6 research outputs found
Tumor markers in breast cancer - European Group on Tumor Markers recommendations
Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel
Genetic analysis of human astrocytic gliomas : xenografts as a research tool
Cancer is a genetic disorder of somatic cells. An accumulation of genetic
changes is believed to result in neoplastic transformation and malignant
progression. In humans, astrocytic gliomas are the most common primary
tumors of brain tissue. They are malignancy graded according to World
Health Organization criteria. In adults, the tumors include astrocytoma,
(grade II), anaplastic astrocytoma, (grade III) and the most malignant
and common form glioblastoma (grade IV). A significant proportion of
astrocytomas (A) and anaplastic astrocytomas (AA) progress into tumors of
higher malignancy grade. Glioblastomas (GB) arise by progression, but may
also develop de novo. Several genes and chromosomal regions are commonly
found amplified, deleted or mutated in these tumors, suggesting a role
for these abnormalities in the development and progression of astrocytic
gliomas. An accumulation of genetic lesions is seen with increasing
malignancy grade.
The aim of the studies described in this thesis was to document genetic
abnormalities in human astrocytic gliomas and to establish human
astrocytic gliomas as xenografts permitting the development of material
for extensive and detailed studies of genetic abnormalities and their
cell biological consequences. In addition, xenografts provide tumour
tissue with well-documented patterns of genetic abnormalities, in an in
vivo environment, for preliminary testing of novel treatment modalities.
Other aims included the determination of whether the xenografts are
representative of the patient's tumour, and to study whether further
genetic abnormalities arise in xenografts and, if so, to identify these.
A series of 198 astrocytic gliomas was examined for loss of genetic
material on chromosome 10. The microsatellite analysis revealed two
commonly deleted regions on 10p, detected in all malignancy grades.
Deletions on 10q were large and found mainly in the glioblastomas. The
findings suggest that a number of loci on chromosome 10 may harbor tumour
suppressor genes relevant to the development and progression of these
tumors. Loci on 10p may be involved in the development of astrocytomas,
and loci on 10q important in the progression of such astrocytomas to
glioblastoma. The tumor suppressor gene PTEN is located at 10q23, and was
studied in 207 astrocytic gliomas from patients, 23 glioblastoma
xenografts and 13 glioma cell lines. Homozygous deletions were found in
7% of the glioblastomas and 40% of glioblastomas showed mutation of a
single retained allele. The mutations mainly affected structurally
conserved regions. PTEN loss was selected for in the glioblastoma
xenografts. Only a few anaplastic astrocytomas harbored mutations and no
alterations were found in astrocytomas. This suggests that PTEN
abnormalities are associated with astrocytic tumour progression.
A glioblastoma xenograft model was established. Of 47 directly and
subcutaneously transplanted patient tumors, 24 grew on serial passaging.
To preserve the system and to increase accessibility, a cryopreservation
protocol for long term storage of viable tumour tissue from any passage
was developed and demonstrated to work successfully for the majority of
the xenografts. A number of genes previously known to show aberrations in
human glioblastomas were found to become mutated in the xenografts, as
studied by comparing the genetic analysis of patient and xenograft tumour
tissues. Acquisition of additional aberrations during passage as
xenografts was detected. For example, one tumour with an amplified EGFR
gene developed a rearrangement of the gene during xenograft cultivation.
This demonstrates the significance of this aberrant variant reported
earlier in clinical material. Furthermore, selection for tumour cells
harboring genetic abnormalities deregulating the G1/S-phase transition
control and p53 pathways was found in the xenografts. Commonly,
abnormalities affecting both G1/S-phase transition control and p53
pathways developed simultaneously.
In summary, the patient tumors were characterized for genetic
abnormalities. Some of the glioblastomas were successfully cultivated as
xenografts. Cryopreservation was developed, and the xenografts
characterized for the acquisition of and selection for genetic mutations.
The characterized xenografts now offer the possibility of analyzing in
detail the development of genetic changes, their cell biological
consequences and the selection process, as well as offering the
possibility of testing novel treatment modalities
Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting beta(2) agonist : observational matched cohort study (PATHOS)
Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting beta(2) agonist. Design Observational retrospective pairwise cohort study matched (1:1) for propensity score. Setting Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009. Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol. Main outcome measures Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality. Results 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each. In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19 170 patient years of follow up. Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol:rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively. The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6). The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003). All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59). Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting beta(2) agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD. Trial registration Clinical Trials.gov NCT01146392
Pneumonia and pneumonia related mortality in patients with COPD treated with fixed combinations of inhaled corticosteroid and long acting beta(2) agonist : observational matched cohort study (PATHOS)
Objective To investigate the occurrence of pneumonia and pneumonia related events in patients with chronic obstructive pulmonary disease (COPD) treated with two different fixed combinations of inhaled corticosteroid/long acting beta(2) agonist. Design Observational retrospective pairwise cohort study matched (1:1) for propensity score. Setting Primary care medical records data linked to Swedish hospital, drug, and cause of death registry data for years 1999-2009. Participants Patients with COPD diagnosed by a physician and prescriptions of either budesonide/formoterol or fluticasone/salmeterol. Main outcome measures Yearly pneumonia event rates, admission to hospital related to pneumonia, and mortality. Results 9893 patients were eligible for matching (2738 in the fluticasone/salmeterol group; 7155 in the budesonide/formoterol group), yielding two matched cohorts of 2734 patients each. In these patients, 2115 (39%) had at least one recorded episode of pneumonia during the study period, with 2746 episodes recorded during 19 170 patient years of follow up. Compared with budesonide/formoterol, rate of pneumonia and admission to hospital were higher in patients treated with fluticasone/salmeterol:rate ratio 1.73 (95% confidence interval 1.57 to 1.90; P<0.001) and 1.74 (1.56 to 1.94; P<0.001), respectively. The pneumonia event rate per 100 patient years for fluticasone/salmeterol versus budesonide/formoterol was 11.0 (10.4 to 11.8) versus 6.4 (6.0 to 6.9) and the rate of admission to hospital was 7.4 (6.9 to 8.0) versus 4.3 (3.9 to 4.6). The mean duration of admissions related to pneumonia was similar for both groups, but mortality related to pneumonia was higher in the fluticasone/salmeterol group (97 deaths) than in the budesonide/formoterol group (52 deaths) (hazard ratio 1.76, 1.22 to 2.53; P=0.003). All cause mortality did not differ between the treatments (1.08, 0.93 to 1.14; P=0.59). Conclusions There is an intra-class difference between fixed combinations of inhaled corticosteroid/long acting beta(2) agonist with regard to the risk of pneumonia and pneumonia related events in the treatment of patients with COPD. Trial registration Clinical Trials.gov NCT01146392