Biomedical subjects

K Possinger

Publications and source records attributed to K Possinger.

148 records · Page 9Linked to original sources

PubMedDate not supplied

Plasma levels of HER-2/neu, tumor type M2 pyruvate kinase and its tyrosine-phosphorylated metabolite in advanced breast cancer.

INTRODUCTION: Tyrosine kinase signal transduction pathways are a focus of interest for therapeutic interventions. The oncoprotein HER-2/neu shows tyrosine kinase activity leading to phosphorylation and activation of numerous second-messenger systems. One target of phosphorylation processes is assumed to be the tumor type M2 isoenzyme of pyruvate kinase (TuM2-PK) which has been shown to be elevated in metastatic breast cancer. MATERIALS AND METHODS: We measured the plasma levels of HER-2/neu, TuM2-PK and tyrosine-phosphorylated TuM2-PK (p-TuM2-PK) in 69 patients (pts) with breast cancer and correlated these parameters to each other and to the classical tumor marker CA 27.29. The samples were measured with ELISA assays while CA 27.29 was determined with an automated chemiluminescence assay. For analysis, we formed 5 subgroups according to the plasma HER-2/neu levels (group 1: < 15 ng/ml, n = 28; group 2: 15 < or = x < 50 ng/ml, n = 21; group 3: 50 < or = x < 100 ng/ml, n = 9; group 4: 100 < or = x < 500 ng/ml, n = 7; group 5: > or = 500 ng/ml, n = 4). RESULTS: From the HER-2/neu group 1 to group 5, there was a statistically significant increase of CA 27.29 from 35.8 U/ml to 1095.8 U/ml (p < 0.001). There was also a trend for increasing TuM2-PK levels with increasing HER-2/neu levels (p = 0.126). From the lowest extinction (0.088) to the highest extinction result (2.167) of p-TuM2-PK we found a 25-fold increase, which was reproducible in spiking and dilution experiments proving that TuM2-PK is phosphorylated at tyrosine residues to a certain extent. However, there was no correlation between plasma HER-2/neu and p-TuM2-PK levels. CONCLUSION: TuM2-PK is phosphorylated at tyrosine residues in breast cancer patients. Using the shed antigen of HER-2/neu in plasma as a surrogate marker, we did not find any evidence that this phosphorylation is initiated by the oncoprotein HER-2/neu.

Adult↗

PubMedDate not supplied

Normalisation of biochemical markers of bone formation correlates with clinical benefit from therapy in metastatic breast cancer.

BACKGROUND: Type I collagen is the most abundant protein of bone. We measured a panel of biochemical markers of bone metabolism including the amino-terminal propeptide (PINP) of type I collagen, the carboxy-terminal telopeptide (ICTP) of type I collagen, the urinary desoxypyridinium (DPD) crosslinks excretion, the alkaline phosphatase (AP) and serum calcium (Ca) levels as well as CA 27.29 as mass tumor marker in 73 breast cancer patients with bone metastases under specific antitumor therapy and supportive treatment with pamidronate. PATIENTS AND METHODS: Representative longitudinal single-time-point evaluations of all markers were correlated to response assessment in UICC criteria. Restaging was done by standard procedures. PINP and ICTP were measured using standardized radioimmunoassays with cut-offs of normal of 84 micrograms/l and 5 micrograms/l, respectively. DPD was measured on a chemiluminescence basis using an upper limit of normal of 13 nmol/mmol. RESULTS: The distributions of all pooled levels of CA 27.29 and AP were statistically significantly different (or just missed statistical significance) between patients with stabilized disease as compared to progressing patients with p = 0.012 for CA 27.29 and p = 0.053 for AP. AP was the only parameter which normalized below the cut-off of normal statistically significantly (p = 0.003) more often in the group of patients with clinical benefit as compared to progressive patients. PINP showed the second best result for normalisation with p = 0.083, though missing statistical significance. CONCLUSION: Clinical benefit from systemic therapy was primarily accompanied by a normalization of biochemical markers representing bone formation. This result reflects the physiology of the "bone remodeling unit". In patients without this normalization, thorough and early restaging is warranted since the systemic therapy may be ineffective.

