Meta-regression detected associations between heterogeneous treatment effects and study-level, but not patient-level, factors

OBJECTIVE: Two investigations evaluate Bayesian meta-regression for detecting treatment interactions. STUDY DESIGN AND SETTING: The first compares analyses of aggregate and individual patient data on 1,860 subjects from 11 trials testing angiotensin converting enzyme (ACE) inhibitors for nondiabetic kidney disease. The second explores meta-regression for detecting treatment interaction on 671 covariates, including the baseline risk, from 232 meta-analyses of binary outcomes compiled from the Cochrane Collaboration and the medical literature. RESULTS: In the ACE inhibitor study, treatment effects were homogeneous so meta-regression identified no interactions. Analysis of individual patient data using a multilevel model, however, discovered that treatment reduced glomerular filtration rate (GFR) more among patients with higher baseline proteinuria. The second investigation found meta-regression most effective for detecting treatment interactions with study-level factors in meta-analyses with >10 studies, heterogeneous treatment effects, or significant overall treatment effects. Under all three conditions, 46% of meta-regressions produced strong interactions (posterior probability >0.995) compared with 6% otherwise. Baseline risk was associated with the odds ratio in 6% of meta-analyses, half the rate found using maximum likelihood. CONCLUSION: Meta-regression can detect interactions of treatment with study-level factors when treatment effects are heterogeneous. Individual patient data are needed for patient-level factors and homogeneous effects.     

Effect of hydroxycitrate on respiratory quotient, energy expenditure, and glucose tolerance in male rats after a period of restrictive feeding

OBJECTIVE: Recently we demonstrated that hydroxycitrate (HCA) suppresses food intake and body weight regain in male rats after substantial body weight loss. However, it is not known whether HCA also affects the respiration quotient (RQ), energy expenditure (EE), and glucose tolerance in this animal model. METHODS: Twenty-four male rats (initial body weight, 378 +/- 3 g) were fed restrictively (10 g/d) for 10 d and then given ad libitum access to a high-glucose diet supplemented with 3% HCA for 6 d. Controls received the same diet without the supplement. RQ and EE were measured during ad libitum days 1, 2, and 6. An oral glucose tolerance test was performed on ad libitum day 4 or 5. RESULTS: HCA decreased RQ and EE during ad libitum days 1 and 2. In all probability, these findings reflect a decrease in de novo lipogenesis. On ad libitum day 6, RQ and EE did not differ between treatment groups. HCA suppressed food intake during the first 3 d ad libitum, but overall body weight regain was not decreased in the HCA group. The oral glucose tolerance test showed that HCA significantly decreased the increase in plasma glucose from baseline (Deltaglucose) and tended to decrease the area under the curve for glucose. Deltainsulin and area under the curve for insulin did not differ between groups. CONCLUSIONS: These results indicate that, in this animal model, HCA suppresses de novo lipogenesis. Moreover, HCA may improve glucose tolerance.     

Cd Accumulation and Cd–Metallothionein as a Biomarker in <Emphasis Type="Italic">Cepaea hortensis</Emphasis> (Helicidae,Pulmonata) from Laboratory Exposure and Metal-polluted Habitats

Cepaea hortensis is a widespread terrestrial pulmonate, contributing significantly to element fluxes in soil ecosystems. Due to its capacity of accumulating certain trace elements in its tissues, Cepaea hortensis can serve as a biological indicator of metal accumulation in contaminated areas. In response to Cd exposure this species and related helicid pulmonates are also able to synthesize an inducible, Cd-binding metallothionein (MT) isoform specifically serving in binding and detoxification of this metal. As shown by field-collected garden-snails from a metal-contaminated site near a zinc smelting works in Avonmouth (UK) and an unpolluted reference site in Reutte (Tyrol, Austria), Cd and Cd–MT concentrations in midgut gland of C. hortensisfrom these sites increased with rising Cd concentrations in the soil substrate from the same contaminated sites. By combining the results of these field data with laboratory experiments it appears that midgut gland Cd–MT of Cepaea hortensis seems to fulfil the criteria of a successful biomarker in many respects. First, the synthesis of the protein can rapidly be induced by Cd exposure. Second, the level of Cd–MT induction in C. hortensis directly reflects the intensity of metal exposure. Third, the induced signal of increased Cd–MT concentration in C. hortensis is persistent over extended periods of time. Fourth, the Cd–MT signal in C. hortensis seems to be very specific for Cd exposure. Regression analyses demonstrate that tissue levels of Cd and Cd–MT in C. hortensis depend on Cd concentrations in the substrate which is represented by either soil or plant material on which snails normally feed. In both cases the best fit for this dependence is exhibited by a semi-logarithmic relationship, with substrate (soil or plant feed) concentrations expressed on a logarithmic scale. It is concluded that C. hortensis and other related pulmonates can successfully be used either as biological indicators of Cd accumulation, or as key species in biomonitoring studies focusing on Cd–MT induction as a biomarker for Cd exposure.     

