Cigdem Himmetoglu

Wwox and Ap2γ Expression Levels Predict Tamoxifen Response

Purpose: Assessment of expression levels of Wwox, Wwox-interacting proteins Ap2α, Ap2γ, and ErbB4, the Ap2γ transcriptional target protein Her2, and the possible Ap2α transcriptional target PrkaRIα, in breast cancers, to determine their roles in tamoxifen resistance. The hypothesis was that sequestration of Wwox interactors in the cytoplasm might control tamoxifen response. Experimental Design: Tissue sections from 51 tamoxifen-sensitive and 38 tamoxifen-resistant, estrogen receptor α–positive breast cancers were stained for the above proteins, as well as progesterone receptor (PR). The relation of tamoxifen resistance and other clinical features, with level of expression of these proteins, and pairwise correlations among various immunohistochemical markers were determined. Results: Menopausal status, tumor, node, and stage, loss of PR, lost or reduced expression of Wwox, and high level of expression of PrkaRIα, Ap2γ, and Her2 were significantly correlated with tamoxifen resistance. In multivariate analysis, Wwox, PrkaRIα, Ap2γ, and ErbB4 were found to be independent markers of tamoxifen resistance. Reduced Wwox expression was better than PR in prediction of resistance, especially in high-risk patients, and nuclear Ap2γ expression was better than Her2, especially in low-risk patients. Conclusion: The results illustrate the complex relationships among the marker proteins assessed in this in vivo study and suggest new markers for prediction of response to tamoxifen treatment as well as possible new targets for treatment of breast cancer. Wwox and Ap2γ emerge as new biomarkers that may be superior to PR and Her2 in predicting tamoxifen response.

Fragile histidine triad protein, WW domain-containing oxidoreductase protein Wwox, and activator protein 2γ expression levels correlate with basal phenotype in breast cancer

The expression of fragile histidine triad protein (Fhit) and WW domain‐containing oxidoreductase protein (Wwox), tumor suppressors that are encoded by fragile (FRA) loci FRA3B and FRA16D, are lost concordantly in breast cancers. In the current study, the authors examined correlations among Fhit, Wwox, the activator protein 2 transcription factors AP2α and AP2γ, cytokeratins 5 and 6 (CK5/6), epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER‐2) and their associations with breast cancer phenotypes.

Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.

Diffuse fatty infiltration in amyloid goiter

Presented herein is a case of diffuse fatty infiltration of amyloid goiter in a 58‐year‐old woman with chronic renal failure. Bilateral total thyroidectomy was performed due to symptoms of dysphagia and hoarseness. Macroscopic and microscopic examination showed that almost all thyroid follicles were replaced by fat cells. Hyalinized stroma intervening the fatty infiltration was shown to harbor amyloid deposition.

Isolated extraocular muscle involvement as the ophthalmic manifestation of leukaemia

Background:  Clinical and imaging features of patients with orbital leukaemia primarily involving extraocular muscles were evaluated.

Omentectomy for gynecologic cancer: how much sampling is adequate for microscopic examination?

CONTEXT Detecting omental metastasis is crucial for staging and treatment of endometrial and ovarian carcinoma. OBJECTIVE To determine the optimal omental sampling for omentectomies to ascertain the stage of the disease in a cost-effective way. DESIGN We reevaluated 258 omentectomies that were performed due to ovarian or endometrial carcinoma. A total of 116 cases were retrospectively studied, and 142 cases were prospectively studied. For prospective study, 10 to 16 blocks were sampled if the omentum showed no signs of gross tumor. Mean omental block sample frequency of 2 groups with the negative macroscopy but with or without microscopic tumor have been compared using an independent samples t test. RESULTS Seven patients had no evidence of tumor metastasis on gross examination but had microscopic tumor metastasis. The mean numbers of blocks were 6.4 for patients having microscopic tumor without macroscopic involvement and 7.8 for patients having neither microscopic nor macroscopic involvement. Approximately twice as many samples were taken in the prospective analysis when compared with retrospective analysis. Two cases with microscopic omental metastasis that had no macroscopic involvement at first impression were reevaluated retrospectively and found to contain 0.3- to 0.5-cm white nodules. The rate of omental metastasis increased with the grade of the tumor (P = .005). CONCLUSION Careful macroscopic examination is the most important step in detecting small omental metastasis. For cases with gross tumor, one section is sufficient. If a macroscopic lesion is not detectable and the patient has a high-grade tumor that will necessitate an adjuvant therapy, 3 to 5 samples seem sufficient for staging. Further studies are needed to determine the optimum sample size for tumors having a low risk of metastasis.

