Bahar Akkaya

Array comparative genomic hybridization analysis of adult acute leukemia patients.

We have performed a retrospective array-based comparative hybridization (array-CGH) study on 41 acute leukemia samples [n=17 acute lymphoblastic leukemia (ALL) patients only at diagnosis, n=3 ALL patients both at diagnosis and relapse; n=20 acute myeloid leukemia (AML) patients only at diagnosis and n=1 AML patient both at diagnosis and relapse] using an Agilent 44K array. In addition to previously detected cytogenetic aberrations, we observed cryptic aberrations in 95% of ALL and 90.5% of AML cases. ALL-specific recurrent abnormalities were RB1 (n=3), PAX5 (n=4), and CDKN2B (n=3) deletions; AML-specific recurrent abnormalities were HOXA9 and HOXA10 (n=2) deletions and NOTCH1 duplication (n=2). Recurrent duplication of the ELK1 oncogene was observed in both ALL (n=2) and AML (n=3) cases. Our results demonstrate that oligo-array CGH (oaCGH) is an effective method for defining copy number alterations and identification of novel recurring unbalanced abnormalities. At least for now, however, the use of oaCGH for routine diagnosis still has some restrictions.

Pauci-immune necrotizing crescentic glomerulonephritis with crescentic and full moon extracapillary proliferation: clinico-pathologic correlation and follow-up study.

The prognostic value of the type and extent of extracapillary proliferation (ECP) in pauci-immune necrotizing crescentic glomerulonephitis (PIGN) was evaluated in this study. In 141 PIGN cases, all glomeruli with ECP were grouped according to type (cellular, fibrocellular and fibrous) and extent of the lesions in Bowmans space; (segmental, semicircumferential and circumferential, which might be termed full moon-FM). Cases with cellular and fibrous lesions involving ≥ 50% of glomeruli with ECP were classified as cellular and fibrous groups, respectively, while the remaining cases were classified as fibrocellular. Cases with segmental and circumferential (FM glomerulus) lesions involving ≥ 50% of glomeruli with ECP were classified as ECPI and ECPIII (FM) groups, respectively, while the rest were classified as ECPII. All the cases were classified according to Berden et al. Significant results were only nearly obtained for the FM group, including the need for dialysis. The Cox regression model revealed a 2.6-fold risk for FM cases regarding dialysis requirement. We propose that the percentage of FM glomeruli should be noted in the pathology report, and cases with more than 50% of FM glomeruli (FM group) should be identified in the group with increased risk of dialysis requirement. Our series also suggests that classification according to Berden et al. is of clinical relevance.

Prognostic value of Ki-67, CD31 and epidermal growth factor receptor expression in basal cell carcinoma.

Recurrence of basal cell carcinoma following treatment is common, and the majority of recurrences appear in the first 3 years. We examined the original tumors of 26 basal cell carcinoma cases, 14 of whom had a recurrence after an average of 3.7 years, and 12 of whom had no recurrence during an average of 4.4 years follow‐up. Using immunohistochemistry, we tested for Ki‐67, CD31 and epidermal growth factor receptor expressions in the tumor tissue. The percentages of expression for Ki‐67, CD31 and epidermal growth factor receptor were significantly higher in the recurrent tumors than in the non‐recurrent ones. Expression of Ki‐67 and CD31 was 271.57 ± 17.91 and 58.1 ± 9.37 for the recurrent group and 187.08 ± 21.48 and 23.9 ± 5.45 for non‐recurrent group respectively (p<0.0001; p<0.0001). Expression of epidermal growth factor receptor was positive in all basal cell carcinoma cells. The staining intensity was strong in 57% of recurrent and 8.3% of non‐recurrent tumors (p=0.014). These results show that Ki‐67, CD31 and epidermal growth factor receptor expression differ between basal cell carcinomas which later recur and those that do not recur.

