Karima Mrad

Optimization of cellulase production by Penicillium occitanis

The mutant Pol6 of Penicillium occitanis is an interesting strain for producing cellulases and hemicellulases. The nitrogen source and substrate that regulate cellulase production were evaluated in shake-flask and fermentor (batch and fed-batch) culture. The nature of the nitrogen source and the C/N ratio markedly affected cellulase production by P. occitanis. When nitrate was used in Mandels and Webers basal growth medium with a C/N ratio below 20.2, it resulted in more cellulase production than from urea or ammonium sulphate. Crude substrates such as wheat bran and wheat flour residues, used in combination with a local cellulose esparto grass paper pulp as an alternative nitrogen source and cellulose substrates, also gave high cellulase yields. Greatest cellulase yields and productivity were obtained by fed-batch cultivation [23 filter-paper activity units (FPU)/ml and 168 FPUI−1h−1].

Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma

Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.

Evaluation of tumor‑free distance and depth of myometrial invasion as prognostic factors in endometrial cancer

The aim of the study was to investigate whether the tumor free distance (TFD), which is the distance in millimeters between the deepest point of invasion and the serosal surface, and absolute depth of invasion (DMI), the distance in millimeters between the endomyometrial junction and the deepest point of myometrial invasion, are useful in surgical staging and in predicting prognosis. The present study retrospectively analyzed 62 cases of endometrial carcinoma with complete surgical staging, carried out over a 4 and half-year period (January 2003 to June 2007). All surgicopathological findings including surgical stages, histological type and grade, myometrial invasion, lymphovascular space invasion, cervical and adnexal involvement, and lymph node metastasis were abstracted from medical records and pathological reports. Univariate and multivariate analyses were performed comparing TFD, DMI and the percentage of mypmetrial invasion (MI) with established prognostic factors. A total of 62 patients were included in the study. A total of 52 (84%) had endometrioid carcinomas and 31 patients (60%) had grade 1 cancer. The deepest MI was <50% in 32 patients (52%). Median DMI was 2.7 mm (range 0-15 mm). Median TFD was 3 mm (range 0-19 mm). There was lymphovascular space invasion (LVSI) in 11 patients (17.5%), cervical involvement in 11 patients (17.5%), extra-uterine extension in 9 cases (14%) and lymph node metastasis in 12 patients (22%). It was demonstrated that 50% MI was significantly associated with prognostic factors (cervical involvement, type 2 carcinomas and LVSI, and was a significant predictor of the 5-year overall survival rate and recurrence-free survival (P=0.05, P=0.01). No significant association was observed between DMI and TFD with clinicopathological parameters and survival rates. The importance of DMI in predicting recurrence of disease was observed to be highest in terms of sensitivity and specificity. The cut-off value with the highest sensitivity and specificity crossing the receive operating characteristic curve was calculated to be 3 mm for DMI and 2.5 mm for TFD. The results indicate that DMI is a superior predictive factor of recurrence of the disease compared with TFD. However, further studies are required in order to prove the prognostic usefulness of these parameters and then to improve management of endometrial cancer.

