Concurrent NRAS-BRAF variants in metastatic colorectal cancer: a Tunisian case report.

Target therapy for metastatic colorectal cancer needs the determination of KRAS, NRAS, and BRAF mutation status to identify patients resistant to anti-EGFR treatment. RAS genes (KRAS/NRAS) are mutated in 40-60% of metastatic colorectal cancer and BRAF in 5-10%. The presence of a double mutation in RAS and BRAF is rare. Therefore, RAS and BRAF mutations were considered exclusive. Herein, we describe a novel concomitant NRAS/BRAF mutation identified in a series of 865 colorectal cancer patients.

[Sex cord tumors with annular tubules: About 4 cases and literature review]. / Les tumeurs des cordons sexuels à tubules annelés : à propos de 4 cas et revue de la littérature.

Sex cord tumor with annular tubules (SCTAT) is a rare ovarian tumor. It belongs to sex cord and stromal tumor of the ovary and represents less than 1% of cases. It includes two forms: the first one associated with Peuz-Jeghers syndrome and the second sporadic. We report 4 cases of SCTAT collected at the department of pathology of Salah Azaiez Institute of Tunis over the 12 last years. The age ranged from 10 to 32 years. Symptoms were non specific except for one case revealed by precocious puberty. One patient had Peutz-Jeghers syndrome associated. Tumors were unilateral. Gross findings showed often a solid tumor with yellow cut surface. Their size ranged from 0.5cm to 28cm. Their morphological features were characteristic. Immunohistochemistry showed that tumor cells expressed inhibin and claretinin. The treatment was surgical, often conservative. The diagnosis of malignancy wasn't focused on histological features, but on tumor extension, clinical course, and presence of metastases. Evolution was often favorable. We also performed a systematic review of the literature that identified 166 cases. Features of these cases were studied. We also compared these features between sporadic and syndromic forms and between benign and malignant forms. In conclusion, SCTAT is a rare tumor, usually benign. Its diagnosis is based on histological examination. There is a malignant potential especially in sporadic forms, estimated at 20%. Treatment is most often conservative, based on oophorectomy.

A novel pre-processing approach based on colour space assessment for digestive neuroendocrine tumour grading in immunohistochemical tissue images.

INTRODUCTION: The complexity of histopathological images remains a challenging issue in cancer diagnosis. A pathologist analyses immunohistochemical images to detect a colour-based stain, which is brown for positive nuclei with different intensities and blue for negative nuclei. Several issues emerge during the eyeballing tissue slide analysis, such as colour variations caused by stain inhomogeneity, non-uniform illumination, irregular cell shapes, and overlapping cell nuclei. To overcome those problems, an automated computer-aided diagnosis system is proposed to segment and quantify digestive neuroendocrine tumours. MATERIAL AND METHODS: We present a novel pre-processing approach based on colour space assessment. A criterion called pertinence degree is introduced to select the appropriate colour channel, followed by contrast enhancement. Subsequently, the adaptive local threshold technique that uses the modified Laplacian filter is applied to minimize the implementation complexity, highlight edges, and emphasize intensity variation between cells across the slide. Finally, the improved watershed algorithm based on the concave vertex graph is applied for cell separation. RESULTS: The performance of the algorithms for nucleus segmentation is evaluated according to both the object-level and pixel-level criteria. Our approach increases segmentation accuracy, with the F1-score equal to 0.986. There is significant agreement between the applied approach and the expert's ground truth segmentation. CONCLUSIONS: The proposed method outperformed the state-of-the-art techniques based on recall, precision, the F1-score, and the Dice coefficient.

Dual Mechanism of Action of Curcumin in Experimental Models of Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is characterized by a combination of inflammatory and demyelination processes in the spinal cord and brain. Conventional drugs generally target the autoimmune response, without any curative effect. For that reason, there is a great interest in identifying novel agents with anti-inflammatory and myelinating effects, to counter the inflammation and cell death distinctive of the disease. METHODS AND RESULTS: An in vitro assay showed that curcumin (Cur) at 10 µM enhanced the proliferation of C8-D1A cells and modulated the production of Th1/Th2/Th17 cytokines in the cells stimulated by LPS. Furthermore, two in vivo pathophysiological experimental models were used to assess the effect of curcumin (100 mg/kg). The cuprizone model mimics the de/re-myelination aspect in MS, and the experimental autoimmune encephalomyelitis model (EAE) reflects immune-mediated events. We found that Cur alleviated the neurological symptomatology in EAE and modulated the expression of lymphocytes CD3 and CD4 in the spinal cord. Interestingly, Cur restored motor and behavioral deficiencies, as well as myelination, in demyelinated mice, as indicated by the higher index of luxol fast blue (LFB) and the myelin basic protein (MBP) intensity in the corpus callosum. CONCLUSIONS: Curcumin is a potential therapeutic agent that can diminish the MS neuroimmune imbalance and demyelination through its anti-inflammatory and antioxidant effects.