Adult↗

PubMedDate not supplied

PINP as serum marker of metastatic spread to the bone in breast cancer patients.

BACKGROUND: Early detection before scintigraphic appearance of osseous metastatic spread might improve the outcome of breast cancer patients. The amino-terminal propeptide (PINP) of type I collagen as an indicator of bone formation is a very promising candidate among all markers of bone metabolism. We investigated the utility of total PINP in breast cancer patients at different stages of the disease. PATIENTS AND METHODS: Precision tests using controls and serum pools were done for total PINP on the Elecsys2010 analyzer (electrochemiluminescence immunoassay - ECLLA). Baseline samples of 51 breast cancer patients with metastatic disease plus 11 patients under neoadjuvant treatment were available. Altogether, 38 patients had been diagnosed with bone metastases while 24 had no evidence of metastatic spread to the bone. RESULTS: For serial precision (intra assay), we found coefficients of variation between 1.2-2%. Total imprecision according to the NCCLS protocol ranged from 1. 7-5.4% only. Retrieval in ring trials was between 94% and 103%. ROC analysis of osseous versus nonosseous metastatic disease revealed an area under the curve (AUC) of 0.72. The sensitivity for the detection of bone lesions was 50% at the preliminary normal cut-off of 95 ng/mL. The baseline levels of the patients with bone metastases were significantly higher than those of patients with visceral of soft tissue spread only (p<0.001). PINP concentrations correlated with osseous spread in terms of number and size of the bone lesions. Generally, non-osseous metastases did not produce elevated PINP levels in only 2/24 patients without bone metastases showing minimally elevated PINP concentrations (95 and 112 ng/ml). CONCLUSION: The Elecsys test for total PINP is highly reproducible. PINP concentrations can discriminate patients with bone metastases from those without osseous spread. The moderate sensitivity for the diagnosis of bone lesions may be biologically related to ineffective bone repair in a certain subset of patients. Further studies must focus on the monitoring of patients with elevated baseline levels and on those patients with low PINP levels in the case of otherwise proven bone metastases.

Adult↗

PubMedDate not supplied

Perspectives of immunotherapy in metastatic breast cancer.

Further improvements in the treatment of breast cancer can be expected with a better understanding of its pathophysiology and through biologically-oriented therapeutic interventions, as well as better identification of patient populations likely to benefit from specific therapies. Trastuzumab (Herceptin) is the first biological modifier, showing significant activity in patients with advanced breast cancer who exhibit HER-2/neu gene amplification and/or protein overexpression. Trastuzumab is approved for use in combination with paclitaxel or docetaxel as first-line chemotherapy. Combinations of a taxane, a platinum salt and trastuzumab are feasible and active and have proven an increased survival advantage. This is in addition to the benefit that has been shown for Herceptin in combination with monochemotherapy alone. Several groups have demonstated the ratio of serum HER-2/neu levels prior to initiation of Herceptin treatment to levels at the time of re-staging examination to be significantly higher in patients with a significant benefit from therapy as compared to patients with progressive disease. As a result of the survival improvements in the metastatic setting, Herceptin was quickly entered into development trials for adjuvant treatment. The significant cardiac toxicity that has been observed with trastuzumab/anthracycline combinations has led to two main strategies for integrating trastuzumab in the adjuvant setting: either the addition of trastuzumab to mostly anthracycline-based programs in a sequential approach, or the biologically-oriented strategy based on synergism between trastuzumab and chemotherapy agents including platinum compounds. Last but not least, the most important prerequisite for the optimal efficacy of Herceptin-based therapy remains a very strict selection of those patients with tumours that have HER-2/neu over-expression.

Antibodies, Monoclonal↗