Absence of mouse pleiotrophin does not affect bone formation in vivo

Pleiotrophin (Ptn) is an extracellular matrix protein that regulates hippocampal synaptic plasticity and learning behavior in vivo. Since the overexpression of Ptn in transgenic mice leads to increased bone formation, we analyzed whether a deficiency in Ptn expression would have a negative effect on bone remodeling. Bones from Ptn-deficient mice and wild-type littermates were analyzed using radiography, μCT imaging and undecalcified histology. Biomechanical stability was determined in a three-point-bending assay. Cellular activities were assessed using dynamic histomorphometry and the determination of urinary collagen degradation products. Skeletons of Ptn-deficient mice have no gross abnormalities, displayed a normal size, and showed no differences in growth plate organization compared to wild-type littermates. There were no obvious differences in bone mass as determined by radiographic and μCT imaging. The absence of a bone remodeling phenotype in Ptn-deficient mice was further confirmed using static histomorphometry and biomechanical testing. Finally, the number, morphology, and function of osteoclasts, osteoblasts, and osteocytes were not altered in Ptn-deficient mice compared to wild-type littermates. The complete skeletal analysis of Ptn-deficient mice presented here demonstrates that the lack of Ptn in mice does not affect bone formation in vivo. Therefore, Ptn does not play a significant role in normal bone physiology.     

Phase II study of ifosfamide plus daily oral etoposide in previously treated ovarian cancer: a Hoosier Oncology Group (HOG) study

Advanced epithelial ovarian carcinoma is a chemosensitive tumor to platinum plus paclitaxel combination chemotherapy. However, most patients develop recurrences following their initial platinum-based regimen and are candidates for subsequent chemotherapy. Several chemotherapeutic drugs have been tested as single therapeutic agents or in combination for relapsed epithelial ovarian carcinoma. The response rate has been modest with no obvious advantage to combination chemotherapy versus single agents. Both oral etoposide and ifosfamide have shown activity as single agents in pretreated patients. We completed a phase II study at the Hoosier Oncology Group utilizing oral etoposide plus ifosfamide in patients with relapsed ovarian epithelial carcinoma. Fourteen patients entered the study. Ifosfamide was given intravenously (IV) at a dose of 1.2 g/m2/d on days 1 to 4 with mesna 300 mg/m2 IV 15 minutes prior to and 4 and 8 hours after ifosfamide infusion. Etoposide was administered as 37.5 mg/m2/d orally on days 1 to 14. This regimen was repeated every 28 days until disease progression or for a maximum of 6 cycles. Grade III to IV granulocytopenia occurred in 9 patients (64%), with 2 neutropenic infections, but with no therapy-related deaths. Grade III to IV thrombocytopenia occurred in 3 patients (21%), and grade III to IV nausea and vomiting in 1 patient. No renal, pulmonary, hepatic, cardiac, or serious neurotoxicity was observed. Two patients (14%) achieved partial response, and additional 5 (35%) patients had stable disease. The 1-year survival probability using Kaplan-Meier analysis was 0.8. In this small sample-size trial, we did not demonstrate an advantage to this combination regimen compared to these or other single agents.     

Efficacy and safety of pioglitazone in type 2 diabetes: a randomised,placebo-controlled study in patients receiving stable insulin therapy

The glycaemic and lipid effects of treatment with pioglitazone in combination with a stable insulin regimen were evaluated in patients with type 2 diabetes. Patients (n=566) receiving stable insulin regimens for > or = 30 days yet who had HbA1c > or = 8.0% and C-peptide > 0.7 microg/l were randomised to receive once-daily 15 mg pioglitazone, 30 mg pioglitazone, or placebo in a 16-week multicentre, double-blind, placebo-controlled trial. Per study protocol, the insulin dose was to remain unchanged, but could be decreased in response to hypoglycaemia. At the end of double-blind treatment, patients receiving pioglitazone (15 mg or 30 mg) showed statistically significant mean decreases relative to baseline HbA1c (-1.0 and -1.3, respectively; p<0.0001) and fasting plasma glucose (FPG) (-34.5 mg/dl [-1.92 mmol/l] and -48.0 mg/dl [-2.67 mmol/l], respectively; p<0.0001); these differences compared with placebo were also significant (p<0.0001). Pioglitazone (15 or 30 mg) yielded significant increases in HDL-C levels (mean increases ranging from +7.1% to + 9.3%) compared with baseline or placebo (p<0.01). The 30 mg dose also significantly reduced mean triglyceride levels (-23.7%) compared with placebo (p=0.0218). No consistent changes in TC or LDL-C levels were observed. The incidence of adverse events was similar in all treatment groups, although the incidences of weight increase, hypoglycaemia and oedema were higher among patients receiving insulin plus pioglitazone. There was no evidence of hepatotoxicity or drug-induced elevations of serum ALT > or = 3 x ULN. Pioglitazone, when added to stable insulin regimens, significantly improved HbA1c and FPG in type 2 diabetes. Pioglitazone treatment also provided significant benefit with respect to plasma HDL-C and triglyceride levels. Whether these lipid changes have an impact on overall diabetic complications remains to be determined.     

