those reported in the Western countries. The aim of this study is to analyze the epidemiological and clinico-pathological features of breast cancer in Tunisia and to determine prognostic factors with special interest to family history, Ki-67 proliferation index and comorbidity. We retrospectively reviewed epidemiological and clinico-pathological data from patients' medical records, treated in the Medical Oncology Department at Abderrahmane Mami Hospital, in the period 2011-2015. Data has been collected on 602 breast cancer patients and analyzed using SPSS software V.23.0. Our study showed high fractions of young breast cancer patients and cases with dense breasts. The most prevalent comorbidities observed in the studied cohort were cardiovascular diseases and diabetes. Familial breast cancer was found in 23.3% of cases and was associated with younger age at diagnosis (p<0.001) and advanced stage (p = 0.015). Ki-67 index >20% was significantly associated with early age at diagnosis, lymph node involvement (p = 0.002), advanced tumor grade (p<0.001) and high risk of relapse (p = 0.007). Ki-67 cut-off 30% predicted survival in luminal cases. Survival was worse in patients with triple negative breast cancer compared to non-triple negative breast cancer, inflammatory breast cancer compared to non-inflammatory breast cancer, moderately to poorly differentiated tumors compared to well-differentiated tumors and with positive lymph nodes compared to pN0 (p<0.05). Our study showed new insights into epidemiological and clinico-pathological characteristics of breast cancer that are not well explored in Tunisian population. Considering our findings along with the implementation of electronic health record system may improve patient health care quality and disease management.

Translation and Validation of the Comprehensive Score of Financial Toxicity for Cancer Patients Into Arabic.

Background and Purpose: We aimed to translate the Comprehensive Score of Financial Toxicity (COST) questionnaire into Arabic and to evaluate its reliability and validity. Methods: We applied the four-step translation method and conducted a pilot validation study over 179 medical oncology patients. Reliability was tested using the Cronbach alpha coefficient and test-retest stability. Validity was tested using the correlation with Functional assessment of Cancer Therapy-General score (FACT-G), factorial analysis and the content validity index. Results: Questionnaire showed high internal consistency and test retest reliability; Cronbach alpha coefficient was 0.77 and Pearson stability coefficient was 0.8. Convergent validity evaluation showed a statistically significant moderate correlation with the FACT-G (r = .42, p =.047). Content validly index was 0.93. Conclusions: The Arabic version of COST questionnaire, was a valid and reliable tool that could be used in clinical practice by healthcare providers to evaluate financial toxicity in Arab speaking cancer patients.

Identification of Eleven Novel BRCA Mutations in Tunisia: Impact on the Clinical Management of BRCA Related Cancers.

BACKGROUND: Breast cancer is the world's most common cancer among women. It is becoming an increasingly urgent problem in low- and middle-income countries (LMICs) where a large fraction of women is diagnosed with advanced-stage disease and have no access to treatment or basic palliative care. About 5-10% of all breast cancers can be attributed to hereditary genetic components and up to 25% of familial cases are due to mutations in BRCA1/2 genes. Since their discovery in 1994 and 1995, as few as 18 mutations have been identified in BRCA genes in the Tunisian population. The aim of this study is to identify additional BRCA mutations, to estimate their contribution to the hereditary breast and ovarian cancers in Tunisia and to investigate the clinicopathological signatures associated with BRCA mutations. METHODS: A total of 354 patients diagnosed with breast and ovarian cancers, including 5 male breast cancer cases, have been investigated for BRCA1/2 mutations using traditional and/or next generation sequencing technologies. Clinicopathological signatures associated with BRCA mutations have also been investigated. RESULTS: In the current study, 16 distinct mutations were detected: 10 in BRCA1 and 6 in BRCA2, of which 11 are described for the first time in Tunisia including 3 variations that have not been reported previously in public databases namely BRCA1_c.915T>A; BRCA2_c.-227-?_7805+? and BRCA2_c.249delG. Early age at onset, family history of ovarian cancer and high tumor grade were significantly associated with BRCA status. BRCA1 carriers were more likely to be triple negative breast cancer compared to BRCA2 carriers. A relatively high frequency of contralateral breast cancer and ovarian cancer occurrence was observed among BRCA carriers and was more frequent in patients carrying BRCA1 mutations. CONCLUSION: Our study provides new insights into breast and ovarian cancer genetic landscape in the under-represented North African populations. The prevalence assessment of novel and recurrent BRCA1/2 pathogenic mutations will enhance the use of personalized treatment and precise screening strategies by both affected and unaffected North African cancer cases.