Changes in expressions of ADAM9, 10, and 17 as well as α-secretase activity in renal cell carcinoma

BACKGROUND ADAM9, 10, and 17 are a class of disintegrins and metallproteinases with α-secretase activity. There are conflicting results regarding the role(s) of ADAM9, 10, and 17 in carcinogenesis, and only a few studies have examined their levels and cellular localization in renal cell carcinoma (RCC). Studies examining changes in α-secretase activity in RCC compared to enzymatic activity of the uninvolved kidney are lacking. METHOD A cross-sectional study was conducted in 56 patients undergoing radical nephrectomy after the diagnosis of RCC. α-Secretase activity was determined using flourogenic substrate in freshly frozen tumor tissues as well as similarly treated tissues from the neighboring kidney. Immunohistochemical analyses of ADAM9, 10, and 17 were also performed. RESULTS α-Secretase activity decreased markedly in all types of RCC as compared to neighboring uninvolved kidney tissue having 5 to 10 times higher levels of α-secretase activity. Although type-dependent variations were observed, tumoral expressions of ADAMs, except for ADAM17, were lower in the tumors compared to that of neighboring tissues, but the changes in α-secretase activity were greater. In RCC tissue, ADAM9 expressions were localized in nuclear and cytoplasmic compartments, whereas ADAM10 and 17 were present predominately in the cytoplasm potentially explaining the markedly decreased enzyme activity. Membranous localization of ADAMs was noted in uninvolved kidney tissue. CONCLUSIONS The loss of α-secretase activity observed here in conjunction with previous findings argue against tumorigenic effects of ADAM9, 10, and 17 supporting that increased nuclear and cytoplasmic expression may be an attempt to compensate for loss of function.

Cutaneous papules, uterine fibroids, and renal cell cancer: one family's tale

In May, 2007, a 35-year-old woman was referred to our dermatology unit with painful papules and nodules on the left side of her body. The lesions had developed on her left arm at the age of 14 years and subsequently appeared on her left leg, buttocks, and back. Pain at these sites was episo dic and aggravated on exposure to cold. More recently, her lesions had progressed and become more painful. Medical history included a subtotal hysterectomy at age 25 years for menorrhagia from uterine leiomyomas. She had a 47-year-old female fi rst cousin with a history of similar skin lesions on her legs since age 34 years, a total hyst erec tomy for uterine leiomyomas at 44 years, and a right mas t ec tomy for breast cancer at 45 years. Her brother, at age 23 years, had a right total nephrectomy for renal cell cancer. On examination, our patient had multiple painful, reddish-brown, fi rm papules on the left arm, shoulder, back, buttocks, and leg (fi gure A, B). Examination of her cousin showed similar lesions on her back and legs. Micro scopic examination of the lesions was consistent with cutaneous leiomyoma (fi gure C, D). Her brother did not show leiomyomas on examination; he later died at age 27 years from metastatic renal cell cancer (fi gure E). The presence of cutaneous leiomyomas, history of hysterectomy for uterine fi broids, and a fi rst-degree relative with renal cell cancer were all consistent with the clinical diag nosis of hereditary leiomyomatosis and renal cell cancer (HLRCC); this was confi rmed by DNA sequencing done at the National Cancer Institute, USA. Our patient was treated with gabapentin 1200 mg per day orally. When last seen in July, 2009 her pain was well-controlled. HLRCC is the autosomal dominant predisposition to cutaneous and uterine leiomyomas and renal cell cancer. Germline mutations in the gene that codes for fumarate hydratase (FH), an enzyme that converts fumarate to malate in the Krebs cycle, predispose to HLRCC. Direct DNA sequencing of the FH gene revealed a novel mutation (c.1328C>A; p.A443D) in all three family members. Cutaneous leiomyomas are benign tumours of smooth muscle diff erentiation that typically have onset during early adult hood; they are the most common and initial presen tation of HLRCC. Clinically, they are red-brown or fl esh-coloured fi rm nodules that may be solitary or multiple. Leiomyomas can be arranged in a linear or segmental pattern, and occur on one or both sides of the body. Treatment can include surgical excision, cryo therapy, electro surgery, CO2 laser ablation, nifedipine, or gaba pentin. Women with an FH germline mutation and those with clinical HLRCC have an eight-to-nine-fold increased risk of developing uterine fi broids and a fi ve-fold increased risk of having treatment for uterine fi broids compared with women without HLRCC. Women with HLRCC usually report dys menorrhoea and pain. 10–16% of individuals with HLRCC have renal cell cancer. The histo logical spectrum includes type 2 papillary, tubulo papillary, and collecting-duct renal cell cancers. HLRCC-associated renal cell cancers are aggressive with 70% of patients dying from metastatic disease within 5 years of diagnosis. Patients with cutaneous leiomyomas and their at-risk relatives should be screened regularly for uterine leio myoma and renal cell cancer. Screening for renal cell cancer is done by CT or MRI. Papillary renal cell cancer can be diffi cult to detect if patients are screened only with renal ultra sono graphy because papillary cancers are often isoechoic. Full body PET-scan to screen for occult neo plasms was normal in our patient and her cousin. Genetic testing and counselling should be off ered to patients and at-risk relatives to determine their mutation status and to inform them about their risk for uterine tumours and renal cell cancers.