Cyclin D1: potential utility as marker for Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disorder of unknown etiopathogenesis. Diagnosis is based on the identification of CD1a positive histiocytic infiltrate. Activation of the mitogen-activated-protein-kinase (MAPK) is constantly observed in LCH and therefore downstream markers such as cyclin D1 may be a useful marker for LCH. The aim of this study was to investigate the expression of cyclin D1 in LCH. We assessed the immunohistochemical expression of cyclin D1 (clone SP4-R) in series of 16 cases of confirmed LCH. Expression of Cyclin D1 was scored as weak, moderate, and strong nuclear staining and results were interpreted by two pathologists. The percentage of positivity was assessed. The mean age of patients was 13.7 years old with a male to female ratio of 1:3. The most common involved site was bone (n = 9; 56,3%), followed by lymph node (n = 5; 31,2%) and skin (n = 2; 12,5%). All cases showed nuclear staining for cyclin D1 with variable intensity. It was assessed moderate in 43,8% (n = 7) and strong in 56,2% (n = 9). The percentage of positive cells was >50% in 13 cases and <50% in 3 cases. Our results have shown that all cases of Langerhans cell histiocytosis from various sites express cyclin D1. This finding may be attributed to MAPK pathway activation that has been described in LCH. Otherwise, cyclin D1 is not significantly expressed in reactive Langerhans cell proliferations. Therefore, cyclin D1 immunohistochemistry may be useful as a diagnostic marker and in excluding non-neoplastic mimics of LCH.

Curcumin Attenuated Neurotoxicity in Sporadic Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl3), which mimics the sporadic form of Alzheimer's disease. Our results showed that treatment with CUR enhances pro-oxidant levels, antioxidant enzymes activities and anti-inflammatory cytokine production and decreases apoptotic cells in AlCl3-exposed hippocampus rats. Additionally, histopathological analysis of hippocampus revealed the potential of CUR in decreasing the hallmarks in the AlCl3-induced AD. We also showed that CUR post-treatment significantly improved the behavioral, oxidative stress and inflammation in AlCl3-exposed rats. Taken together, our data presented CUR as a nutraceutical potential through its protective effects that are more interesting than recovery ones in sporadic model of AD.

[Endometrial carcinoma: An histopathological and histoprognotic study about 62 patients in a center in the Tunisian north]. / Les carcinomes de l'endomètre : étude anatomopathologique et histopronostique à propos de 62 cas dans un centre du Nord tunisien.

Endometrial cancer is the most prevalent genital tract cancer in occident and the third most common cancer among women in Tunisia. It is dominated by carcinoma. The identification of prognostic factors allows a better understanding of its outcome and guides its therapeutic approach. We propose to describe the clinicopathological features and identify the histoprognostic factors of this cancer. It is a retrospective analysis of a series of 62 total hysterectomy specimens with bilateral salpingo-oophorectomy from women with primary carcinoma of the endometrium, colligated in Anatomy Laboratory and Pathology Salah Azaiz Institute of Tunis over a period of 5 years, from January 2003 to December 2007. The median age was 60 years. At the time of diagnosis, 25% of patients were nulliparous and 86% were menopaused. The endometrioid adenocarcinoma was the most common, accounting for 84% of cases (5% of them were grade 3). A myometrial invasion superior or equal to 50% was observed in 40% of cases. 42% of cases were classified as stage IA, 14% in stage IB, 16% in stage II, 18% stage III and 10% in stage IV. 22% of patients had nodal involvement. Overall survival at 5 years was 81%. In multivariate analysis, stage IV, nodal involvement and brachytherapy have influenced this rate. Event-free survival at 5 years was 71%. It was directly related to stage and nodal involvement. Stage, histological type, tumor grade, invasion of more than half of the myometrium and lymph node involvement were the most important adverse prognostic factors, dictating an appropriate management of these tumors.