Primary osteosarcoma of the urinary bladder following cyclophosphamide therapy for systemic lupus erythematosus: a case report

IntroductionThe association of systemic lupus erythematosus with malignancies is an uncommon occurrence. We present the case of an osteosarcoma of the urinary bladder developing in a patient with a prolonged history of active systemic lupus erythematosus. This is a previously unreported association. Primary osteosarcoma is an extremely rare disease in the urinary bladder.Case presentationA 24-year-old Caucasian woman with a 13-year history of systemic lupus erythematosus, who had been treated with high dose immunosuppressive agents, presented with pain and hematuria. A deeply invasive high-grade tumor was detected in the urinary bladder and the patient underwent radical surgery. A diagnosis of osteosarcoma was made based on the characteristic histology.ConclusionPredisposing factors for primary sarcomas in the urinary bladder are mostly unknown; however, in our case, long-term administration of immunosuppressive agents, as well as long standing systemic lupus erythematosus, may both be of significance.

Study of FHIT and WWOX expression in mucoepidermoid carcinoma and adenoid cystic carcinoma of salivary gland

Mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ACC) are salivary gland neoplasms with divergent morphological features and clinical behavior. ACC is a basaloid tumor whereas MEC is a glandular epithelial neoplasm. FHIT and WWOX are tumor suppressor genes that encompass the FRA3B and FRA16D fragile sites at chromosomes 3p14.2 and 16q23.3, respectively. In previous studies, we have shown concordant loss of Fhit and Wwox expression in breast cancer, with significantly more frequent loss in cancers of basal-like phenotype. To determine if there is a similar association in salivary gland neoplasms, we designed a study of MEC and ACC of salivary gland on tissue microarrays (TMA). TMAs were constructed from 25 MEC and 19 ACC of salivary gland. Fhit and Wwox protein expression was assessed by immunohistochemical staining of cores on TMAs. Correlations among immunohistochemical markers and histological type were determined by statistical analyses. Significantly reduced Fhit and Wwox expression was observed in ACC (p=0.002 and p<0.001, respectively). The results suggest that, as for breast cancer, loss of Fhit and Wwox expression might have a role in the pathogenesis of basaloid differentiation in salivary gland neoplasms; alternatively, differences in chromatin structure at chromosome fragile regions might make fragile genes more accessible to DNA damage and rearrangement early during preneoplastic stages of basaloid cancers. Studies of basaloid tumors of other organ systems may show similar results and these findings may have implications for treatment modalities designed for basal-like tumors.

Successful outpatient management of pelvic actinomycosis by ceftriaxone: a report of three cases

Pelvic actinomycosis is a chronic granulomatous suppurative disease caused by actinomyces israeli. Intravenous penicillin is the preferred antimicrobial but it requires hospitalization up to one month. An outpatient treatment strategy would be cost effective and a good choice for patients. Here we present three cases in which intramuscular ceftriaxone was successfully used in the outpatient settings following surgery and IV penicillin treatment in the hospital.

A 41-Year-Old Man wıth Drug-Resıstant Complex Partıal Seızures

A 41-year-old male patient administered to hospital with the complaint of medically intractable complex partial seizures since 3 years of age. The frequency of focal seizures despite multimedication treatment was 4–5 /month. Brain MR imaging revealed a non-enhancing cortical lesion with subcortical involvement in the left parietal lobe. Imaging characteristics of the lesion on T1-W was peculiar in that both hypoand isointensity was present with accompanying peripheral hyperintensity (Fig. 1a). The lesion was hyperintense with microcysts on FLAIR (Fig. 1b). Following lobectomy the patient remained seizure free and showed no evidence of tumor recurrence in the 48-months follow-up period.