Docetaxel monotherapy induces necrotic acute pancreatitis.

INTRODUCTION: Drug-induced acute pancreatitis (AP) is uncommon and represents 0.1 to 2% of all AP cases. Chemotherapy-induced AP is very rare. Docetaxel monotherapy-induced AP has been reported only once in the literature. Herein we report the second case of docetaxel-related AP and the first case of necrotic AP induced by this agent. CASE REPORT: We describe the case of a severe docetaxel-induced AP classified as stage E Balthazar in a 55-year-old female treated with adjuvant docetaxel for localized breast cancer. Symptoms occurred five hours following the first infusion of docetaxel. MANAGEMENT AND OUTCOME: The patient was hospitalized for 15 days for appropriate management. According to the CTCAE (Common Terminology Criteria for Adverse Events) version 5.0 this was a grade 4 toxicity and chemotherapy was withdrawn thereafter. Drug rechallenge was not possible because of the severity of the presentation. DISCUSSION: Medical oncologists should be aware that docetaxel may induce severe pancreatitis. Therefore, they should prompt testing of serum lipase when patients consult for unusual abdominal pain following chemotherapy infusion. Recognizing this entity is paramount to allow early and appropriate management.

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.

Navigating the Cancer Journey: Experiences and Perspectives of Young Adult Patients in Tunisia.

Purpose: This study aimed to explore the experiences of young adult cancer patients within the Tunisian context. Methods: A total of 104 patients between the ages of 20 and 40, undergoing treatment for various types and stages of cancer, participated in a questionnaire-based survey. The survey encompassed topics related to the socioeconomic and psychological impacts of cancer, coping mechanisms, relationships, sexuality, and future aspirations. Results: Of the participants, 78 were women (75%) and 26 were men (25%), with an average age of 33 years. Financial difficulties were reported by 60 patients (57.7%). The most common emotional responses to the diagnosis were sadness (54.8%), followed by denial (18.3%) and anger (5.8%). Thirteen patients (12.5%) choose not to receive information about the stage of their disease. In addition, 42 patients (40.4%) experienced a decrease in perceived physical attractiveness, while negative effects on sexuality were observed in 44.2% of cases. The primary concerns reported by patients were the fear of recurrence or progression (48%) and infertility (48%). Furthermore, 43 patients (41.3%) expressed a decrease in self-confidence, notably influenced by financial difficulties (OR: 2.77 [95% CI: 1.12-6.87]), physical alterations (OR: 0.18 [95% CI: 0.07-0.45]), and sexual issues (OR: 0.17 [95% CI: 0.06-0.48]). Notably, 78 patients (75%) continued to make future plans, particularly those under 30 years of age (OR: 0.2 [95% CI: 0.04-0.96]). Moreover, 47.1% of patients expressed an inclination toward immigration to developed countries, primarily due to perceived superior health care systems (61.5%). Conclusions: Young cancer patients face a range of social and psychological challenges, suggesting the necessity for a specialized care approach.

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.

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.

Amenorrhea and elevated ßhuman chorionic gonadotropin of unknown origin: An unexpected location of choriocarcinoma.

Choriocarcinoma is a rare malignancy originating from trophoblastic cells that is known to arise from the placenta. In this report, we describe the case of a 28-year-old female who consulted for amenorrhea and elevated ßhCG mimicking a pregnancy of an unknown location, which ultimately turned out to be primary choriocarcinoma of the lung.

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.

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.

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.

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.

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.

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.

Targeted Therapies in HER2-Overexpressing Metastatic Breast Cancer.

Human epidermal growth factor receptor-2 (HER2) is amplified in 25-30% of breast cancers and is associated with aggressive disease and poorer survival. Multiple anti-HER2 targeted therapies have dramatically changed management and outcome of this subgroup, both in adjuvant and metastatic settings. Despite the improvement of survival thanks to trastuzumab, unclear mechanisms of resistance occur, which has led to the development of new anti-HER2 therapies such as lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1). The optimal sequence of the available drugs is still not well established. All this progress raises the question of toxicity that need to be managed, especially with longer survival of patients. In this article, we review different anti-HER2 therapies used in HER2-positive m etastatic breast cancer.

[Primary small intestinal lymphoma: epidemiological, histological and therapeutic transition in Tunisia]. / Transition épidémiologique, histologique et thérapeutique des lymphomes primitifs du grêle (LPG) en Tunisie.

INTRODUCTION: Primary small intestinal lymphoma (PSIL) is the second Non-Hodgkin lymphoma (NHL) of the digestive tract (after gastric NHL). PURPOSE: To evaluate during the past 28 years the epidemiological, anatomoclinical and therapeutic changes of PSIL in Tunisia through an acquired experience of more than a quarter of a century. METHODS: Our retrospective study included patients with histologically confirmed small intestinal lymphoma from 1981 to 2008 in Tunisia at Salah Azaiz Institute. The cohort of 210 patients was divided into two groups: A group from 1981 to 1992 (152 patients) and B group from 1993 to 2008 (58 patients). We analysed the epidemiological, anatomoclinical, histological, and therapeutic characteristics. RESULTS: We observed a significant decrease in the annual incidence of PSIL but also a significant transition of diffuse immunoproliferative small intestinal disease (IPSID) also known as "Mediterranean" PSIL, which were progressively replaced by "Western" lymphomas. Laparotomy with or without a debulking surgery, largely performed in group A, has disappeared at the cost of a primary chemotherapy (p < 0.001). Five-year actuarial global and relapse free survivals were respectively 60.5 and 57.3%. CONCLUSION: PSIL in Tunisia were subjected to a triple transition: epidemiological, histological and therapeutic.