Analysis of prognostic factors of nephroblastoma in a Tunisian cohort.

BACKGROUND: Nephroblastoma is the most common childhood abdominal malignancy. Many studies allowed a better understanding of prognostic factors and they permitted to adapt treatment according to a risk stratification approach. AIM: To assess the most significant factors influencing the survival of patients presenting nephroblastoma. METHODS: We conducted a retrospective study over a 10-year period between 2001 and 2010 including 42 nephrectomy specimens, assessed in the pathology department of Salah Azaiz Institute, from all children diagnosed with nephroblastoma. The tumors were subdivided into histological subtypes and histological risk groups according to the SIOP-2001 classification. Statistical analyses were performed using the Kaplan-Meir and the Cox regression methods. RESULTS: The median age was 38 months. The mixed type was the most common (40% of cases). The tumors were subdivided into intermediate histological risk group (81%) and high risk group (14%). The tumors were classified as stage I (38%), stage II (24%), stage III (9%), stage IV (17%) and stage V (12%). The four-year survival rate was 83% and the event free survival rate was 85%. Age, laterality, histological risk group, tumor volume, blastema volume, stage, capsular rupture and incomplete resection had a significant impact on survival. Predictive factors of relapse were: laterality, tumor volume, blastema volume, histological risk group, stage, capsular rupture and incomplete resection. CONCLUSION: Histological type and stage were identified as the most important prognostic factors in nephroblastoma. Further large studies are needed to establish the impact of absolute blastemal volume.

Thyroid oncocytic neoplasms.

BACKGROUND: Oncocytic tumors (OT) are rare, representing 3 to 10% of epithelial tumors of the thyroid. It is important to individualize these TO given the relatively high frequency of carcinomas in this group: 30% against 15% for micro-vesicular lesions of classical cytology and the aggressiveness of malignant OT due to their low iodine uptake. AIM: The aim of our study was to describe the anatomo-clinical aspects of oncocytic tumors of the thyroid. METHODS: Our study was retrospective, realized on 99 cases of oncocyte thyroid tumors collected at the Anatomy and Pathology Cytology laboratory of Tunis Charles Nicolle Hospital during a 10-year period (2004-2014). RESULTS: Our series included: 76 oncocyte adenomas, 13 oncocytic papillary carcinomas, 7 oncocytic carcinomas and 3 tumors of uncertain malignant potential (3%). The correlation of the anatomo-clinical data with the diagnostic categories showed a statistically significant difference concerning the macrovesicular architecture. We found no difference between benign and malignant TO, in relation to age, echogenicity, tumor size, macroscopic appearance, capsule thickness, percentage of oncocyte cells, and the presence of associated lymphocyte thyroiditis. CONCLUSIONS: In view of the literature data and the findings of our study, it seems that there are no predictive factors for the malignancy of oncocytic tumors at the pre- and peroperative stage, with the exception of papillary-type nuclear atypia for Oncocytic papillary carcinoma.

Stromal Expression of MARCKS Protein in Ovarian Carcinomas Has Unfavorable Prognostic Value.

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer. Identification of new therapeutic targets is crucial. MARCKS, myristoylated alanine-rich C-kinase substrate, has been implicated in aggressiveness of several cancers and MARCKS inhibitors are in development. Using immunohistochemistry (IHC), we retrospectively assessed MARCKS expression in epithelial and stromal cells of 118 pre-chemotherapy EOC samples and 40 normal ovarian samples from patients treated at Salah Azaiez Institute. We compared MARCKS expression in normal versus cancer samples, and searched for correlations with clinicopathological features, including overall survival (OS). Seventy-five percent of normal samples showed positive epithelial MARCKS staining versus 50% of tumor samples (p = 6.02 × 10-3). By contrast, stromal MARCKS expression was more frequent in tumor samples (77%) than in normal samples (22%; p = 1.41 × 10-9). There was no correlation between epithelial and stromal IHC MARCKS statutes and prognostic clinicopathological features. Stromal MARCKS expression was correlated with shorter poor OS in uni- and multivariate analyses. Stromal MARCKS overexpression in tumors might contribute to cancer-associated fibroblasts activation and to the poor prognosis of EOC, suggesting a potential therapeutic interest of MARCKS inhibition for targeting the cooperative tumor stroma.

