Boris Futerman

The prognostic impact of the ubiquitin ligase subunits Skp2 And Cks1 in colorectal carcinoma

Loss of the cell‐cycle inhibitory protein p27Kip1 is associated with poor prognosis in colorectal carcinoma. The decrease in p27Kip1 levels is the result of increased proteasome‐dependent degradation, mediated and rate‐limited by its specific ubiquitin ligase subunits S‐phase kinase protein (Skp) 2 and cyclin‐dependent kinase subunit (Cks) 1. Recently, Skp2 and Cks1 expression were found to be increased in some colorectal carcinomas, but their potential role as prognostic markers for survival is unknown. The present study was undertaken to assess the prognostic value of both Skp2 and Cks1 in colorectal carcinoma.

Alterations in the Expression of the Cell Cycle Regulatory Protein Cyclin Kinase Subunit 1 in Colorectal Carcinoma

Low levels of p27Kip1 are associated with high aggressiveness and poor prognosis in various malignancies, including colorectal carcinoma. The authors showed that S phase kinase protein 2 (Skp2), the specific ubiquitin ligase subunit that targets p27Kip1 for degradation, was overexpressed and was inversely related to p27Kip1 levels in patients with colorectal carcinoma. The essential role of cyclin kinase subunit 1 (Cks1) in Skp2‐dependent p27 degradation was recently discovered, but its role in human malignancies is unknown.

Central Nervous System Involvement in Children with Sarcoma

Objectives: To summarize and analyze the experience in CNS involvement (CNSI) in children with sarcomas treated in the above-mentioned institutions. Patients and Methods: From 1990 to 2001, all medical charts were retrospectively reviewed: 19 sarcoma patients (12 boys and 7 girls) were diagnosed with CNSI (4 osteogenic sarcomas, 11 Ewing sarcomas, 2 rhabdomyosarcomas, 1 alveolar soft part sarcoma and 1 mesenchymal chondrosarcoma). Mean age of all patients at the time of initial diagnosis was 14.9 years (range: 4–24 years), mean age at the time when CNSI was diagnosed was 16.9 years (range: 5.5–27 years). Results: The frequency of CNSI among our patients was 6.17%. The following symptoms and signs (sometimes combined) presented: headache (10 patients), nausea and vomiting (6 patients), seizures (11 patients) and focal neurological signs (9 patients). The mean duration of time elapsed since diagnosis of CNSI till death or last follow-up was 5.2 months (SD: ±5.7 months). Four patients received chemotherapy (CT) alone, 8 CT and radiotherapy (RT), 2 RT alone, 3 supportive treatment only, 1 CT and surgery and 1 surgery alone. Sixteen patients died; there was no significant difference in the duration of survival between those who were treated with RT or surgery (mean ± SD: 6.77 ± 6.56 months) and those who received only CT or supportive treatment (mean ± SD: 2.60 ± 2.94 months) (p = 0.07). Brain disease was the main cause of death in all but 1 patient who died 4 days after autologous bone marrow transplantation from uncontrolled sepsis. In 16 patients, CNSI was part of a metastatic disease. Conclusions: Among children with sarcoma, CNSI is encountered in 6.17% of cases. More effective therapy has to be developed in order to improve their outcome.

Cancer incidence and survival among children and adolescents in Israel during the years 1998 to 2007.

Our goal was to describe childhood cancer incidence and survival in Israel and to identify demographic and epidemiologic variations among children and adolescents with cancer. We used data from the Israel National Cancer Registry to examine the incidence and survival of pediatric cancer in Israeli children aged 0 to 19 years, diagnosed during the years 1998 to 2007. Cases were analyzed according to sex, age, ethnicity, and geographic region. Among the 4255 cases of childhood cancer, there was a total age-adjusted incidence rate of 172.4 per million for children aged 0 to 19 years and 153.4 per million for children aged 0 to 14 years. The incidence rate for boys was higher than for girls (192.5 and 153.3, respectively) and higher for Jewish children than for Arab children (177.6 and 156.8, respectively). The largest groups were leukemias (22%), lymphomas (20.2%), and central nervous system tumors (17.4%). The number of new cases increased each year, but the incidence rate remained steady. The survival probability updated to December 2008 was estimated and the 5-year survival was calculated for the new cases until the end of 2003. The overall survival at 5 years was 80.8%, with 72.8% for the Arabic population and 83.2% for the Jewish population, and depended on the diagnosis. Incidence and survival in childhood cancer in Israel is at the same medium level compared with other parts of the world. This study may set the basis for investigating the genetic and environmental factors that cause pediatric cancer in Israel, delineating the genetic basis for ethnic origin disparities in survival.

