Canan Akyüz

Growth inhibition and apoptosis of myeloma cells by the CDK inhibitor flavopiridol

Although myeloma shows responsiveness in intensive chemotherapy, overall survival remains less than 40% at 2 years. Since myeloma appears to be dependent on cytokines, such as IL-6, we hypothesized that targeting signal transduction molecules could effectively treat myeloma. Two myeloma cell lines U266 and RPMI-8226 and CD38+ myeloma cells were studied by immune complex kinase assay or anti-phosphotyrosine blot for evidence of constitutive activation of tyrosine kinases. Growth arrest and apoptosis were evaluated in these two cell lines following their treatment with specific kinase inhibitors. We found that a variety of Src and Janus kinases were present and constitutively active in U266 and RPMI-8226 cells. Inhibitors of both Src and Janus kinases were inferior to the cyclin-dependent kinase inhibitor, flavopiridol, in inducing both growth arrest with GI50 of 100 nM and apoptosis in both cell lines and CD38+ myeloma cells. Although, flavopiridol did not affect cyclin D1 and cyclin A levels, it inhibited Mcl-1 and Bcl-2 protein levels and cyclin-dependent kinase 2 activity. Flavopiridol is a well-tolerated drug, currently in phase I-II trials for a variety of tumors. A clinical trial using flavopiridol should be performed in patients with myeloma. Its mechanism of action may involve targets other than the cyclin-dependent kinases.

Second neoplasms in pediatric patients treated for cancer: a center's 30-year experience.

To investigate the incidence and outcome of secondary neoplasms in pediatric patients treated for childhood cancer. Between December 1971 and January 2000, a total of 5859 patients younger than age 17 were diagnosed and treated for childhood cancers in our center. Of this group, 1511 (36%) patients were followed for more than 36 months. These long-term survivors were included in this analysis. Twenty-six patients developed a secondary malignancy with an overall risk of 1.7% in this cohort. The male:female ratio was 17:10, with a median age of 7.66 at diagnosis (range, 2 to 16 y). Four patients (14.8%) with Hodgkin lymphoma; 3 each (11.1%) with retinoblastoma and rhabdomyosarcoma; 2 each (7.4%) with Wilms tumor, Ewing sarcoma, medulloblastoma, ganglioneuroblastoma, and non-Hodgkin lymphoma; and 1 each (3.7%) with ependymoma, nasopharyngeal carcinoma, osteosarcoma, astrocytoma had a secondary malignant disease during the long-term follow-up period. Secondary malignant diseases were osteosarcoma in 6 patients, acute lymphoblastic leukemia in 2, acute myelogenous leukemia in 2, and rare malignant disease in others. Four patients with osteosarcoma developed disease within the radiation field. Osteosarcoma was the most frequently occurring secondary neoplasm. Less toxic treatment modalities should be used to decrease the risk of secondary malignant diseases.

MANAGEMENT OF CUTANEOUS HEMANGIOMAS: A RETROSPECTIVE ANALYSIS OF 1109 CASES AND COMPARISON OF CONVENTIONAL DOSE PREDNISOLONE WITH HIGH-DOSE METHYLPREDNISOLONE THERAPY

The effectiveness of the different pharmacological agents and different doses of systemic cortico steroids was analyzed. A total of 1109 patients (median age 8 months; F/M: 2.3) with hemangioma, followed up in our unit for 23 years, were evaluated retrospectively. Forty-five of them received systemic corticosteroids. Two different pharmacological agents, prednisolone (in 26 patients) and methyl prednisolone (in 19 patients), had been used in three different regimens. Groups were compared according to the final results and rebound regrowth. Response was considered good or excellent in 16 patients (36%). There were no differences in response to therapy among the three regimens. No difference was found in response to therapy between prednisolone and methylprednisolone and the two different doses of the methylprednisolone. Rebound regrowth was significantly higher in methyl prednisolone than in the prednisolone group (p = .045). In multivariate analysis the dimension of the lesion (p = .0065) and age at initiation of treatment (p = .0041) were the most important factors affecting the response. In conclusion, the systemic corticosteroids are effective in 36% of patients, independent of dosage and pharmacological agents and duration of the therapy. The dimension of the lesion and age at initiation of treatment are the most important factors affecting the response to treatment.

Hodgkin's disease in Turkish children : Clinical characteristics and treatment results of 210 patients

Although Hodgkins disease (HD) is one of the common malignancies in childhood, there is limited information from developing countries in English literature. The aim of this study is to give epidemiologic features and treatment results of 210 previously untreated children with HD from a developing country. Between 1 June 1984 and 31 December 1992, all children seen who were younger than 18 years old with newly diagnosed, untreated, biopsy-proven Hodgkins disease were included in this study. A clinical staging system was used to determine the dissemination of the disease. While patients with stage I-II disease received canapé treatment protocol (three cycles COPP [cyclophosphamide, vincristine, procarbazine, prednisolone] or ABVD [doxorubicin, bleomycine, vinblastine, dacarbazine] plus low-dose involved-field radiotherapy), patients with stage III-IV disease were treated by sandwich protocol (six cycles COPP plus low-dose involved-field radiotherapy). A total of 210 patients with a median age of 8 years were eligible for this study. Male to female ratio was 3:1 and 37 (17.6%) were less than 5 years of age. The major histologic subtype was mixed cellularity (69.6%). Overall survival rates were 91.5 and 87.7%, and event-free survival rates were 71.5 and 70.5% at 5 and 10 years, respectively. No secondary malignancy has been observed so far. The prevalence of Hodgkins disease in young children is higher and the distribution of histologic subtypes is also different from many Western countries. Canapé and sandwich treatment protocols could be used safely in clinically staged childhood HD with tolerable toxicity.

