Brentuximab in the treatment of CD30-positive enteropathy-associated T-cell lymphoma.

Enteropathy-associated T-cell lymphoma (EATL) is a rare aggressive lymphoma that confers a poor prognosis with current treatment strategies. Given the rarity of this disease, prospective randomized trials are limited, and thus a standard validated treatment strategy is lacking. This report presents the disease course of a patient with EATL who was treated with single-agent brentuximab vedotin, an anti-CD30 conjugated antibody.

The impact of systemic methotrexate and surgical management on fertility preservation in tubal ectopic pregnancy among Saudi women.

BACKGROUND: The impact of various management plans on subsequent fertility after tubal ectopic pregnancy (EP) is not well known. The objective of the present study was an evaluation of the subsequent fertility outcome among women with EP managed either surgical or medical with systemic methotrexate or medical management followed by surgical one. PATIENTS AND METHODS: A retrospective cohort study was done by reviewing of medical records of all women diagnosed with EP at King Faisal Military Hospital, Southern Region, Saudi Arabia throughout the period from January 2015 to December 2016 provided that they were hemodynamic stable, with starting ßhCG level less than 10000 IU/L, and adnexal mass less than 5 cm. These cases were followed for four years from January 2017 to December 2020. RESULTS: The study included 85 women with EP. Their mean age was 31.3 ± 6.7 years. Medical management (systemic Methotrexate) was followed in 48.2% of cases whereas surgical management was applied for 43.5% of them while medical management followed by surgical one was seen in 8.2% of cases. Complete follow-up throughout 2017-2020 was available for 52 women. A history of recurrent EP was observed among 3 women (5.8%). Most of them (75%) had a viable pregnancy. There was no statistically significant association between the method of management of EP and subsequent fertility, although the rate of normal pregnancy (intrauterine viable pregnancy ≥ 24 weeks which is the age of viability at our hospital) was higher among those managed surgically or by medical followed by surgical management than those managed medical only (84.6% and 100% vs. 62.5%). CONCLUSION: Although the normal pregnancy rate was higher among those managed surgically or by medical followed by surgical management than those managed medically only, this was not statistically significant.

Nf1-/- Schwann cell-conditioned medium modulates mast cell degranulation by c-Kit-mediated hyperactivation of phosphatidylinositol 3-kinase.

Neurofibromatosis type 1 (NF1) is a common genetic disorder and is characterized by both malignant and nonmalignant neurofibromas, which are composed of Schwann cells, degranulating mast cells, fibroblasts, and extracellular matrix. We and others have previously shown that hyperactivation of the c-Kit pathway in an Nf1 haploinsufficient microenvironment is required for both tumor formation and progression. Mast cells play a key role in both tumorigenesis and neoangiogenesis via the production of matrix metalloproteinases, heparin, and a range of different growth factors. In the present study, we show that tumorigenic Schwann cells derived from Nf1(-/-) embryos promote increased degranulation of Nf1(+/-) mast cells compared with wild-type mast cells via the secretion of the Kit ligand. Furthermore, we used genetic intercrosses as well as pharmacological agents to link the hyperactivation of the p21(Ras)-phosphatidylinositol 3-kinase (PI3K) pathway to the increased degranulation of Nf1(+/-) mast cells both in vitro and in vivo. These studies identify the p21(Ras)-PI3K pathway as a major regulator of the gain in Nf1(+/-) mast cell degranulation in neurofibromas. Collectively, these studies identify both c-Kit and PI3K as molecular targets that modulate mast cell functions in cases of NF1.

Chlamydia trachomatis infection in primary fallopian tube and high-grade serous ovarian cancers: a pilot study.

BACKGROUND: The aim of this study was to evaluate the association of Chlamydia trachomatis (CT) infection with primary tubal and high-grade serous ovarian cancers. METHODS: This is a cross-sectional, retrospective study conducted at Ain Shams University Maternity Hospital, Egypt, from February 2008 to October 2017. Sixty-seven paraffin archival blocks specimens were retrieved from cases who underwent staging laparotomy due to high-grade serous ovarian cancer (30 cases), primary tubal serous cancer (25 cases), and control specimens of (12) tubal specimens from cases of benign gynecological conditions. All samples were examined for CT DNA using semiquantitative qRT-PCR. RESULTS: CT DNA was detected in 84% of high-grade tubal serous cancer, 16.7% of high-grade serous ovarian cancer, and 13.3% in controls (P<0.0005). Mean CT DNA relative quantity was significantly high (256) in tubal carcinoma, in comparison to that in high-grade serous ovarian cancer and controls (13.5 and 0.28, respectively; P<0.0005). CONCLUSION: To the best of our knowledge, this is the first report on relation of CT to the tubal serous cancer, so the responsibility of CT tubal infection in the pathogenesis of primary tubal cancer needs to be considered.

Transcriptional repression of the Neurofibromatosis-1 tumor suppressor by the t(8;21) fusion protein.