Soft Tissue Myoepithelial Carcinoma in a Child: Case Report.

BACKGROUND: Myoepithelial carcinoma was only recently recognized to occur primarily in soft tissue. Only a small number has been reported in children. OBSERVATION: We report a rare case of myoepithelial carcinoma of the leg in a 4-month-old boy with a good response to chemotherapy initially. However, he presented secondarily during chemotherapy a local and metastatic progression. CONCLUSIONS: The rarity of the tumor and unusual age of discovery have prompted us to report this case. Our case suggests that this disease can have an aggressive behavior. This is why we advise a rapid and correct diagnosis followed by an aggressive treatment.

Prognostic factors in children with extracranial malignant germ cell tumors: a monocentric pediatric Tunisian study.

Background Extracranial Germ cell tumors (GCT) are a rare and a heterogeneous group of pediatric cancers but highly curable. Aim We aimed to review management, outcome and prognostic factors that influence overall survival (OS) in a pediatric Tunisian oncologic unit. Methods We retrospectively evaluated between January 1998 and December 2012, 33 patients affected by extracranial germ cell tumors and treated according to TGM95 protocol established by the SFOPin a pediatric Tunisian oncologic unit. Results Patients had a mean age of 57 months (ranges: 1 day-13 years). There were 19 girls and 14 boys. Primary sites included 12 sacrococcygeal, 11 ovarian, 6 testicular, 3retro peritoneal and 1 mediastinal site. After a mean follow up of 26.1 months (ranges: 0-96 months), OSat 2 years and 5 years were respectively 82% and 75%. Event-free survival were respectively 79% at 2 years and 74% at 5 years. Various prognostic factors have been studied according to Kaplan-Meier. Univariate analyses identified significant factors which influence strongly OS: the stage (p=0.04), the completeness of surgery (p<0.001) and the relapse (p = 0, 0001). A multivariate study showed that only the quality of resection and the clinical stage remained strong significant prognostic factors (p=0,021) for 5-year OS. Conclusion Disease stage, completeness of surgery and relapse have been established as the most powerful prognostic parameter in our analysis. The improvement of survival of patients affected by extracranial germ cell tumors in Tunisia is a real achievement mainly due to the success of salvage treatments.

Ovarian mass in a patient with invasive breast carcinoma: A case report of an unexpected diagnosis.

INTRODUCTION: Ovarian steroid cell tumors not otherwise specified (OSCT-NOS) are extremely rare ovarian sex cord stromal tumors, accounting for <0.1 % of all ovarian tumors. In 25 % of cases, they are asymptomatic leading to a delay in diagnosis. We, herein, report a singular case of OSCT-NOS diagnosed incidentally during the spread assessment of an invasive breast carcinoma of no special type (IBC-NOS). To the best of our knowledge, this is the first reported case of co-occurrence of OSCT-NOS and IBC-NOS. We aim to study the clinic-pathological characteristics of this rare tumor. CASE PRESENTATION: A 56-years old postmenopausal female, with no previous medical history, was diagnosed with an invasive IBC-NOS. The tomography performed during the spread assessment of IBC-NOS showed a suspicious mass of the right ovary. Pelvic MRI revealed an ovarian solid T1 isointense and T2 hyperintense mass. The first evoked diagnosis was an ovarian metastasis of the IBC-NOS. The patient underwent bilateral salpingo-oophorectomy. On gross examination, an ovarian solid mass measuring 2,5x2cm, with a firm gray yellowish cut surface was noted. Microscopic examination and immunostaining concluded to OSCT-NOS and ruled out the diagnosis of an ovarian metastasis of IBC-NOS. CONCLUSION: OSCT-NOS are rare neoplasms. Their diagnosis might be challenging especially in absence of hormonal symptoms. A better knowledge of this rare entities would enable early diagnosis.

Advancing understanding of the role of IL-22 in myelination: insights from the Cuprizone mouse model.