Increased 6-sulfatoxymelatonin excretion in women with polycystic ovary syndrome.

OBJECTIVE To determine melatonin production in hyperandrogenic women. DESIGN Controlled prospective study. SETTING Outpatients in an academic medical center. PATIENT(S) Twenty-two women with polycystic ovary syndrome (PCOS), 20 women with idiopathic hirsutism, and 15 age-matched individuals who had similar body mass indexes as controls. INTERVENTION(S) Fasting blood samples and 24-hour urinary samples were obtained from all participants. MAIN OUTCOME MEASURE(S) All participants provided serum samples for the measurement of LH, FSH, testosterone, E(2), DHEAS, 17 alpha-hydroxyprogesterone (17-OHP), and insulin levels, as well as urinary 6-sulfatoxymelatonin (aMT6s). RESULT(S) Women with PCOS had higher aMT6s, testosterone, LH/FSH ratio, and insulin values than either women with idiopathic hirsutism or control women. Testosterone inversely correlated with aMT6s in PCOS. Regression analysis revealed that only testosterone was an important determinant of aMT6s in PCOS. CONCLUSION(S) Women with PCOS have increased melatonin production.

Factors Influencing Outcome and Incidence of Late Complications in Children who Underwent Allogeneic Hematopoietic Stem Cell Transplantation for Hemoglobinopathy

Background: Hematopoietic stem cell transplantation (HSCT) remains the only potentially curative treatment for severe hemoglobinopathy (HGP). Late complications (LCs) are all events occurring beyond two years post-HSCT. We retrospectively analyzed prevalence, factors influencing occurrence, and prognosis of LCs post-HSCT for HGP. Patients and Methods: Between 2000 and 2011, 47 patients (21 males, 26 females; 43 with beta thalassemia major, four with sickle cell disease) who had survived more than two years post-HSCT for HGP were retrospectively reviewed. Mean age at HSCT was 7.7 years (1.1–32 years); mean follow-up was 7.1 years (2–11.6 years); 11 patients were splenectomized; mean ferritin level was 3022 ng/mL (350–10900); and seven patients underwent a second HSCT. Results: Endocrinological complications were observed with primary gonadal failure in 16/20 mature females and 4/11 mature males, in five patients with primary hypothyroidism and in four with insulin-dependent diabetes mellitus (DM). Skeletal complications were observed in 10 with secondary osteoporosis; 22 patients had elevated transaminase levels; two had hepatitis B reactivation. Neurological, cardiac and ocular manifestations were relatively rare. A higher incidence of LCs was observed in splenectomized than in nonsplenectomized patients: cGVHD −64% versus 13% (P = .003); endocrine abnormalities –91% versus 30.5%, (P = .001); elevated transaminase levels −73% versus 33% (P = .043); mortality –18% versus 2.7% (NS). Conclusions: LCs post-HSCT for HGP are common and heterogeneous. Etiology is multifactorial with iron overload (IO), class, splenectomy, age, chronic GVHD, and corticosteroid (CS) treatment. Our data may help build follow-up guidelines to limit, detect, and treat any LCs and improve quality of life.

Does regular follow-up influence the survival of patients with sarcoma after recurrence? The Miri Shitrit pediatric oncology department experience.

Despite comprehensive management of pediatric sarcomas, only 60% to 70% of children become long-term survivors. This study was undertaken to evaluate whether regular follow-up improves overall survival of children with recurrent sarcomas. The medical charts of 107 children diagnosed with soft tissue and bone sarcomas were reviewed, of whom 29 relapsed. They were divided into 2 groups according to the way of relapse diagnosis: due to complaints/physical examination (14) or on routine imaging studies (15). All were followed by regular physical examination and imaging studies (chest computed tomography, magnetic resonance imaging, and bone scan/positron emission tomography-computed tomography scan with fluorodeoxyglucose) at regular intervals. Analysis of the results showed that (1) regular imaging studies do not facilitate earlier recognition of relapse in children with sarcomas; (2) regular follow-up with imaging studies does not influence overall survival of children with sarcomas; (3) other diagnostic and treatment approaches are needed to improve the survival of children with recurrent sarcomas.

Burkitt lymphoma in children: the Israeli experience.

