Pharmacogenetics of cyclophosphamide in patients with hematological malignancies.

PURPOSE: A high degree of interindividual variation in cyclophosphamide (CPA) pharmacokinetics was reported in certain cancer patient groups. To better understand the mechanisms underlying the variation in CPA metabolism, we have investigated the pharmacokinetics of CPA and its active metabolite 4-hydroxycyclophosphamide (4-OH-CPA) in patients with hematological tumors. The pharmacokinetics of CPA and its active metabolite were related to the genotype of CYP2B6, CYP2C9 and CYP2C19. The influence of liver function on CPA metabolism was also evaluated. METHODS: Twenty-nine patients with hematological malignancies (MM, ALL or NHL) treated with a conventional CPA dose (1g/m(2)) were recruited to this study. Blood samples were collected before, during and after CPA treatment. HPLC was used to measure plasma concentrations of CPA and 4-OH-CPA. Patients were genotyped for the CYP2B6 G516T, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3 alleles. Serum bilirubin levels were measured before the treatment. Data was analyzed individually and by population pharmacokinetic methods, using non-linear mixed effect modeling. RESULTS: The interindividual variability in exposure to CPA, 4-OHCPA and 4-OH-CPA/CPA was 5.8-, 3.3- and 10.3-fold, respectively. A positive correlation between half-lives of CPA and 4-OH-CPA was found while a significant negative correlation between AUCs of CPA and 4-OH-CPA was detected. In the population analysis, the CYP2B6 G516T variant allele contribution to CPA clearance was about twice as the contribution from the wild type gene while the genotype of CYP2C9 and CYP2C19 did not influence clearance. A negative correlation was observed between bilirubin level and CPA bioactivation. CONCLUSION: This study demonstrates for the first time that the presence of the CYP2B6 G516T mutation increases the rate of 4-OH-CPA formation in patients with hematological malignancies. The liver function prior therapy as assessed by s-bilirubin influences CPA metabolism.     

Maternal androgen and estrogen concentrations are not associated with blood pressure changes in uncomplicated pregnancies.

Systolic blood pressure increase between the second and third trimester of pregnancy has been associated with a substantially reduced maternal breast cancer risk, and it has been suggested that elevated androgens mediate the association. Androgen and estrogen concentrations were measured in maternal serum collected in 86 uncomplicated, singleton pregnancies. Overall, there were no consistent or statistically significant patterns of association between the hormones and systolic, diastolic, or mean arterial blood pressure or blood pressure change between trimesters. Results were similar with adjustment for factors related to the hormones. These data are not consistent with the hypothesis that elevated androgen concentrations mediate the observed reduction in maternal breast cancer risk associated with increases in blood pressure over the pregnancy.     

The membrane targeted apoptosis modulators erucylphosphocholine and erucylphosphohomocholine increase the radiation response of human glioblastoma cell lines in vitro

Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutical modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be assayed. A strategy currently being investigated is the use of newer radiosensitizers alone or in combination with platinum compounds. In the present work, we present preclinical information on known and newer cytotoxic agents as radiosensitizers on cervical cancer models, as well as the clinical information emanating from early phase trials that incorporate them to the cervical cancer management. In addition, we present the perspectives on the combined approach of radiation therapy and molecular target-based drugs with proven radiosensitizing capacity.     

Radiation-induced effects on gene expression: an in vivo study on breast cancer.

BACKGROUND AND PURPOSE: Breast cancer is diagnosed worldwide in approximately one million women annually and radiation therapy is an integral part of treatment. The purpose of this study was to investigate the molecular basis underlying response to radiotherapy in breast cancer tissue. MATERIAL AND METHODS: Tumour biopsies were sampled before radiation and after 10 treatments (of 2 Gray (Gy) each) from 19 patients with breast cancer receiving radiation therapy. Gene expression microarray analyses were performed to identify in vivo radiation-responsive genes in tumours from patients diagnosed with breast cancer. The mutation status of the TP53 gene was determined by using direct sequencing. RESULTS AND CONCLUSION: Several genes involved in cell cycle regulation and DNA repair were found to be significantly induced by radiation treatment. Mutations were found in the TP53 gene in 39% of the tumours and the gene expression profiles observed seemed to be influenced by the TP53 mutation status.     

The serum ferritin concentration is a significant prognostic indicator of survival in primary lung cancer.

The prognostic significance of serum ferritin on survival in lung cancer was evaluated. One hundred and ninety-seven patients were referred for evaluation of pulmonary lesions; 115 patients (85 men) had primary lung cancer. Their median age was 57 years. Seventy-four patients (43 men) with benign lung disease were enrolled as controls. Their median age was 53 years. Serum ferritin was measured at diagnosis. Non-small cell lung cancer (NSCLC) (n=90) was graded according to the TNM-system and small cell lung cancer (SCLC) (n=25) in limited and extensive disease. Follow-up was median 30 months (range 23-36). Patients with lung cancer had higher median ferritin than controls (245 vs. 145 microg/l, p<0.00001): the prevalence of ferritin >300 microg/l was 37% in patients with lung cancer and 14% in controls (p<0.001). There was no significant difference in ferritin between patients with different stages either in NSCLC or in SCLC. Patients with SCLC had higher median ferritin than patients with NSCLC (344 vs. 233 microg/l, p<0.05). No significant differences in ferritin could be demonstrated among the other histological tumour types. The overall survival rate in patients with lung cancer was 52% after 1 year, 33% after 2 years, and 13% after 3 years. Survival rate was lower in patients with ferritin >300 microg/l than in those with ferritin < or =300 microg/l (p<0.0001). The probability of survival 1, 2 and 3 years after diagnosis in patients with ferritin >300 microg/l was 36, 20 and 4%, respectively, and in patients with ferritin < or =300 it was 63, 42 and 18%, respectively (p<0.0001). An elevated ferritin was a significant prognostic factor (p<0.01) even after adjustment for performance status, age, sex, TNM stage, and histological tumour type. TNM stage and performance status were likewise predictors of survival (p<0.01 and p<0.001, respectively). There exists a clinically relevant relationship between serum ferritin concentration and the prognosis of survival in patients with primary lung cancer. The routine use of serum ferritin should be considered in the evaluation and follow-up of pulmonary malignancies.     