Increased plasmatic soluble HLA-G levels in endometrial cancer

HIGHLIGHTSsHLA‐G is significantly increased in patients with EC.sHLA‐G is highly increased in early stages and in high grade EC.HLA‐G5 are more represented than sHLA‐G1 molecules in patients with EC.sHLA‐G are represented majorly in monomeric forms.sHLA‐G dimeric forms are specifically associated to early stages of EC. ABSTRACT Human Leukocyte Antigen‐G (HLA‐G) is known as an immune suppressive molecule; it interacts with several immune cells and inhibits their functions. HLA‐G molecule is highly represented in pathological conditions including malignant transformation. To the best of our knowledge this is the first study that focuses on the expression of soluble HLA‐G (sHLA‐G) in endometrial cancer (EC). We aimed at exploring sHLA‐G plasma levels and its prognostic value in EC. We examined total sHLA‐G expression as well as the sHLA‐G1 and HLA‐G5 isoforms expression in plasma samples from 40 patients with EC and 45 healthy controls by a specific sandwich ELISA. Immunoprecipitation and Coomassie blue staining were performed to explore the presence of plasmatic sHLA‐G monomers and dimers. sHLA‐G plasma level was significantly enhanced in patients with EC compared to healthy controls (p=0.028). Additionally, HLA‐G5 molecules were highly represented than sHLA‐G1 molecules in EC, at the borderline of significance (p=0.061). Interestingly, sHLA‐G has been shown to be increased in early stages (Stages I and II) as well as in high grade EC (Grade 3) that is associated with rapid spread of the disease (p=0.057). sHLA‐G positive EC plasma were majorly in monomeric form (75%). Clinically, all the HLA‐G dimers were detected in early stages and in high grade of EC. Our data strengthen the implication of HLA‐G molecules in EC etiology and especially in progression.

Survival and prognostic factors of lymphadenectomy in endometrial cancer: a Tunisian single center experience

Endometrial cancer (EC) is the most common pelvic gynecological cancer. The International Federation of Gynecology and Obstetrics (FIGO) 2009 staging system recommend a surgical staging of EC without defining the appropriate limits of each lymphadenectomy (pelvic and paraoaortic) or a cut off number of lymph node (LN) required for an optimal procedure. Thus, the preoperative staging of the disease is necessary, in order to avoid an excessive surgical procedure, or on the contrary insufficient.

Prognostic factors of ALK-negative anaplastic large-cell lymphoma: a single-institution experience

Dear Editor, Anaplastic large-cell lymphoma (ALCL) was recognized as a subgroup of tumors which is defined as a neoplastic proliferation of lymphoid cells, with bizarre morphologic features, that are anaplastic in appearance, have a propensity to grow cohesively, invade lymph node sinuses, and consistently express the CD30. Revisions of the fourth edition of the WHO classification (2016) have classified anaplastic lymphoma kinase (ALK)-ALCL as a definitive and recognized entity [1]. Our aim was to study the most relevant prognostic factors that impact the clinical course of ALK-ALCL. This study is retrospectively carried out over an 18year period (1999–2016) and conducted at our pathology department (Salah Azaïz Institute, Tunisia). Based on the criteria of the 2016 WHO classification, 52 cases were systematically reviewed. A total of consecutive 34 pa t i en t s w i th ALK-ALCL were inc luded . Immunohistochemistry study was performed to determine the phenotype of tumor cells. Clinical information for each patient including the age, the gender, and Ann Arbor stage was abstracted from the medical records. Additional data recorded including the performance status (PS), the level of LDH, extranodal involvement, and medullary invasion were obtained. The International Prognostic Index (IPI) was used to stratify patients within the various disease entities. Treatment outcome was determined by overall survival (OS). IBM SPSS 16 software was used for the statistical analyses. Statistical tests used were the log rank test, the method of Kaplan and Meier, and the chi-square test. P values less than 0.05 were considered significant. Characteristics of ALK-ALCL are summarized in Table 1. In contrast to increased age, gender, IPI score, LDH rate, lymphoma’s phenotype, and extranodal sites except medullar involvement, advanced Ann Arbor stage and medullar involvement were significant poor prognostic factors (P = 0.004 and P = 0.000, respectively) (Table 1). ALK-ALCL occurs generally in patients with a peak incidence in adults (40–60 years) with preponderance of male [1, 2]. ALK-ALCLs are characterized by unfavorable clinical features (high age and advanced stage at diagnosis, high-risk IPI features) and a poor prognosis which is reported to be better than peripheral T cell lymphoma, not otherwise specified, and to be worse than ALK + ALCL (4, 5, 7). In our study, the OS was 48.5% and this is comparable with prior estimates (30–49%) [2–4]. Most patients presented with advanced disease (stage III and IV) were all aged more than 50 years, suggesting that ALK-ALCL with advanced stage occurs frequently in adults more than children and young adults. Bone marrow involvement are considered as a prognostic factor either in our study (P = 0.000) or in the literature review [3, 5, 6]. ALK-ALCL was always CD30−, more frequently cytotoxic marker-positive and EMA-positive, and was less likely to express various T cell markers (CD2, CD3, CD4, CD43) [3]. Other prognostic factors have been reported in the literature including the expression of proteins involved in the regulation of apoptosis and of CD56 [4] and other genetic rearrangements [1] without a real consensus. * Yoldez Houcine daddoussa87@hotmail.fr