Von Recklinghausen's disease is a relatively common familial genetic disorder characterized by inactivating mutations of the Neurofibromatosis-1 (NF1) gene that predisposes these patients to malignancies, including an increased risk for juvenile myelomonocytic leukemia. However, NF1 mutations are not common in acute myeloid leukemia (AML). Given that the RUNX1 transcription factor is the most common target for chromosomal translocations in acute leukemia, we asked if NF1 might be regulated by RUNX1. In reporter assays, RUNX1 activated the NF1 promoter and cooperated with C/EBPalpha and ETS2 to activate the NF1 promoter over 80-fold. Moreover, the t(8;21) fusion protein RUNX1-MTG8 (R/M), which represses RUNX1-regulated genes, actively repressed the NF1 promoter. R/M associated with the NF1 promoter in vivo and repressed endogenous NF1 gene expression. In addition, similar to loss of NF1, R/M expression enhanced the sensitivity of primary myeloid progenitor cells to granulocyte-macrophage colony-stimulating factor. Our results indicate that the NF1 tumor suppressor gene is a direct transcriptional target of RUNX1 and the t(8;21) fusion protein, suggesting that suppression of NF1 expression contributes to the molecular pathogenesis of AML.

Assessment of hysteroscopic role in management of women with recurrent pregnancy loss.

OBJECTIVES: To assess the hysteroscopic value in the management of intrauterine lesion in women with recurrent pregnancy loss. METHODS: This study was done in Ain Shams Maternity Hospital after the approval of the research Ethics Committee, during the period between August 2014 and December 2015 where 200 nonpregnant women with a history of three or more consecutive unexplained first and second trimester miscarriages before 20 weeks were recruited from recurrent miscarriage clinic. A written informed consent was obtained from all women before participation. RESULTS: This current study was conducted in Ain Shams University Maternity Hospital during the period between August 2014 to May 2015 a total of 200 women with history of recurrent miscarriage were included in the study. Regarding the results of this study the mean age was 30.5(5.7), the mean number of previous abortion 3(3-5) the mean number of the first trimesteric abortion was 2 with range (2-2) the mean number of second trimesteric abortion was 2 with range (1-2). In this study, 88% of patients were nullipara. It was also found that hysteroscopic findings were found in 58.5%. Uterine anomalies was present in 21%, including septate uterus and intrauterine adhesion (IUAs) were present in 12.5%. Endometrial polyps were present in 8.5%, bicornute uterus in 4.5%, unicornuate uterus in 4.5% while submucous myomas were present in 7.5%. It was found that 48.5% need hysteroscopic intervention including 21% need septectomy 12.5% need adhesiolysis, 6.5% need myomectomy while 8.5% need polypectomy. The study found that no statistically significant difference between patients with normal hysteroscopic finding and patients with abnormal hysteroscopic finding as regard age, time of previous abortion and number of previous abortion. But there was statistically significant difference as regard number of previous delivery and abnormal HSG. CONCLUSIONS: It appears that hysteroscopy is a useful tool in the diagnosis and treatment of the causes of recurrent miscarriage that can be performed safely without anesthesia in most cases. The prevalence of uterine anomalies in patients with recurrent miscarriages is 54.5%, septate uterus is the most common anomaly and for this reason uterine anomalies should be systematically assessed in patients with recurrent miscarriage.

Endometrial Volume Measured by VOCAL Compared to Office Hysteroscopy for Diagnosis of Endometrial Polyps in Premenopausal Women with Abnormal Uterine Bleeding.

The aim is to compare hysteroscopy, two-dimensional transvaginal ultrasound (2D TVUS), and three-dimensional (3D) Virtual Organ Computer-aided AnaLysis™ (VOCAL) to detect endometrial polyps (EPs) in premenopausal women with abnormal uterine bleeding (AUB). This prospective study was done at Ain Shams Maternity Hospital, Egypt, from March 5, 2015, to December 30, 2015, enrolling 118 premenopausal women with AUB. 2D TVUS, 3D VOCAL, and hysteroscopy were done. 109 patients reached final analysis. 36 women (33%) were diagnosed with EP by 2D TVUS. 50 (45.9%) had EP by hysteroscopy. Endometrial thickness was 10.1 mm by 2D TVUS and endometrial volume was 4.92 mL by VOCAL in women with EP by hysteroscopy compared to 9.9 mm and 3.50 mL in women with no EP, respectively (P = 0.223; P = 0.06). 2D TVUS has sensitivity, specificity, and positive and negative predictive values of 54%, 84.7%, 75%, and 68.5%, respectively. Endometrial thickness of >7.5 mm has sensitivity, specificity, positive and negative predictive values, and overall accuracy of 82%, 37.3%, 52.6%, 71%, and 57.8%, respectively. Endometrial volume of >1.2 mL has sensitivity, specificity, positive and negative predictive values, and overall accuracy of 90%, 42.4%, 57%, 83.3%, and 64.2%, respectively. 3D VOCAL may be used as a noninvasive method for the diagnosis of EP in premenopausal women with AUB.

Interferon-alpha 2b and vesnarinone influence levels of tumor necrosis factor-alpha, apoptosis, or interleukin 6 in ESKOL, a hairy cell leukemic cell line. A potential cytokine and oncogene relationship regulating apoptosis is suggested.