Glottic carcinoma--patterns of failure and salvage treatment after curative radiotherapy in 861 consecutive patients.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the patterns of failure and the treatment of recurrences, in a series of primary irradiated patients with squamous cell carcinoma of the glottic larynx. MATERIALS AND METHODS: Eight hundred and sixty-one consecutive patients were included in this study from 1963 to 1991, out of which 74 were females and 787 males. The stages were: I 56, II 26, III 15, and IV 3%. In 847 of 861 cases (98%) the primary treatment was delivered with curative intent, and out of these 834 patients received primary radical radiotherapy. RESULTS: With a minimum follow up of 5 years, 274/861(32%) patients had persistent or recurrent disease; in 91% of these the persistent or recurrent disease was in the T-position, 15% in the N-position, and 5% developed distant metastases. Curative salvage attempt was possible in 207 patients, and 145 were subsequently controlled. A total of 718 (83%) patients obtained ultimate tumour control, 584 (68%) without a laryngectomy (134 of the controlled had a laryngectomy, 109 had a total laryngectomy and 25 had a partial laryngectomy). In the patients treated with curative intent, the overall 5-year local tumour control, loco-regional tumour control, disease specific survival rate and overall survival rate was 72, 70, 86 and 66%, respectively. For patients with small tumours the disease specific survival for T1a, T1b and T2 was 95, 93 and 83%, respectively. In the 718 patients cured for their glottic carcinoma, 204 new primary malignant tumours were detected. CONCLUSIONS: The study shows that laryngeal glottic carcinoma can be effectively managed by primary radiotherapy and surgery salvage. The control is obtained with a high proportion of laryngeal preservation (68%). Recurrences treated with surgical salvage have a success rate of 70%. New primaries are a major problem.     

Cemented femoral impaction bone grafting for severe osteolysis in revision hip arthroplasty

Ten hips underwent impaction bone grafting with cement as revision of the femoral stem for severe osteolysis. At clinical follow-up of a median of 4 years (range 3.0–4.6 years) there were no failures. The median Harris hip score increased from 53 to 80, and pain score from 25 to 40. Radiographically, there was no resorption of the impacted grafts. All of the 9 patients with radiographical follow-up of more than 1 year showed trabecular remodelling, 7 of whom had signs of cortical repair. Subsidence was a median of 2 mm, with the maximum subsidence being 5 mm. The results appeared clinically stable after 4 years with radiographic reconstitution of the bone stock.     

Peroxisome proliferator-activated receptor-γ2 Pro12Ala polymorphism, cod liver oil and risk of type 1 diabetes

Objective:  We have previously described an association between use of cod liver oil (a dietary n-3 fatty acid supplement) and reduced risk of type 1 diabetes. n-3 fatty acids are ligands for the peroxisome proliferator-activated receptor-γ ( PPARG ), which has recently been implicated in the control of inflammation and possibly autoimmunity. We aimed to estimate the association between the common Pro12Ala polymorphism of PPARG2 and risk of type 1 diabetes, and to test whether there is gene–environment interaction with use of cod liver oil in the first year of life or gene–gene interaction with the established insulin gene ( INS ) and human leukocyte antigen DQ ( HLA-DQ ) genetic susceptibility loci.
Methods:  We designed a population-based case–control study of childhood-onset type 1 diabetes in Norway with information on use of cod liver oil in the first year of life from questionnaires and PPARG2 genotype data for 483 cases and 1520 control subjects. We used logistic regression for analysis.
Results:  The odds ratio for the PPARG2 Ala/Ala or Pro/Ala vs. Pro/Pro genotype and type 1 diabetes was 0.89 (95% CI: 0.69–1.13, p = 0.33). There was no significant interaction with cod liver oil in the first year of life [P (interaction) = 0.35] or with the INS polymorphism [P(interaction) = 0.42].
Conclusions:  Although the association between PPARG2 and type 1 diabetes was not significant, the observed odds ratio was almost identical to that observed in two previous studies and can contribute to meta-analysis indicating a weak but significant association. Our hypothesized interaction between cod liver oil and PPARG2 in reducing type 1 diabetes risk was not supported.     

The effect of adding group-based counselling to individual lifestyle counselling on changes in dietary intake. The Inter99 study – a randomized controlled trial

Background  

Few studies have investigated the specific effect of single intervention components in randomized controlled trials. The purpose was to investigate the effect of adding group-based diet and exercise counselling to individual life-style counselling on long-term changes in dietary habits.