Despite significant advancements in the field, the pathophysiology of multiple sclerosis (MS) remains partially understood, with limited therapeutic options available for this debilitating condition. The precise impact of Interleukin-22 (IL-22) in the context of MS is still incompletely elucidated with some evidence suggesting its protective role. To provide a more comprehensive understanding of the role of IL-22, we investigated its effect on remyelination in a mouse model of demyelination induced by Cuprizone. Mice underwent a 6 week regimen of Cuprizone or vehicle, followed or not by intraperitoneal administration of IL-22. Behavioral assessments including tail suspension and inverted screen tests were conducted, alongside histological, histochemical, and quantitative PCR analyses. In Cuprizone-treated mice, IL-22 significantly improved motor and behavioral performance and robustly promoted remyelination in the corpus callosum. Additionally, IL-22 administration led to a significant elevation in MBP transcription in brain biopsies of treated mice. These findings collectively suggest a crucial role for IL-22 in the pathophysiology of MS, particularly in supporting the process of remyelination. These results offer potential avenues for expanding therapeutic strategies for MS treatment. Ongoing experiments aim to further unravel the underlying mechanisms of IL-22 action.

VISTA/CTLA4/PD1 coexpression on tumor cells confers a favorable immune microenvironment and better prognosis in high-grade serous ovarian carcinoma.

Introduction: Immunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer. Methods: In this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed. Results and discussion: CTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage (p=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (p=0.005, p=0.001, p=0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (p=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (p=0.01) and the coexpression of VISTA+/CTLA4+/PD1+ (p=0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA+/CTLA4+/PDL1+ and VISTA+/CTLA4+/PD1+ checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and p<0.001; respectively). VISTA+/CTLA4+/PD1+ in TCs and CD4+/CD8+TILswere associated with better 2-yer OS. This correlation may refer to the role of VISTA as a receptor in the TCs and not in the immune cells. Thus, targeting combination therapy blocking VISTA, CTLA4, and PD1 could be a novel and attractive strategy for HGSOC treatment, considering the ambivalent role of VISTA in the HGSOC tumor cells.

Ovarian ALK+ diffuse large B-cell lymphoma: a case report and a review of the literature.

Through this case presentation and a review of the literature, we aim to describe clinical and pathologic features and to distinguish the outcome of these tumors. A 25-year-old woman presented with pelvic pain and an iliac mass. Workup revealed a 53-mm cystic partitioned mass of the left ovary infiltrating the left sacrum. She underwent a left adnexectomy. Gross examination revealed a ruptured ovarian mass. When dissected, it showed grayish cerebroid aspects. Histologic examination revealed a malignant tumor proliferation of the diffuse large cells. An immunohistochemical analysis showed negative results for PLAP, αFP, ßHCG, CD117, CK20, and CD30. It also showed lack of B markers and T marker (CD3) and an expression of CD138 and anaplastic lymphoma kinase. The patient was treated by 6 cycles of CHOP chemotherapy and a pelvic radiotherapy. She presented with a 15-cm splenomegaly 26 months later and died of febrile neutropenia. Most patients follow an aggressive disease and are unlikely to respond to the standard.

Unusual presentation of uterine tumors resembling ovarian sex cord tumor: A rare case report of cervical involvement.

INTRODUCTION AND IMPORTANCE: Cervical localization of uterine tumor resembling an ovarian sex cord tumor is very rare (UTROSCT) and this is the third case reported in the English literature. Given its rarity, the diagnosis is frequently challenging. Our aim was to discuss pathological characteristics and treatment choices of this rare disease happening in a rare location. CASE PRESENTATION: Our case interested a 19-year-old female patient who presented with a lower abdominal pain and irregular menstrual cycles for a duration of two months. Gynecological examination revealed a cervical firm mass. The patient underwent a cervical lumpectomy. Microscopically, the tumor had nested and trabecular/cord patterns. Tumor cells had abundant cytoplasm, ovoid and spindle-shaped nuclei with fine chromatin. Mitoses were < 1/10 HPFs. A delicate vascular network of small capillaries was noted. Immunohistochemical staining showed that tumor cells were positive for Calretinin, AE1/AE3, Desmin, progesteron receptors, SMA and h-caldesmon. Pathological examination concluded to an UTROSCT. CLINICAL DISCUSSION: UTROSC is a rare tumor with only two cases with cervical involvement reported so far. They have an indolent clinical history and thus require a more cautious and less invasive therapeutic decision. The diagnosis remains on the pathological examination. CONCLUSION: This case is original by its location and the age of presentation. Careful follow-up is necessary searching for local recurrence or metastasis.