An Atypical Case of POEMS Syndrome with IgG Kappa M Protein and End Stage Renal Failure

POEMS syndrome is a rare plasma cell dyscrasia which is characterized by small amounts of monoclonal protein, and a multisystem complex manifested by various combinations of polyneuropathy, organomegaly, endocrinopathy and skin changes. Here, we presented an atypical case of POEMS syndrome with IgG kappa monoclonal protein, chronic demyelinating polyneuropathy, hepatosplenomegaly, hypothyroidism, gynecomastia and severe renal impairment. The finding of IgG kappa type of monoclonal protein in our patient was interesting because the majority of cases were reported to have lambda light chain. Also, the absence of typical skin and bone lesions were atypical. Though speculative, these atypical features may account for the unusual presentation of this case. Our patient rapidly progressed to end-stage renal failure and died of cachexia. Renal involvement in POEMS syndrome is rare but may show substantial clinical and pathological variations. Proteinuria, hematuria, renal dysfunction and renal failure requiring hemodialysis can be seen. The pathogenesis of renal dysfunction is unclear. As a conclusion, POEMS syndrome may present with diverse clinicopathologic manifestations. In this syndrome, renal involvement may lead to end stage renal failure and the course may be fatal due to severe polyneuropathy and wasting.

Diclofenac induced gastrointestinal and renal toxicity is alleviated by thymoquinone treatment

The aim of this study was to investigate whether thymoquinone (TQ) could alleviate diclofenac (DCLF)-induced gastrointestinal and renal toxicity in rats. Diclofenac was administered via intramuscular injection twice daily for 5 days and TQ was given by gavage for the same period. Hematological and biochemical profiles were measured with autoanalyzers while reactive oxygen/nitrogen species (ROS/RNS) generation and total antioxidant capacity (TAC) were assayed by standard kits. Tissue injuries were evaluated by microscopy and histopathological scoring. Diclofenac treatment caused kidney and liver function test abnormalities, reduced hematocrit and hemoglobin levels but increased WBC and platelet counts. Histopathological findings showed renal tubular damage, gastrointestinal lesions and increased fibrosis in DCLF treated rats. Thymoquinone administration, along with DCLF treatment, attenuated hematological test abnormalities and DCLF induced renal functional impairment as evident by significantly restored serum creatinine and blood urea nitrogen levels. Similarly, TQ treatment significantly alleviated liver function test abnormalities and decreased tissue injury in the stomach and duodenum. Diclofenac treatment caused increased ROS/RNS formation and decreased TAC in the kidney, stomach and duodenal tissue. Thymoquinone administration increased gastrointestinal and renal TAC in DCLF treated rats. These results indicate that TQ could ameliorate gastrointestinal and renal toxicity induced by high dose DCLF treatment.

