Gokhan Demir

Crosstalk Between BCR/ABL Oncoprotein and CXCR4 Signaling through a Src Family Kinase in Human Leukemia Cells

Stromal-derived factor (SDF)-1 and its G protein–coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein–coupled receptor signaling and function of mammalian precursors.

Serum erythropoietin level in anemic cancer patients

Anemia is a frequent complication of cancer and its treatment. A defect in erythropoietin production has been advocated as being the main cause of anemia in cancer patients. We studied serum erythropoietin levels in 74 patients with solid tumors and in a control group consisting of 20 otherwise healthy individuals without any malignancy, who have only iron deficiency anemia. Serum erythropoietin levels were measured by enzyme immunoassay in cancer patients without anemia (n=34), and in anemic cancer patients (n=40); either receiving chemotherapy (n=21) or not (n=19). Anemic cancer patients were found to have decreased response of erythropoietin for a given hemoglobin level (mean, 40.1±34.7 u/ml), compared with the patients having only iron deficiency anemia (mean, 69.7±68.6 u/ml) (P<0.05). In patients with iron deficiency anemia having no malignancy, erythropoietin response was remarkably high and inversely correlated with the level of hemoglobin (r=−0.69;P=0.05). Although there was no correlation between hemoglobin and erythropoietin response in cancer anemia (r=−0.07), serum levels of erythropoietin were found to be higher in anemic cancer patients (mean, 40.1±34.7 u/ml), compared with cancer patients with normal hemoglobin values (mean, 19.96±18.4 u/ml). There was not any statistically significant difference between erythropoietin levels in anemic cancer patients with or without chemotherapy (mean, 43.7±37.7 u/ml and 41.9±30.08 u/ml respectively;P>0.05). No difference in serum erythropoietin levels were noted in patients treated with cisplatin or non-cisplatin containing regimens (mean, 48.36±33.12 u/ml and 38.55±43.52 u/ml, respectively;P>0.05). In this study, we demonstrated that anemia in cancer patients was caused by blunted erythropoietin response, rather than its quantitative deficiency. Serial measurements, however, should be considered in patients receiving chemotherapy.

Usefulness of the epithelial tumor marker CA-125 in Non-Hodgkin's lymphoma

CA-125, a commonly used tumor marker for epithelial ovarian cancer, is a glycoprotein found in normal tissues derived from coelomic epithelia. Increased serum levels of CA-125 have also been found in nongynecologic tumors and nonmalignant diseases involving the peritoneum. A few recent studies and sporadic case reports have reported increased CA-125 levels in patients with non-Hodgkins lymphoma (NHL). In our study, we aimed to evaluate the serum levels of CA-125 in patients with NHL and determine its potential role to show disease activity in NHL. Serum levels of CA-125 were measured in 61 patients with NHL and were found to be correlated with clinical stage, site of involvement, and disease activity.

Long extensive transverse myelitis associated with aquaporin-4 antibody and breast cancer: Favorable response to cancer treatment

Abstract Context Long extensive transverse myelitis (LETM) seldom develops in patients with breast cancer who are aquaporin-4 antibody (Aqp-4 Ab)-positive. Whether this association is coincidental is not well understood. Findings A 62-year-old woman presented with treatment-resistant LETM and Aqp-4 Ab. Two months later, a stage 3 invasive ductal carcinoma was detected in her right breast. Following tumor resection and chemotherapy, her neurologic symptoms and magnetic resonance imaging findings significantly improved and serum Aqp-4 Ab disappeared. The breast tumor samples of this patient and neurologically normal patients showed inflammatory infiltrates and Aqp-4 expressing cells. Conclusion/Clinical Relevance The temporal association between tumor treatment, amelioration of clinical findings, and seroreversion suggest that coexistence of cancer and LETM is not coincidental. Cancer screening should be considered at least in treatment-resistant LETM cases.

A Case of Metastatic Malignant Melanoma Presenting with Hematuria

We report a case of metastatic malignant melanoma that presented with macroscopic hematuria and lower urinary tract symptoms. Effective palliation of urinary tract symptoms was achieved with transurethral resection of metastatic lesions in the bladder. However, the patient was lost due to widespread disease despite systemic therapy. Solitary or multiple dark blue-black nodular or vegetating lesions encountered during cystoscopy should raise the suspicion of metastasis of malignant melanoma and be investigated accordingly.

Bilateral inflammatory breast metastases of epithelial ovarian cancer.

Metastases to the breast are rare. Secondary breast involvement from an epithelial ovarian cancer heralds widespread dissemination and a very poor prognosis. We report an unusual case of a patient who had epithelial ovarian cancer and who showed signs of recurrence with inflammatory metastases to both breasts, 2 years after her diagnosis of ovarian cancer. She died within 3 months of breast involvement. Our case has unique features, with both bilateral breast metastases and also with its inflammatory pattern of metastasis, which is extremely rare.

