Pediatric Plasmablastic Lymphoma in the Setting of CD70 Deficiency.

Combined immunodeficiency due to CD70 deficiency is characterized by increased susceptibility to infections, hypogammaglobulinemia, and malignancy. These patients typically present with chronic Epstein Barr virus (EBV) viremia, severe EBV-related hemophagocytic lymphohistiocytosis, lymphoproliferation, and Hodgkin and non-Hodgkin lymphomas. Plasmablastic lymphoma (PBL) is an extremely rare malignancy in all ages and is predominantly seen in male adults with human immunodeficiency virus infection. EBV infection, immunosuppression, solid organ transplantation, and age-related immune deterioration are also suspected causes of PBL. Nevertheless, there is scarce data about its association with primary immunodeficiencies in the literature. Here, we present the first case of a CD70-deficient pediatric patient with PBL.

Niraparib-induced pure red cell aplasia.

INTRODUCTION: Niraparib, a strong poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, contributed significantly to progression-free survival as a maintenance therapy in the platinum-sensitive period in both first-line and recurrent ovarian cancer, regardless of the BRCA mutation. Grade 3-4 anemia, which has a manageable side effect profile, especially hematological, is seen in almost 1 out of every 4 patients. To the best of our knowledge, there has been no reported case of pure red cell aplasia (PRCA) induced by niraparib treatment. CASE REPORT: A 65-year-old woman diagnosed with stage 3 serous carcinoma of the tuba received niraparib front-line maintenance treatment had grade 4 anemia after 3 months of niraparib treatment. She underwent bone marrow aspiration and biopsy because of refractory anemia, which needs red blood cell (RBC) transfusions despite interruption of treatment. MANAGEMENT AND OUTCOME: The patient was treated with 1 mg/kg methyl prednisolone, after histopathological assessment was consistent with PRCA. The hemoglobin count returned to the normal range with steroid treatment. DISCUSSION: In daily practice, it should be kept in mind that in the case of refractory anemia induced by niraparib, the underlying cause might be PRCA and can be improved with steroid administration.

Relationship Between Metabolic Activity, Cellularity, Histopathological Features of Primary Tumors and Distant Metastatic Potential in Breast Cancer.

Objectives: The aim of this study was to evaluate the relationship between the types of distant metastatic spread, histopathological features, and imaging features of primary tumor on positron emission tomography/magnetic resonance imaging (PET/MRI) for primary staging in newly diagnosed breast invasive ductal carcinoma (IDC) patients. Methods: Data from 289 female patients were retrospectively evaluated. Maximum standardized uptake value, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and minimum apparent diffusion coefficient (ADCmin) values of primary tumors were obtained from PET/MRI. The patients were grouped as non-metastatic, oligometastatic (1-5 metastatic lesions) and multimetastatic (>5 metastatic lesions) disease according to the number of distant metastases, and divided into two groups as isolated bone metastasis (IBM) and mixed/soft tissue metastasis (M-SM) groups according to the sites of metastatic spread. Results: Metabolic parameters had higher values and ADCmin had lower values in the multimetastatic and oligometastatic groups than in the non-metastatic group. MTV was the only parameter that showed significant difference between the multimetastatic and oligometastatic groups. MTV and TLG were significantly higher in the M-SM group than in the IBM group. 18F-fluorodeoxyglucose PET parameters had significantly higher values in grade 3, hormone receptor negative, human epidermal growth factor receptor 2 positive, triple negative, and highly proliferative (Ki-67 ≥14%) tumors. The prediction models that included imaging parameters to predict the presence of distant metastasis had higher discriminatory powers than the prediction models that included only histopathological parameters. Conclusion: Primary tumors with higher metabolic-glycolytic activity and higher cellularity were more aggressive and had higher metastatic potential in breast IDC. Compared with histopathological parameters alone, the combination of imaging parameters and histopathological features of primary tumors may help to better understand tumor biology and behavior.

Does Venipuncture Increase Lymphedema by Triggering Inflammation or Infection? An Experimental Rabbit Ear Lymphedema Model Study.