A systematic overview of radiation therapy effects in uterine cancer (corpus uteri)

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for uterine cancer is based on data from one randomized study. Moreover, data from two prospective studies and seven retrospective studies were used. In total, 10 scientific articles are included, involving 3,446 patients. The results were compared with those of a similar overview from 1996 including 13 597 patients. The conclusions reached can be summarized as: There is fairly good evidence that there is no need for adjuvant radiotherapy in patients with good risk uterine cancer. There is fairly good evidence that adjuvant radiotherapy reduces the relapse rate in high-risk patients but has no impact on survival. There is substantial documentation showing that medically inoperable patients and patients with locally recurrent uterine cancer can be treated with radiotherapy alone with curative effect.     

A systematic overview of radiation therapy effects in cervical cancer (cervix uteri)

A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for cervical cancer is based on data from 1 meta-analysis and 34 randomized trials. In total, 35 scientific articles are included, involving 7 952 patients. The results were compared with those of a similar overview from 1996 including 34 024 patients. The conclusions reached can be summarized in these points: There are limited scientific data supporting that postoperative pelvic radiotherapy improves disease-free survival in early cervical cancer. No firm conclusion can be drawn. There is moderate scientific evidence that external beam radiotherapy combined with brachytherapy gives a similar disease-free and overall survival rate as radical hysterectomy in early cervical cancer. There is strong scientific evidence that concomitant radiochemotherapy improves disease-free and overall survival compared to radiotherapy alone in early cervical cancer. The NCI has recently published an announcement stating that cisplatin-based chemotherapy should be used concomitantly with radiotherapy in cervical cancer. No solid documentation for this statement can be found concerning locally advanced stages ( >IIB). There is a strong scientific evidence that cisplatin-based chemotherapy given concomitantly with radiotherapy is superior to concomitant chemotherapy with hydroxyurea. There is no scientific evidence to show that neoadjuvant chemotherapy followed by radiotherapy improves disease-free or overall survival compared to radiotherapy alone in patients with localized cervical cancer. There is moderate scientific evidence that high-dose-rate brachytherapy gives the same local control rate as low-dose-rate brachytherapy but with fewer rectal complications.     

A phase II study of carboplatin plus gemcitabine in advanced non-small-cell lung cancer (NSCLC): a hoosier oncology group study

The purpose of this study was to evaluate the toxicity and determine the response rate, duration of remission, and survival using gemcitabine plus carboplatin in non-small cell lung cancer (NSCLC). This was a phase II study of gemcitabine and carboplatin in chemotherapy-naive patients with advanced NSCLC and Karnofsky Performance Status of at least 80. Gemcitabine was administered intravenously at 1,000 mg/m2 weekly for 3 weeks followed by 1 week rest. Carboplatin was administered immediately after gemcitabine at an area under the curve (AUC) of 5 given intravenously on day 1 of an every-4-week cycle. Seven patients were entered in the study and five were evaluable for toxicity. The median age of patients was 68 years (range, 52-72). The protocol was prematurely terminated because of severe and unexpected hematologic toxicity. Grade 3-4 thrombocytopenia was observed in four of the first five patients. These toxicities were all observed with the first course of chemotherapy. There were no objective responses seen. Median survival time was 130 days. Carboplatin plus gemcitabine was a logical combination. However, because of the severe thrombocytopenia associated with this regimen, we do not recommend this two-drug combination in the dose and schedule used in this study.     

Impairment of cell-mediated immunity in ectodermal dysplasia with aplastic anemia.

A case of ectodermal dysplasia and aplastic anemia is presented in which a cell-mediated immunodeficiency led to a fatal Pneumocystis carinii infection. Elevated levels of IgG, IgA and IgD were present with normal specific antibody titres. A deficient cell-mediated immunity was documented by low T cell numbers, poor in vitro mitogenic responses, negative skin tests and by the histologic finding at autopsy of thymic dysplasia.     

The effects of prior exposure to bleomycin on the incidence of pulmonary toxicities in a group of patients with disseminated testicular carcinomas

The incidence of pulmonary toxicities in 12 patients with prior exposure to bleomycin (BLM) was compared to the incidence of pulmonary toxicities in a matched group of 73 patients with stage III or IV testicular carcinomas treated with a regimen containing vinblastine, bleomycin, and cis-diamminedichloroplatinum. The comparison demonstrates that prior exposure to bleomycin constitutes a significant risk factor and that the risk is additive; ie, prior doses should be added to current doses to determine the cumulative dose-related probability of development of pulmonary toxicities.     

Prospective evaluation of serum CA 125 levels for early detection of ovarian cancer.

Detection of ovarian cancer at an early stage should reduce the mortality associated with this disease. Through the Stockholm Population Registry, 5550 apparently healthy women were enrolled in a study designed in part to define the use of the CA 125 radioimmunoassay (RIA) as an initial test for early detection of ovarian cancer. Women whose CA 125 levels were elevated and an equal number of age-matched controls with normal levels were followed by means of pelvic examinations, transabdominal sonography, and serial CA 125 determinations. Of the 175 women with high CA 125 levels, six were found to have ovarian cancer: two each in stages IA, IIB, and IIIC. Of those with normal-range CA 125 levels, three had ovarian cancer as identified through the Swedish Cancer Registry; all three were under 50 years of age. Ovarian cancer was diagnosed on laparotomy in six of the women age 50 or over. Using thresholds of 30 and 35 U/mL, the rates of specificity for the CA 125 RIA were 97 and 98.5%, respectively, for women age 50 or older, and 91 and 94.5%, respectively, for those younger than 50 years of age. Thus, the specificity of the CA 125 RIA is adequate in postmenopausal women to undertake a larger study to determine whether screening using CA 125 influences survival of patients with ovarian cancer.