Identification of BRCA2 Cis Double Heterozygous Breast Cancer Cases Using Whole Exome Sequencing: Phenotypic Expression and Impact on Personalized Oncology.

BRCA1 and BRCA2 are the most commonly mutated breast cancer susceptibility genes that convey a high risk of breast and ovarian cancer. Most BRCA1 or BRCA2 mutation carriers have inherited a single heterozygous mutation. In recent years, very rare cases with biallelic or trans double heterozygous mutations on BRCA1 and or BRCA2 have been identified and seem to be associated with distinctive phenotypes. Given that this genotype-phenotype correlation in cancer predisposing hereditary conditions is of relevance for oncological prevention and genetic testing, it is important to investigate these rare BRCA genotypes for better clinical management of BRCA mutation carriers. Here we present the first report on Cis double heterozygosity (Cis DH) on BRCA2 gene identified using Whole exome sequencing (WES) in a Tunisian family with two BRCA2 mutations namely: c.632-1G>A and c.1310_1313DelAAGA that are both reported as pathogenic in ClinVar database. Subsequent analysis in 300 high-risk Tunisian breast cancer families detected this Cis double heterozygous genotype in 8 additional individuals belonging to 5 families from the same geographic origin suggesting a founder effect. Moreover, the observed Cis DH seems to be associated with an early age of onset (mean age = 35.33 years) and severe phenotype of the disease with high breast cancer grade and multiple cancer cases in the family. The identification of unusual BRCA genotypes in this Tunisian cohort highlights the importance of performing genetic studies in under-investigated populations. This will also potentially help avoiding erroneous classifications of genetic variants in African population and therefore avoiding clinical misdiagnosis of BRCA related cancers. Our findings will also have an impact on the genetic testing and the clinical management of North African breast cancer patients as well as patients from different other ethnic groups in regard to several emerging target therapies such as PARP inhibitors.

National approaches to managing cancer care: responses of countries in the MENA region to the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic presents serious challenges to cancer care because of the associated risks from the infection itself and the disruption of care delivery. Therefore, many professional societies have published recommendations to help manage patients with cancer during the current pandemic. The objective of our study is to assess the national responses of Middle East North Africa (MENA) countries in terms of publishing relevant guidelines and analyse various components of these guidelines. METHODS: A survey based on the preliminary review of the literature regarding cancer care adaptations has been developed and then completed by a group of oncologists from the following Arab countries affected by the pandemic: Algeria, Egypt, Iraq, Jordan, Kuwait, Lebanon, Morocco, Oman, Saudi Arabia, Syria, Tunisia, United Arab Emirates and Yemen. The survey inquired about COVID-19 cases, national recommendations regarding general measures of COVID-19 prevention and patient care in oncology as well as their implementation about cancer care adaptations during the pandemic. RESULTS: Analysis of the COVID-19 pandemic-related guidelines revealed at least 30 specific recommendations that we categorised into seven essential components. All included countries had national guidelines except one country. Estimated full compliances with all specific category recommendations ranged from 30% to 69% and partial compliance ranged from 23% to 61%. CONCLUSION: There is a very good response and preparedness in the Arab Middle East and North Africa region surveyed. However, there are inconsistencies in the various components of the guidelines across the region, which reflects the evolving status of the pandemic in each country as well as the lack of clear evidence-based guidelines for many of the issues in question. There is a need for a clear framework on essential components that should be included in these guidelines to assure providing the best guidance to the oncology community.

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia.

Hereditary breast cancer accounts for 5-10% of all breast cancer cases. So far, known genetic risk factors account for only 50% of the breast cancer genetic component and almost a quarter of hereditary cases are carriers of pathogenic mutations in BRCA1/2 genes. Hence, the genetic basis for a significant fraction of familial cases remains unsolved. This missing heritability may be explained in part by Copy Number Variations (CNVs). We herein aimed to evaluate the contribution of CNVs to hereditary breast cancer in Tunisia. Whole exome sequencing was performed for 9 BRCA negative cases with a strong family history of breast cancer and 10 matched controls. CNVs were called using the ExomeDepth R-package and investigated by pathway analysis and web-based bioinformatic tools. Overall, 483 CNVs have been identified in breast cancer patients. Rare CNVs affecting cancer genes were detected, of special interest were those disrupting APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 seem to correlate with good clinical response to tamoxifen. Our study revealed new insights regarding CNVs and breast cancer risk in the Tunisian population. These findings suggest that rare and common CNVs may contribute to disease susceptibility. Those affecting mismatch repair genes are of interest and require additional attention since it may help to select candidates for immunotherapy leading to better outcomes.