Background: Recent guidelines recommend avoiding venipuncture to prevent lymphedema for breast cancer patients. This study investigated whether single or multiple sterile venipuncture procedures develop a systemic inflammation or infection and increase lymphedema in the rabbit ear lymphedema model. Methods and Results: Eighteen New Zealand white female rabbits were included. The right ear lymphedema model was created by surgical procedure; then, rabbits were divided into three randomized groups. Single and multiple venipuncture procedures were applied at least the 60th day after surgery for Group I and II, respectively. Group III was a control group. C-reactive protein (CRP) and procalcitonin (PCT) levels were analyzed to determine inflammation and infection. Ear thickness measurements were applied using a vernier caliper to assess the differences in lymphedema between the ears. All rabbits were euthanized on the 90th day after surgery. Histopathological analysis was performed to evaluate lymphedema by measuring tissue thicknesses. Ear thickness measurements showed that ear lymphedema was developed and maintained with surgical operation in all groups (p < 0.05). There was no difference in the ear thickness measurements between and within-groups results (p > 0.05). CRP and PCT levels were below the lower detection levels in all groups. According to the differences of histopathological ear distances, there were significant differences within-groups for all groups (p < 0.05), and no differences were identified between groups (p > 0.05). Conclusion: This experimental study demonstrated that single or multiple sterile venipuncture procedures did not trigger infection or inflammation and did not exacerbate ear lymphedema in the rabbit ear lymphedema model.

Eltrombopag may induce bone marrow fibrosis in allogeneic hematopoietic stem cell transplant recipients with prolonged thrombocytopenia.

Poor graft function (PGF) and secondary failure of platelet recovery (SFPR) are significant causes of transplant related morbidity and mortality. Although thrombopoietin receptor agonists (TPO-RA), particularly Eltrombopag (EPAG), have been reported to be efficacious in the treatment of prolonged thrombocytopenia, potential long term adverse effects remain to be elucidated. This retrospective study was performed to determine the efficacy and toxicity profile of TPO-RAs in allogeneic hematopoietic stem cell transplant (alloHCT) recipients. Medical records of 27 patients [median age: 55(21-73) years; male/female: 15/12] who received posttransplant EPAG for SFPR or PGF were analysed. Eltrombopag was started on day 110(33-670) after transplant. Median initial dose was 25(25-50) mg/day which was properly escalated to a maximum dose of 75(50-100) mg/day. Duration of the treatment was median 120(31-377) days. Overall response rate (ORR) was 59.3% in the study population. Time-to-treatment response was 42(3-170) days. Mild-to-moderate bone marrow fibrosis was detected in the posttreatment biopsies of 12/22 patients (54.5%), 9 of whom did not represent any grade of myelofibrosis in their inital biopsies. The grade of posttreatment fibrosis was significantly increased when time-to-treatment response was longer (p = 0.008). Long term use of TPO-RAs may be considered as a potential cause of myelofibrosis in alloHCT recipients.

Treatment with the soluble guanylate cyclase activator BAY 60-2770 normalizes bladder function in an in vivo rat model of chronic prostatitis.

BACKGROUND AND PURPOSE: Chronic pelvic pain syndrome (CPPS) is a common and bothersome condition for which no pharmacological treatment options with acceptable efficacy exist. The aim of this study was to investigate the effects of the soluble guanylate cyclase (sGC) activator BAY 60-2770 and the COX-2 inhibitor celecoxib on bladder function in a rat model of CPPS. EXPERIMENTAL APPROACH: Forty-eight male Sprague-Dawley rats were intraprostatically injected with either saline, serving as control, or zymosan, to induce prostatitis. On days 8-20, the rats were treated with either dimethylsulphoxide (DMSO; vehicle), celecoxib, BAY 60-2770 or a combination of celecoxib and BAY 60-2770. Thereafter, micturition parameters were assessed in a metabolic cage and urine samples were collected. The following day, cystometry was performed. Subsequently, the urinary bladder and prostate were removed and examined histopathologically. KEY RESULTS: Induction of prostatitis led to a significant increase of micturition frequency and corresponding decrease of volume per micturition. These alterations were ameliorated by celecoxib, and completely normalized by BAY 60-2770. Induction of prostatitis led to a significantly increased number of non-voiding contractions, decreased bladder compliance and increased voiding time. These parameters were normalized by treatment with BAY 60-2770, either alone or in combination with celecoxib. The immunohistochemical analysis showed signs of prostate inflammation, but not bladder inflammation. CONCLUSION AND IMPLICATIONS: Induction of prostatitis led to significant impairment in bladder function. These alterations could be prevented by BAY 60-2770, alone or in combination with celecoxib. This is the first study to show that sGC activators could be a promising option for the treatment of CPPS.

Comparison of the effects of operating microscopes with light emitting diode and halogen light source on the eye: a rabbit study.