Serum Cardiolipin Antibodies in Cancer Patients with Thromboembolic Events

This study was undertaken to investigate a pos sible association of anticardiolipin antibodies (ACLAs) in can cer patients with thromboembolic events. Twenty-five patients with solid tumors complicated with acute thrombosis, 36 cancer patients without any thrombotic events, and a group of 20 healthy volunteers without thrombosis or malignancy were in cluded. The mean age of the cancer patients with and without thrombosis and healthy subjects were 50 years (range 20-75), 45 years (range 23-66), and 40 years (range 20-68), respec tively. Deep venous thrombosis (n = 16) and thrombosis of the central venous port-catheter systems (n = 9) were confirmed by Doppler sonography in all patients. IgG and IgM isotypes of ACLAs were quantitated by enzyme-linked immunosorbent as say with normal levels of <23 GPL and <11 MPL, respectively. Mean values of IgG ACLAs were found similar in cancer pa tients with acute thrombosis (13.8 ± 4.9 GPL), without throm bosis (12.8 ± 5.4 GPL) or in healthy subjects (14.8 ± 5.5 GPL). Although the mean values of IgM ACLAs were within normal limits in all groups, cancer patients with thrombotic events had higher levels of IgM ACLAs (mean = 10.5 ± 2.2 MPL) than cancer patients without thrombosis (mean = 4.6 ± 2.4 MPL) (p = .01). Healthy subjects also had lower levels of IgM ACLAs (mean = 7.1 ± 3.2 MPL) than cancer patients with thrombosis (p = .16). In addition, a higher percentage of cancer patients with or without thrombosis had IgM and IgG ACLA levels above normal limits compared with healthy controls. In con clusion, our study suggests an association between ACLAs or IgG and particularly IgM isotypes and venous thrombosis in malignancy. Identification of cancer patients who are at higher risk for developing thromboembolic events might lead to a better selection of patients for prophylactic anticoagulant therapy.

Salivary total sialic acid levels increase in breast cancer patients: a preliminary study.

Breast cancer is the most common cancer in women living in the Western world, even though it occurs worldwide. Cancer and cancer therapy induce multiple oral complications including dental and periodontal disease. Saliva is a complex and dynamic biologic fluid, which reflects both oral and systemic changes. While saliva is easily accessible body fluid, there has been little effort to study its value in cancer diagnosis. Sialic acids (SA), the end moieties of the carbohydrate chains, are biologically important and essential for functions of glycoconjugates that are reported to be altered in both blood and saliva of various cancer patients. Increased sialylation has been shown to be a characteristic feature in cancer tissue and blood in breast cancer patients. However, there is no data about salivary SA in breast cancer. The aim of this study was to evaluate salivary total sialic acid (TSA) levels in breast cancer patients who were under chemotheraphy. The study included 15 breast cancer patients in different stages and 10 healthy individuals as age-matched controls. Unstimulated whole saliva was collected. Salivary total protein and SA levels were determined. Flow rate was calculated from salivary volume by the time of secretion. Salivary SA was significantly higher and total protein was lower in breast cancer patients compared to controls. It is concluded that sialylation may be increased in saliva of patients with breast cancer as the same way for cancer tissue and for blood . Increased salivary SA may therefore be useful as a non-invasive predictive marker for breast cancer patients and for the prevention and management of oral complications of cancer and cancer therapy to improve oral function and quality-of-life. The effects of different types of chemotherapies and different stages of the disease on salivary SA levels and salivary sialo-glycomic are worthy of being further investigated in breast cancer patients.

Is awareness of its risk enough to stop people from smoking

A questionnaire to elicit information about smoking habits and knowledge of the risks of smoking was administered to 100 students (53 men and 47 women) in the graduating class of 1993 at the Cerrahpaşa Medical School of Istanbul. Forty-three percent of the men and 27% of the women students were smokers. All but one of the 100 students were aware that smoking is a risk factor for both lung and laryngeal cancers, and 44% of the smokers believed that cessation of smoking by the smoking population could decrease the incidence of lung cancers to less than half of its present level. These data suggest that awareness of the risks of smoking is not enough to motivate smokers to quit, even when they are young physicians. Of the nonsmokers, 87.5% indicated that they would attempt to restrain their younger siblings from smoking, whereas the corresponding figure for smokers was 58.3%. The smokers and the nonsmokers answered two of the questions on the questionnaire significantly differently. Thirty-six percent of the mothers of the nonsmokers and 31% of their siblings were also smokers, whereas the corresponding figures for the nonsmokers were 18% and 13% (half of the fathers in both groups smoked). Thus, family and the environment appear to influence smoking behavior. Successful modification of smoking habits will necessitate more education of the general public.

Low dose daily rhGM–CSF application activates monocytes and dendritic cells in vivo

Granulocyte macrophage colony stimulating factor (GM-CSF) is a powerful cytokine with multiple actions. We investigated the effects of low dose daily rhGM-CSF application on monocytes and peripheral circulating dendritic cells (DC) in malignant melanoma patients in vivo. Twenty patients were included; rhGM-CSF was given as daily subcutaneous injections for 14 days. A significant increase was noted in monocytes and granulocytes, starting on the 5th day. Expression of CD95 (Apo-1/Fas) and CD45RO on monocytes increased significantly on the 5th day, and CD4 expression on monocytes increased significantly on the 14th day. Peripheral circulating dendritic cells which were 0.94% in the beginning, increased to 1.35% (P<0.04) and to 1.96% (P<0.001) on days 5 and 14, respectively.