Health-related quality of life in pediatric cancer survivors: a multifactorial assessment including parental factors.

Aim: We aimed to evaluate the health-related quality of life (HRQOL) and the effect of associated factors such as cancer type, treatment strategies, sex, age, and parental factors like education and psychopathology in pediatric cancer survivors and make a comparison with healthy children. Patients and Methods: “Pediatric Quality of Life Inventory (PedsQL) 4.0 TM, Generic Core Scale” for children and parents, and “Brief Symptom Inventory” for parents were used. Three hundred and two survivors without major mental or motor deficit and 272 healthy controls of 8 to 18 years of age were enrolled to study. Results: Comparison of scores according to child self-report between survivor and control groups revealed lower points in physical and school subscale of survivor group (P<0.01 and P<0.001, respectively). Female survivors had reported significantly worse HRQOL in physical and emotional subscales of PedsQL than male survivors (P<0.001). Female survivors of ≥16 years of age had reported worse scores in school subscale than females of younger age groups and male survivors of same age group. Parents of control group reported better results in school subscales (P<0.001) and social functioning subscales (P<0.05) than parents of survivor group. Brief Symptom Inventory score had significant effect on child self-report and parent proxy-report of physical functioning (P<0.001), emotional functioning (P<0.001), social functioning (P<0.001), and school subscales (P<0.001) of PedsQL. Significantly better scores of physical functioning subscale in the survivors whose parents are university graduate than the survivors whose parents are primary school graduate were detected (P<0.001). The survivors with central nervous system tumors had reported lower scores in the social, emotional, physical, and school functioning subscales of PedsQL than patients with non-Hodgkin and Hodgkin lymphoma (P<0.001). Child self-report school subscale scores were lower in survivors treated with radiotherapy in combination or as sole therapy than survivors in whom radiotherapy was not given (P<0.001). Conclusions: Our study has provided evidence about less-studied determinants of HRQOL like parental factors such as psychopathology or educational level in childhood cancer survivors. Future research can build on this evidence to obtain additional factors other than well-known medical and treatment-related factors.

Optic glioma in children: a retrospective analysis of 101 cases.

Aim:To evaluate the clinical characteristics and long-term outcome of pediatric patients with optic glioma. Patients and Methods:A total of 101 patients with optic glioma newly diagnosed between 1975 and 2008 were evaluated retrospectively. COPP (cyclophosphamide, vincristine, procarbazine, prednisolone) and cisplatin plus etoposide were the most commonly used chemotherapy regimens. Radiotherapy was administered in patients with progressive or unresponsive disease. Results:The median age at the time of diagnosis was 6 years, and the male/female ratio was 1.15. The most common referral complaint was strabismus. The most common site of optic glioma was the hypothalamic-chiasmatic region (31.7%). Fifty-three patients (52.5%) had neurofibromatosis type 1 (NF-1). Treatment consisted of surgery, radiotherapy, and chemotherapy. Forty-nine patients (48.5%) underwent surgery, which was predominantly subtotal resection, radiotherapy was administered to 39.4%, and 30 patients received chemotherapy. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 65.8% and 88.4%, respectively, and the 10-year PFS and OS were 54.2% and 83.4%, respectively, with an 8-year median follow-up. OS was significantly lower in patients with hypothalamo-chiasmatic involvement and significantly higher in patients with NF-1. The 5- and 10-year PFS rates were significantly higher in patients 10 years or older at diagnosis (P=0.0001) and in patients with intraorbital involvement (P=0.032). Eighteen patients (17.8%) died of disease. Conclusions:Patients with NF-l and those older than 10 years have a better prognosis, whereas patients younger than 3 years and those with hypothalamic-chiasmatic optic glioma have a worse outcome. Further studies are needed to find appropriate treatment strategies.