PURPOSE: To evaluate the potential toxicity of operation microscopes with halogen and light emitting diode (LED) light source on the rabbit eyes. MATERIALS AND METHODS: Thirty-two eyes of 16 male New Zealand pigmented rabbits were involved in the study. The rabbits were divided into two groups according to the type of light source applied. Only one eye of each rabbit was exposed to illumination light, unexposed fellow eyes served as the control group. Experimental groups included group 1 exposed to halogen light for 2 h and evaluated 1 day and 1 week after the illumination, group 2 exposed to LED light for two hours and evaluated 1 day and 1 week after the illumination. On the first and seventh days after exposing the light, we evaluated the rabbit corneas using in vivo confocal microscopy (IVCM). At the end of the seventh day, the Hematoxylin-eosin staining and TUNEL staining were performed to investigate the presence of apoptosis in the retina and retina pigment epithelium. RESULTS: Early IVCM findings revealed corneal epithelial cell ovalization and indistinct intercellular borders in the halogen light group. We also observed more increase in the keratocyte density index (23.7% vs 14.1%, p = 0.001, respectively) and the Bowman reflectivity index (12.4% vs 4.1%, p = 0.001, respectively) at first day of the light exposure in halogen light group compared to LED light group. However, late IVCM indicated that these findings disappeared one week later. No apoptosis was observed in the corneal and retinal layers in early and late examination groups. CONCLUSION: The present experimental study demonstrated that both halogen and LED lights, which were commonly used for microscopic eye surgery, had no sustained adverse effect on the cornea and retina of the rabbits; however, halogen light had a temporary adverse effect on corneal epithelium and stroma, which resolved within 1 week.

Epigenetic silencing of the tumor suppressor genes SPI1, PRDX2, KLF4, DLEC1, and DAPK1 in childhood and adolescent lymphomas.

The aim of the study was to investigate the expression and methylation status of seven distinctive genes with tumor suppressing properties in childhood and adolescent lymphomas. A total of 96 patients with Hodgkin Lymphoma (HL, n = 41), Non-Hodgkin Lymphoma (NHL, n = 15), and reactive lymphoid hyperplasia (RLH, n = 40, as controls) are included in the research. The expression status of CDKN2A, SPI1, PRDX2, DLEC1, FOXO1, KLF4 and DAPK1 genes were measured with QPCR method after the RNA isolation from paraffin blocks of tumor tissue and cDNA conversion. DNA isolation was performed from samples with low gene expression followed by methylation PCR study specific to promoter regions of these genes. We found that SPI1, PRDX2, DLEC1, KLF4, and DAPK1 genes are significantly less expressed in patient than the control group (p = 0.0001). However, expression of CDKNA2 and FOXO1 genes in the patient and control groups were not statistically different. The methylation ratios of all genes excluding the CDKN2A and FOXO1 were significantly higher in the HL and NHL groups than the controls (p = 0.0001). We showed that SPI1, PRDX2, DLEC1, KLF4 and DAPK1 genes are epigenetically silenced via hypermethylation in the tumor tissues of children with HL and NHL. As CDKN2A gene was not expressed in both patient and control groups, we conclude that it is not specific to malignancy. As FOXO1 gene was similarly expressed in both groups, its relationship with malignancy could not be established. The epigenetically silenced genes may be candidates for biomarkers or therapeutic targets in childhood and adolescent lymphomas.

Ciliary Tissue Transplantation in the Rabbit Eye: Does the Localization of the Graft Affect Survival?

PURPOSE: To examine whether ciliary body transplantation is applicable, the graft is viable and the localization of the graft material affects graft survival. METHODS: Fifteen female New Zealand white rabbits were used. Three of them were used as donors, and a ciliary body graft was prepared from their enucleated eyes. There are two groups in the study according to the localization of the ciliary body graft in the anterior chamber. The graft was placed on the iris surface close to the pupil margin in group 1 and adjacent to the anterior chamber angle in group 2. Immunosuppressive treatment with cyclosporine A was given to the rabbits of both groups. The rabbits were sacrificed 1 month after ciliary transplantation, and their eyes were enucleated. After fixation, the graft and the surrounding tissue were examined by a pathologist macroscopically and microscopically with hematoxylin and eosin staining. RESULTS: One month after the transplantation, the treated eyes remained inflammation free, and the transplants seemed to be viable with evident vascularization and without hemorrhage and necrotic tissue. When we compared groups 1 and 2, there were no statistically significant differences in the histopathological findings between the groups. The grafts were found to be similar with normal ciliary tissue in regard to necrosis, hemorrhage and fibrosis, and there were no statistically significant differences in inflammatory cell density and in the epithelial cell morphology between the normal ciliary tissue and the grafts. CONCLUSION: Transplantation of allograft ciliary tissue either onto the surface of the iris or the anterior chamber angle under immunosuppression could be an effective treatment for chronic ocular hypotony.