Background We analyzed the results of the French-American-British-LMB 96 protocol performed in 9 centers in Israel on 88 patients with B-cell non-Hodgkin lymphoma treated from 2000 to 2005. Procedure The majority of the patients was male (63/88, 72%), with a median age of 8.9 years (range, 2.5 to 20 y). Ethnic origin was Jewish in 73% (64/88), and Arabic in 27%. Fifty (57%) patients were classified as Burkitt lymphoma, 5 (5.7%) as Burkitt-like lymphoma, 22 (25%) as diffuse large B cell (DLBC), and 9 (10.2%) as Burkitt leukemia with over 25% of their bone marrow (BM) involved. Initial disease sites included the abdomen in 43%, head and neck in 45%, and mediastinum in 7%. Stage I: 9.1%; stage II: 28.4%; stage III: 45.5%, stage IV: 17%. Two patients had BM involvement alone, 5 patients had central nervous system (CNS) involvement alone, and 4 had both CNS and BM. The children were divided into 3 groups according to risk factors, with 5 in group A, 69 in group B, and 14 in group C. Results With a median follow-up of 3 years (12 mo to 7.6 y), the Kaplan-Meier for event-free survival (EFS) and overall survival (OS) according to whole group treatment was 88.6% and 90.9%, group A was 100% and 100%; group B was 89.9% and 92.8%; and group C was 78.6% and 78.6%. There were no untoward events or deaths in group A, whereas 6 patients relapsed in group B, 4 of whom died (all relapsed during the first year), with tumor lysis syndrome in 3 patients and death of toxicity in 1 patient who had multiorgan failure 2 days after initiation of COP. Three patients in group C relapsed and died (all patients relapsed during the first 6 months), with tumor lysis syndrome in 4 patients but no deaths from toxicity. EFS for LDH less than twice was 96.4%, EFS for LDH more than twice was 73.3% (P=0.002). OS according to primary site: bone and ovary: 100%; head and neck: 95%; abdomen: 92%; mediastinum: 50%. The difference between the mediastinal primary site to all other primary sites was statistically significant with P=0.003. All the mediastinal tumors were of DLBC origin but no significant differences in outcome were found when DLBC was compared with other histologies (DLBC: 81.8%, other B line: 90.9%). OS for patients of Arabic ethnic origin was 79.2%, for Jewish patients was 95.3%, P=0.02. We could not determine any prognostic factors that were different between the groups, which raises the question of a genetic influence. Conclusions In nonresected mature B-cell lymphoma of childhood and adolescence with no BM or CNS involvement, a 93% cure rate can be achieved, similar to the French-American-British/LMB 96 trial. Patients with primary DLBC mediastinal mass had a significantly reduced OS, indicating the need for a different therapeutic approach.

Cancer Incidence and Survival Among Infants in Israel, 1998-2007

Cancer during the first year of life is relatively rare and often has clinical and biological properties different from those of the same histologic type of cancer occurring in older children. The aim of this study was to find differences in epidemiology and survival between infants and older children and to compare the percentage of distribution of infant cancer types in Israel with that reported in the United States. We collected infant <1 year of age cases diagnosed between 1998 and 2007 as having cancer from the database of the Israel National Cancer Registry, a total of 309 cases with an incidence rate of 228.5 cases per million. The largest group was diagnosed with neuroblastoma (35%) with an incident rate of 80 per million, followed by leukemia (15.9%), with acute lymphoid leukemia and acute myeloid leukemia accounting for most of this group and central nervous system malignancies comprised 10.7% of infant cancer. One hundred and fifty four new cases of infant girls was diagnosed compared to 155 infant boys with an incidence rates of 234 cases per million for girls and 224.7 for boys, not statistically significant (F:M rate ratio of 1.04). The 5-year survival rates seen in the different groups were leukemia: 55.3%, lymphoma: 71%, CNS tumors: 53.3%, neuroblastoma: 93.4%, retinoblastoma: 94.7% renal tumors: 90.9%, hepatic tumors: 63.3%, soft tissue sarcoma: 76.2%, germ cell neoplasms: 83.3%, and other epithelial neoplasms: 100%. Our study did not find survival differences with statistical significance upon comparing survival rates between different genders and ethnic groups.

Cancer incidence and survival among adolescents in Israel during the years 1998 to 2009

Our goal was to describe adolescent cancer incidence and survival in Israel, and to identify demographic and epidemiologic variations among adolescents with cancer.