Teratoid Medulloepithelioma: A Rare Intraocular Tumor of a Child

Medulloepithelioma is a rare congenital neuroepithelial tumor commonly arising from the non-pigmented ciliary body epithelium and rarely from iris, retina or the optic nerve. It occurs in patient under 10 years. It is a rare neuroepithelial tumor and is the second most frequent intraocular tumour in children after retinoblastoma. Unlike cases reported in the literature in which the tumour recurs rapidly, recurrence occurred in our case five years later.

A New Case of Primary Signet Ring Cell Carcinoma of the Uterine Cervix: A Case Report and Review of the Literature

Primary signet-ring cell carcinoma of cervix is extremely rare in the literature. Usually Signet-Ring Cell Carcinomas (SRCCs) of the cervix are metastatic from a primary gastric, colonic, ovarian, or breast carcinoma. A 48-year-old woman was referred to our Department due to persistent abnormal vaginal bleeding during the last two months. Gynecologic examination revealed cervical tumor. Biopsy revealed a signet ring cell type of mucinous adenocarcinoma. Extensive systemic examination reveals liver metastases biopsies confirmed. The patient was treated with palliative chemotherapy. The prognosis of primary signet ring cell adenocarcinoma of the uterine cervix is still unclear because of the rare incidence of cases. In this report we reviewed the literature to identify the clinical, pathological and immunohistochemical features of this rare malignancy.

Giant Cell Tumor of Soft Tissues: A Case Report and Review of Literature

Background: Primary giant cell tumor (GCT) of soft tissue (GCTST) is an extremely rare slow-growing entity bearing a high similarity to conventional bone TCG (GCTB). The term, malignant tumor of giant cells of soft tissues have been reserved for histologically high-grade lesions. Although the gold standard remains surgical carcinological resection, bisphosphonates are beginning to prove their benefit in the treatment of GCTST. Results and Discussion: A 37-year-old man came to the outpatient department of medical oncology with a painful swelling arising from his right elbow. Magnetic resonance imaging (MRI) of the right elbow was done and revealed a 19 cm × 7 cm, T1 and T2 hypointense lesion with significant postcontrast enhancement of calcified tissue nodules, distance extension report was negative. An echo-guided biopsy of the right elbow was performed. The anatomopathological examination showed a poorly delimited encapsulated tumor proliferation composed of sheets of histiocytic cells admixed with multinucleated giant cells dispersed uniformly among this tumor. Cells were embedded in a richly vascularized tissue. No significant nuclear pleomorphism or mitotic activity was appreciated. There were focal areas of osseous metaplasia. On the basis of these date, the diagnosis of giant cell tumor of low malignant potential was retained. Due to its intra-articular extension, the mass was judged unresecable. The case was discussed in a multidisciplinary consultation meeting indicating medical treatment with zoledronic acid given the unavailability of denosumab. After 8 monthly injections of zoledronic acid, a control imaging of the right elbow and forearm concluded to tumor stability. Conclusion: GCTST is a slow-growing tumor known as soft tissue tumor. Numerous studies show the role of bisphosphonates when complete surgical excision cannot be performed. Further studies are needed to establish a standardized treatment protocol particularly in the context of inoperable large primary GCTST.

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.