Therapy Modalities for Antibody Mediated Rejection in Renal Transplant Patients.

ABSTRACT Introduction: The aim of our study was to determine the effectiveness of immunoglobulin, rituximab and plasmapheresis in renal transplant patients with antibody mediated rejection (AMR). Patients and Methods: Fourteen renal transplant patients with AMR were included in this study. The mean age of the patients was 33.9 ± 10.3 years and 10 (71.4%) of them were male. Lymphocyte cross match was negative for all patients and 10 (71.4%) of them were living donor transplants. Six patients were administered tacrolimus, three patients cyclosporine, two patients everolimus, and three patients sirolimus for immunosuppression. The patients with AMR were administered IVIG, rituximab and plasmapheresis. Results: Patient survival rate was 100%, graft survival rate after AMR was 50% in the first year and 33% in the 2nd and third years. AMR developed 31.9 ± 25.9 months after transplantation. Seven (50%) patients lost their grafts. Delayed graft function was observed in 28.6%, chronic allograft dysfunction in 78.5%, diabetes after transplantation in 14.3%, and cytomegalovirus infection in 7.1% of the patients. At the last follow-up, the mean blood creatinine was 3.1 ± 1.4, the mean proteinuria was 2300 (1300–3300) mg/day and the mean GFR was 34.5 ± 17.6 ml/min. C4d was positive in peritubullar capillaries in all patients, while neutrophil accumulation in peritubular and glomerular capillaries was observed in 8 patients. Chronic allograft vasculopathy was observed in 12 patients. Conclusion: AMR leads to progressive loss of renal function and has low graft survival. More effective treatment alternatives are needed for this clinical issue.

C-MYC and BCL2 translocation frequency in diffuse large B-cell lymphomas: A study of 97 patients.

Purpose: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. MYC and BCL2 rearrangements have been reported in a proportion of DLBCLs, where they may be associated with an adverse clinical outcome. The aim of this study was to determine the frequency of MYC and BCL2 translocations in DLBCL and assess the prognostic impact in DLBCL patients. Materials and Methods:   In the present study, we evaluated the expression patterns of CD 10, BCL6, and MUM 1 by immunohistochemistry in 121 cases with DLBCL in tissue microarray (TMA): 62 cases in germinal center B-cells (GCBs); and 59 cases in activated B-cells (ABCs) of which 60 were females and 61 were males. MYC and BCL2 rearrangements were investigated by interphase fluorescence in situ hybridization on TMAs in 97 DLBCLs. Result: MYC rearrangements were observed in 11 of 97 cases. There was no association with other clinical features, including age, sex, and nodal/extranodal disease. MYC rearrangement was associated with significantly worse overall survival (P < 0.01). BCL2 rearrangements were observed in 14 of 97 cases. There was no association with other clinical features including age and sex. BCL2 rearrangement had a worse outcome (P < 0.01). MYC and BCL2 rearrangements were observed in 3 of 97 cases with the age of  53 (female), 53, 63 years old, respectively, died in 24, 18, and 35 months after the diagnosis. Two cases had primary nodal and one case primary extranodal presentations. All these patients had stage IV disease. Conclusion: We concluded that C-MYC and BCL2 may contribute to aggressive transformation, and more mechanism-based therapy should be explored. Targeted therapies involving these rearrangements and its associated pathways may change the fate of DLBCLs. Analysis of MYC gene rearrangement along with BCL2 is critical in the identification of high-risk patients with poor prognosis.

Hydatid disease involving some rare sites in the body.

A hydatid cyst is an endemic disease in our country. Clinical manifestation includes cyst formation, most commonly in the liver and lungs. Renal, brain, and subcuteneous localizations are rare. Here we report four cases: two cases of primary renal hydatid disease, one of intracranial hydatid cyst, and one of subcutaneous hydatid cyst. We discuss the prevalence, diagnostic workup, and management of echinococcosis.