Cellular immunotherapy after allogeneic stem cell transplantation in hematologic malignancies

PURPOSE OF REVIEW: The chimeric state after allogeneic stem cell transplantation provides an ideal platform for adoptive immunotherapy of hematologic malignancies using donor-derived cells. The present review aims to summarize recent results of the transfusion of donor-derived cells with regard to the diseases treated, the cells used for treatment, and the origin of these cells. RECENT FINDINGS: The transfusion of donor lymphocytes has been studied widely, not only in patients with recurrent disease, persistent disease, and mixed chimerism but also in a variety of hematologic malignancies. Donors of lymphocytes and hematopoietic stem cells have been HLA-identical siblings, HLA-matched unrelated donors, and HLA-different haploidentical family members. A variety of cells have been used for adoptive immunotherapy, including plain lymphocytes, selected T cells, T cell lines, and T cell clones. The possible therapies have been expanded by natural killer cells and natural killer T cells as well as antibodies directing the effector cells toward the malignancy. SUMMARY: Adoptive immunotherapy in chimeras has become not only a routine form of treatment of recurrent hematologic malignancy but also a prophylactic measure in high-risk leukemia and lymphoma.     

High expression of focal adhesion kinase (p125<Superscript>FAK</Superscript>) in node-negative breast cancer is related to overexpression of HER-2/neu and activated Akt kinase but does not predict outcome

Introduction

Focal adhesion kinase (FAK) regulates multiple cellular processes including growth, differentiation, adhesion, motility and apoptosis. In breast carcinoma, FAK overexpression has been linked to cancer progression but the prognostic relevance remains unknown. In particular, with regard to lymph node-negative breast cancer it is important to identify high-risk patients who would benefit from further adjuvant therapy.

Methods

We analyzed 162 node-negative breast cancer cases to determine the prognostic relevance of FAK expression, and we investigated the relationship of FAK with major associated signaling pathways (HER2, Src, Akt and extracellular regulated kinases) by immunohistochemistry and western blot analysis.

Results

Elevated FAK expression did not predict patient outcome, in contrast to tumor grading (P = 0.005), Akt activation (P = 0.0383) and estrogen receptor status (P = 0.0033). Significant positive correlations were observed between elevated FAK expression and HER2 overexpression (P = 0.001), as well as phospho-Src Tyr-215 (P = 0.021) and phospho-Akt (P < 0.001), but not with phospho-ERK1/2 (P = 0.108). Western blot analysis showed a significant correlation of FAK Tyr-861 activation and HER2 overexpression (P = 0.01).

Conclusions

Immunohistochemical detection of FAK expression is of no prognostic significance in node-negative breast cancer but provides evidence that HER2 is involved in tumor malignancy and metastatic ability of breast cancer through a novel signaling pathway participating FAK and Src.

     

Lung cancer during pregnancy involving the products of conception and a review of the literature

Approximately 1 per 1,000-1,500 pregnancies is complicated by maternal malignancies. Metastatic involvement of the products of conception is a rare event. There have been 62 cases of placental and/or fetal metastatic involvement originating from maternal cancer reported since 1866. Only 14 cases of lung cancer associated with pregnancy have been documented. We report on an additional case involving the products of conception, and the management of lung cancer in pregnancy is discussed based on an extensive review of the literature. The case of a 29-year-old woman presenting during the 31(st) week of gestation with metastatic non small-cell lung cancer to the placenta, liver and bone is described. The mother was delivered by caesarean section of a healthy baby girl during her 32(nd) week of gestation. The mother's postpartum course was complicated by disseminated pulmonary and bony metastases and malignant pericardial and pleural effusions causing the patient's death within 1 month after lung cancer was diagnosed. Malignancies spreading to the products of conception are melanoma (32%), leukemia and lymphomas (15%), breast cancer (13%), lung cancer (11%), sarcoma (8%), gastric cancer (3%) and gynecologic cancers (3%), reflecting malignancies with a high incidence in women of reproductive age. All lung cancers were diagnosed with widely disseminated, inoperable neoplastic disease, including distant metastases in 46%. The mean age was 35.1 years (range, 30-45 years) and 60% of patients had a history of tobacco use. The mean survival was 7.5 months (range: 1-42 months). Placenta involvement was present in 7 out of 15 cases. Fetal involvement was reported in only one case. Because there is no evidence of a direct adverse effect of pregnancy on the course of lung cancer, we recommend delivery at a time when enough fetal maturity can be assumed and the subsequent treatment of the mother.     

Clinical and endocrine follow-up of patients after testicular sperm extraction

OBJECTIVE: To evaluate the risk of testicular damage from testicular biopsies that are carried out for testicular sperm extraction (TESE) in infertile men. DESIGN: Prospective controlled clinical study. SETTING: Academic hospital. PATIENT(S): Forty infertile males with azoospermia.Examination of the clinical, endocrine, biochemical, and sonographic data in average after 18 months after TESE was performed. MAIN OUTCOME MEASURE(S): Measurements before and after TESE: hormone values, testicular size, morphologic characteristics, and power Doppler after scrotal sonography. RESULT(S): Comparison of preoperative and postoperative values of basal testosterone, FSH, LH, and estradiol levels did not reveal any differences. Twelve of 26 patients had subnormal testosterone values before TESE; 14 of 39 patients had subnormal levels afterward. Postoperative sonographic measurements showed no significant difference of the testicular volume as compared with the preoperative values. Results of power Doppler sonography revealed pathological conditions (n = 5) in patients with former iliacal or testicular operations. CONCLUSION(S): Endocrine testicular function and testicular size were not impaired after testicular biopsy when compared with preoperative data. However, patients with nonobstructive azoospermia seem to be at risk for androgen deficiency due to primary testicular failure after repeated testicular biopsies.