Assessing the financial toxicity in Tunisian cancer patients using the Comprehensive Score for Financial Toxicity (COST).

BACKGROUND: Cancer care-related out-of-pocket expenses and financial toxicity (FT) are a rising burden for patients. We aimed to evaluate patient-reported FT and to identify relevant correlates within a Tunisian population. METHODS: We conducted a survey using the 11-item Comprehensive Score for Financial Toxicity (COST) that could range from 0 = high to 44 = low. FT was grade 0 if ≥ 26, grade 1 = (14-25), grade 2 = (1-13), and grade 3 = 0. Scores were collected along with data regarding patient medical/social features and out-of-pocket expenses. Univariate and multivariate analyses were performed to identify factors associated with higher financial burden. RESULTS: Among the 179 participants, median COST score was 20.8 (Q1 17-Q3 24), with 80.4% of patients experiencing financial toxicity: grade 0 = 20%, grade 1 = 68.4%, grade 2 = 11.7%, grade 3 = 0%. Most patients (66.5%) used to work before cancer and 44.7% reported ceasing work because of cancer. The time to go to the hospital was > 30 min in 66.5% of cases. Unemployment, time to hospital > 30 min, ceasing work because of cancer, and expenses on non-chemotherapy drugs exceeding 70 dinars (25 US dollars) were mostly associated with higher FT on univariate analysis. Distance to hospital and ceasing work because of cancer were the single most significant factors in multivariate analysis. CONCLUSIONS: Losing work due to cancer and unequal distribution of health care particularly in cities with long travel times to the nearest hospital are the main sources of financial distress.

Identification of Novel BRCA1 and RAD50 Mutations Associated With Breast Cancer Predisposition in Tunisian Patients.

BACKGROUND: Deleterious mutations on BRCA1/2 genes are known to confer high risk of developing breast and ovarian cancers. The identification of these mutations not only helped in selecting high risk individuals that need appropriate prevention approaches but also led to the development of the PARP-inhibitors targeted therapy. This study aims to assess the prevalence of the most frequent BRCA1 mutation in Tunisia, c.211dupA, and provide evidence of its common origin as well as its clinicopathological characteristics. We also aimed to identify additional actionable variants using classical and next generation sequencing technologies (NGS) which would allow to implement cost-effective genetic testing in limited resource countries. PATIENTS AND METHODS: Using sanger sequencing, 112 breast cancer families were screened for c.211dupA. A set of patients that do not carry this mutation were investigated using NGS. Haplotype analysis was performed to assess the founder effect and to estimate the age of this mutation. Correlations between genetic and clinical data were also performed. RESULTS: The c.211dupA mutation was identified in 8 carriers and a novel private BRCA1 mutation, c.2418dupA, was identified in one carrier. Both mutations are likely specific to North-Eastern Tunisia. Haplotype analysis supported the founder effect of c.211dupA and showed its recent origin. Phenotype-genotype correlation showed that both BRCA1 mutations seem to be associated with a severe phenotype. Whole Exome Sequencing (WES) analysis of a BRCA negative family revealed a Variant of Unknown Significance, c.3647C > G on RAD50. Molecular modeling showed that this variant could be classified as deleterious as it is responsible for destabilizing the RAD50 protein structure. Variant prioritization and pathway analysis of the WES data showed additional interesting candidate genes including MITF and ANKS6. CONCLUSION: We recommend the prioritization of BRCA1-c.211dupA screening in high risk breast cancer families originating from the North-East of Tunisia. We also highlighted the importance of NGS in detecting novel mutations, such as RAD50-c.3647C > G. In addition, we strongly recommend using data from different ethnic groups to review the pathogenicity of this variant and reconsider its classification in ClinVar.

Reproductive Risk Factors of Inflammatory Breast Cancer according to Luminal, HER2-Overexpressing, and Triple-Negative Subtypes: A Case Comparison Study.