Malignant ovarian tumors in children : 22 years of experience at a single institution

Purpose Malignant ovarian tumors of childhood are relatively rare and thus, management is still unclear. We reviewed our experience with these tumors to evaluate their histopathologic characteristics, treatment, and outcome. Patients and Methods From January 1975 to December 1997, 56 patients had their malignant ovarian tumors diagnosed, treated, and followed-up in our institution. All tumors were completely excised when possible; otherwise, biopsy was performed. Staging was made according to Federation Internationale de Gynecologie Oncologique classification. Chemotherapy was recommended for all patients. Twelve cases were treated with vincristine, actinomycin, cyclophosphamide (VAC) before 1986; 12 with cisplatin, vinblastine, and bleomycin (PVB) from 1986 to 1989; and 23 with the bleomycin, etoposide, and cisplatin (BEP) regimen from 1989 to present. The Kaplan–Meier survival method was used to calculate the survival. The log-rank test was used to compare groups with respect to survival. Results Age range was 0 to 16 years (median 11 yrs; average 9.8 yrs). Only two patients were younger than 1 year. The most common presenting symptom was abdominal pain, occurring in 27 patients (48.2%). Thirty-three patients (60%) had total one-sided salpingo-oophorectomy and three patients had bilateral salpingo-oophorectomy. Nineteen patients had stage I, 15 had stage II, 19 had stage III, and 3 had stage IV disease. Dysgerminoma was the most common type. Overall survival (OAS) and event-free survival were 68% (median follow-up time: 71 mos) and 57%, respectively, after 22 years. Histopathology was not correlated with survival. Two important predictors for survival are age (P < 0.0001) and treatment protocol (P = 0.013). The BEP protocol was superior to the other regimens. The OAS was 74.6% in BEP, 55% in PVB, and 63.6% in VAC regimens. Conclusion Although age at diagnosis and treatment with BEP regimen have major roles in determining prognosis of the ovarian tumors in childhood, for patients with advanced ovarian germ cell tumors, intensification of chemotherapy or the development of new approaches is necessary.

Thyroid cancer in pediatric age group: an institutional experience and review of the literature.

Very few have been reported on children with differentiated thyroid cancer (DTC), although 15% of them are diagnosed below 20 years of age. Children with DTC present with more advanced disease; however, they have a more favorable outcome. In this paper, we aimed to present the data in our institution on pediatric DTC patients, making an emphasis on the risk factors of metastasis and recurrence, as well as to the outcome of treatment. Clinical data of 50 pediatric patients referred to our institution for radioiodine treatment (RAI) between 1976 and 2010 were obtained. Papillary carcinoma was the most common histopathologic diagnosis (36 patients) followed by papillary carcinoma with follicular variant (10 patients). Multifocality was reported in 66% of the pathology reports. At the time of diagnosis 35 patients had regional lymph node metastasis, 18 had local invasion, and 11 had distant metastasis. No distant metastasis was present in patients with unifocal disease (P=0.018). The mean duration of follow-up was 77.6±62.7 months. Patients with local disease had longer disease-free survival than patients with distant metastasis (P=0.033). Despite the small number of patients, the follow-up was relatively long and the presented results confirmed overall good prognosis in children with DTC.

Neuroblastoma in Turkish children: experience of a single center.

Objective and Method The survival of the patients with neuroblastoma has improved in last few decades. But still it depends on various clinical and biological factors. To assess the clinical features and trends in survival, the data for 500 newly diagnosed patients between January 1972 and December 2004 from a single center were retrospectively analyzed. Results Histopathologic subtypes were neuroblastoma (NBL) in 462 patients (92.4%) and ganglioneuroblastoma in 38 patients (7.6%). The median age was 2.9 years and Male/Female ratio was 1.3/1. Primary tumor sites were abdomen, thorax, pelvis, neck, and others with the frequency of 72.2%, 14.9%, 3.8%, 3.2%, and 5.9%, respectively. There were 30, 49, 133, 257, 31 patients with stage 1, 2, 3, 4, 4S disease and their 10-year survival rates were 100%, 75.8%, 34.1%, 6.5%, and 59.4%, respectively. The outcome has significantly improved according to 10-year periods. The 5-year overall survival rates were 14%, 26.1%, 39.2%, and 52.4% for the years of 1970s, 1980s, 1990s, and after 2000. Surgical procedure involving total or near total tumor removal improved the survival (P=0.002). Both 5-year overall survival and event free survival rates were higher when partial resection was performed, especially in stage 3 disease (P=0.002 and P=0.02). In multivariate analysis, age above 18 months at diagnosis (P=0.01), stage 4 disease (P<0.001), abdominal primary tumor site (P<0.001), NBL subtype in histopathology (P=0.001), responsiveness to chemotherapy (P<0.001) positive or high Vanillyl mandelic acid levels (P=0.02) and male sex (P=0.008) were the determinants of poor prognosis. Conclusions The survival rates in children with local disease are comparable with the results of developed countries; however, the results in children with advanced disease are still not satisfactory. To improve the outcome, especially in children with advanced disease, more effective chemotherapy regimens and molecular therapies should be investigated. Sharing the knowledge and capacity building to improve the treatment results in NBL are also critical for developing countries.

An Unusual Presentation of Infantile Fibrosarcoma in a Male Newborn

We describe a 10-day-old male presenting with drop foot and immobility in his right leg; no abnormality in physical examination had been found upon delivery or discharge. Magnetic resonance imaging showed a pelvic mass with an extension to the great sciatic foramen. Fine-needle aspiration biopsy revealed congenital infantile fibrosarcoma. He was started on vincristine, actinomycin-D, cyclophosphamide chemotherapy. However, he died soon after the second cycle due to veno-occlusive disease of the liver. Differential diagnosis of drop foot and immobility in lower extremity must include infiltrating neoplasms in pelvis.