The in vitro effects of interferon-alpha (IFN) on levels of secreted interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF alpha), and nuclear matrix proteins (NMP) were examined in ESKOL, a B-lymphoblastoid cell line resembling hairy cell leukemia (HCL). IFN enhances differentiation in ESKOL, decreases TNF alpha levels, decreases apoptosis, increases IL-6 levels, and down regulates the expression of several oncogenes. Vesnarinone (Ves), a TNF alpha repressor, lowers TNF-alpha and decreases apoptosis in the same cell line. ESKOL exhibits enhanced apoptosis and reduced B-cell lymphomas (Bcl-2) levels over WIL-2. IL-6 and TNFalpha have been shown to decrease and increase apoptosis in B-cells respectively; however, treatment of ESKOL with these cytokines had no significant effect on apoptosis. We suggest that IFN decreases apoptosis by mechanisms involving enhanced IL-6 and Bcl-2 levels, decreased TNF alpha and the down regulation of apoptotic oncogenes, including c-myc.

K-ras is critical for modulating multiple c-kit-mediated cellular functions in wild-type and Nf1+/- mast cells.

p21(ras) (Ras) proteins and GTPase-activating proteins (GAPs) tightly modulate extracellular growth factor signals and control multiple cellular functions. The specific function of each Ras isoform (H, N, and K) in regulating distinct effector pathways, and the role of each GAP in negatively modulating the activity of each Ras isoform in myeloid cells and, particularly, mast cells is incompletely understood. In this study, we use murine models of K-ras- and Nf1-deficient mice to examine the role of K-ras in modulating mast cell functions and to identify the role of neurofibromin as a GAP for K-ras in this lineage. We find that K-ras is required for c-kit-mediated mast cell proliferation, survival, migration, and degranulation in vitro and in vivo. Furthermore, the hyperactivation of these cellular functions in Nf1(+/-) mast cells is decreased in a K-ras gene dose-dependent fashion in cells containing mutations in both loci. These findings identify K-ras as a key effector in multiple mast cell functions and identify neurofibromin as a GAP for K-ras in mast cells.

Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling.

Neurofibromas are common tumors found in neurofibromatosis type 1 (NF1) patients. These complex tumors are composed of Schwann cells, mast cells, fibroblasts and perineurial cells embedded in collagen that provide a lattice for tumor invasion. Genetic studies demonstrate that in neurofibromas, nullizygous loss of Nf1 in Schwann cells and haploinsufficiency of Nf1 in non-neuronal cells are required for tumorigenesis. Fibroblasts are a major cellular constituent in neurofibromas and are a source of collagen that constitutes approximately 50% of the dry weight of the tumor. Here, we show that two of the prevalent heterozygous cells found in neurofibromas, mast cells and fibroblasts interact directly to contribute to tumor phenotype. Nf1+/- mast cells secrete elevated concentrations of the profibrotic transforming growth factor-beta (TGF-beta). In response to TGF-beta, both murine Nf1+/- fibroblasts and fibroblasts from human neurofibromas proliferate and synthesize excessive collagen, a hallmark of neurofibromas. We also establish that the TGF-beta response occurs via hyperactivation of a novel Ras-c-abl signaling pathway. Genetic or pharmacological inhibition of c-abl reverses fibroblast proliferation and collagen synthesis to wild-type levels. These studies identify a novel molecular target to inhibit neurofibroma formation.

K-Ras is essential for normal fetal liver erythropoiesis.

In vitro studies suggest that Ras activation is necessary for erythroid cell development. However, genetic inactivation of the Ras isoforms H-Ras, N-Ras, and K-Ras in mice reportedly did not affect adult or fetal erythropoiesis, though K-Ras(-/-) embryos were anemic. Given these discrepancies, we performed a more detailed analysis of fetal erythropoiesis in K-Ras(-/-) embryos. Day-13.5 K-Ras(-/-) embryos were pale with a marked reduction of mature erythrocytes in their fetal livers. The frequency and number of both early (erythroid burst-forming unit [BFU-E]) and late erythroid progenitors (erythroid colony-forming unit [CFU-E]) were reduced in K-Ras(-/-) fetal livers compared with wild-type controls and displayed a delay in terminal erythroid cell maturation. Further, K-Ras(-/-) hematopoietic progenitors had reduced proliferation in response to erythropoietin and Kit ligand compared with control cells. Thus, these studies identify K-Ras as a unique Ras isoform that is essential for regulating fetal erythropoiesis in vivo.

Epigenetic regulation of tumor suppressors in t(8:21)-containing AML.

The t(8;21) is perhaps the most frequent chromosomal translocation associated with acute myeloid leukemia. The translocation creates a fusion protein that consists of the DNA binding domain of the RUNX1 transcription factor fused to the MTG8 transcriptional co-repressor to create a potent transcriptional repressor. Here, we discuss the possibility that the t(8;21) fusion protein represses tumor suppressors that regulate the RAS signaling pathway and the p53 oncogenic checkpoint.