OBJECTIVE: We evaluated the risk factors of inflammatory breast cancer (IBC) compared to non-IBC and according to histological subtype. METHODS: Cases of IBC (n = 160) and controls of non-IBC (n = 580) were collected from the cohort of breast cancer patients treated in two oncology centers matched based on age at cohort entry. Data about breast cancer risk factors were collected. We evaluated correlation and ORs using conditional logistic regression analysis for each case group versus the control group. We also evaluated those factors in three further subgroups: luminal (HR+, HER2-), HER2-overexpressing (HER2+, HR-), and triple-negative (TN) patients. RESULTS: Long duration of breastfeeding of ≥12 months (OR = 4.64, 95% CI 2.97-7.26), body mass index ≤25 (OR = 2.48, 95% CI 1.71-3.58), and use of oral contraceptives (OR = 2.48, 95% CI 1.62-3.84) were the most significant risk factors in favor of IBC compared to non-IBC. There was no impact of contraceptives use in the luminal subgroup and no impact of long duration of breastfeeding in the TN subgroup. The role of socioeconomic and educational levels was unclear. Age at menarche, age at first pregnancy, and age at menopause were nonsignificant risk factors of IBC. CONCLUSION: Reproductive risk factors were distinct in IBC patients reflecting the clinical entity of IBC.

Use of complementary and alternative medicine in cancer: A Tunisian single-center experience.

INTRODUCTION: We aimed to explore the use of complementary and alternative medicine (CAM) and to identify their side effects, when used in cancer patients. We also assessed the communication of the patients and families with the oncologist about this issue. METHODS: A cross-sectional survey of 120 adult patients treated for cancer in our medical oncology department between January and April 2019, using an anonymous questionnaire to assess complementary and alternative medicine use. RESULTS: One hundred twenty patients participated in the survey, among them 102 used CAM (85%). A majority of users were female patients (n=72, 70.6%), and mean age was 52.4 years±11.6. Patients had breast cancer in 48% of cases. Wild herbs were the most commonly used alternative therapy (67.7%), particularly Ephedra foeminea (Alanda) in 52% of cases. Patients' families incited them to use CAM in 64.7% of cases. Internet and social network (Facebook) were the major sources of information on CAM (79.4%), followed by family and friends (72.5%). Fourteen patients (13.7%) reported nausea and vomiting secondary to CAM use. We reported disruption of liver function in 9.8% of cases, and renal failure in 1.96%, with fatal issue in one patient using Ephedra. Nineteen patients (18.6%) informed their oncologist about the alternative therapy they received. CONCLUSION: The oncologist has to explore the use of alternative therapies with their patients. Communication about CAM should be a part of cancer care. It may protect patients from some dangerous side effects and improve efficacy of conventional therapy.

Correction to: Aromatase inhibitor-induced carpal tunnel syndrome: prevalence in daily practice.

The original version of this article unfortunately contained a mistake. The given name and family name were swapped.

Ongoing formative assessment in the training of post graduate students.

INTRODUCTION: There is growing evidence that formative assessment is valuable tool in enhancing learning. Integrating formative assessment into post graduate students can be challenging. AIM: Authors aimed in this study to describe an ongoing formative assessment activity in post graduates. We reported resident's performance and satisfaction. METHODS: Authors performed an exploratory study over a 3-year period. Twenty five oncology residents participated. The first phase was test preparation by senior oncologists, according to residency curricula then taking the test by a small group of residents with an immediate feedback. The third phase was distribution of a survey each 6 months evaluating resident's perception of the testing. RESULTS: Twenty two tests were taken by 17 medical oncology, 2 surgical oncology and 4 radiation therapy residents.  At the first test, median scores was 51/100 [30%-72%] with a mean of 53/100. Individual scores of each resident improved with time, becoming 68/100 (t(16)=3.172, p<0.02) with a mean of 64/100 and decrease between student's scores. All the students rated the correction session with a 5. The majority reported that the test reached their expectations (73% rated4-5), and considered it, as having an impact on their daily practice (77% rated4-5). Residents also considered the test as highly difficult (80% rated4-5). CONCLUSION: Ongoing formative assessment showed improvement in overall knowledge of residents with high level of satisfaction.

Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases.

BACKGROUND: A family history of breast cancer has long been thought to indicate the presence of inherited genetic events that predispose to this disease. In North Africa, many specific epidemio-genetic characteristics have been observed in breast cancer families when compared to Western populations. Despite these specificities, the majority of breast cancer genetics studies performed in North Africa remain restricted to the investigation of the BRCA1 and BRCA2 genes. Thus, comprehensive data at a whole exome or whole genome level from local patients are lacking. METHODS: A whole exome sequencing (WES) of seven breast cancer Tunisian families have been performed using a family-based approach. We focused our analysis on BC-TN-F001 family that included two affected members that have been sequenced using WES. Relevant variants identified in BC-TN-F001 have been confirmed using Sanger sequencing. Then, we conducted an integrative analysis by combining our results with those from other WES studies in order to figure out the genetic transmission model of the newly identified genes. Biological network construction and protein-protein interactions analyses have been performed to decipher the molecular mechanisms likely accounting for the role of these genes in breast cancer risk. RESULTS: Sequencing, filtering strategies, and validation analysis have been achieved. For BC-TN-F001, no deleterious mutations have been identified on known breast cancer genes. However, 373 heterozygous, exonic and rare variants have been identified on other candidate genes. After applying several filters, 12 relevant high-risk variants have been selected. Our results showed that these variants seem to be inherited in a family specific model. This hypothesis has been confirmed following a thorough analysis of the reported WES studies. Enriched biological process and protein-protein interaction networks resulted in the identification of four novel breast cancer candidate genes namely MMS19, DNAH3, POLK and KATB6. CONCLUSIONS: In this first WES application on Tunisian breast cancer patients, we highlighted the impact of next generation sequencing technologies in the identification of novel breast cancer candidate genes which may bring new insights into the biological mechanisms of breast carcinogenesis. Our findings showed that the breast cancer predisposition in non-BRCA families may be ethnic and/or family specific.

Tumor location impact in stage II and III colon cancer: epidemiological and outcome evaluation.

BACKGROUND: We aimed to describe clinico-pathological characteristics and differences between right-sided (RCC) and left-sided colon cancer (LCC) in Tunisian population. We also analyzed outcome to determine whether location is of prognostic significance. METHODS: Clinico-pathological characteristics and Kaplan Meier survival were compared between two groups of LCC [150] and RCC [53] patients with stage II and III adenocarcinoma treated with curative intent between 2003-2014. RESULTS: RCC patients were significantly more likely to be female, (56.6% vs. 39.3%, P=0.029) and to have undifferentiated tumor (87.1% vs. 8.4%, P=0.014), then LCC. After a median follow up of 49 months, 5-year overall survival (OS) was significantly worse in RCC vs. LCC [42% vs. 78%; hazard ratio (HR) =2.07; 95% CI: 1.05-4.09; P=0.03], no difference in relapse free survival (RFS) was observed. Median time to relapse was significantly shorter in RCC (15 months) vs. LCC (24 months), P=0.005. Tumor location significantly impacted survival in stage III, 5-year OS was 45% in RCC, and 63% in LCC, (HR =2.28; 95% CI: 1.01-5.24; P=0.04), there was no impact of tumor location in stage II, (HR =1.94; 95% CI: 0.54-6.93; P=0.29). CONCLUSIONS: Prognostic impact of tumor location should be considered as a stratification factor in the future clinical trials.

Brain metastases epidemiology in a Tunisian population: trends and outcome.

AIM: We reported anatomo-clinical features of brain metastases (BMs) collected in a Tunisian medical oncology department. PATIENTS & METHODS: We retrospectively identified all cases of BM within a cohort of 7055 patients, treated for a histologically confirmed nonhematological cancer between 2000 and 2016. Data about age, sex and primary tumor were collected. RESULTS: Incidence was 1.9% and mean age was 54 years with a 1.24 sex ratio. BMs were symptomatic in 73.7% of cases after a median time of 16 months. A total of 73.4% patients receiving local therapy, 88% by whole brain radiation therapy and 21.6% had a metastasectomy. Lung and breast cancers were the primary in 80% of the BM. CONCLUSION: BM showed trends of young with underestimated incidence.

Aggressive primary hepatic epithelioid hemangioendothelioma: a case report and literature review.

A new case of epithelioid hemangioendothelioma is reported to have occurred to a 67-year-old patient who consulted for right-sided chest pain. The work-up showed multiple right pulmonary lesions associated with bilateral moderate pleural effusion and left-sided pleural thickening and three hypodense nodules in the right lobe of the liver, peritoneal thickening, ascites, and multiple vertebral lytic lesions. The diagnosis of an epithelioid hemangioendothelioma was concluded through a histological examination of a computed tomography scan guided biopsy of the liver. The patient received a primary mono-chemotherapy with Adriamycin (75 mg/m2 every three weeks) and intravenous bisphosphonates without response and general status impairment. The patient died after 16 months of follow-up.