Annemieke Cats - Academia.edu (original) (raw)
Papers by Annemieke Cats
Pharmacogenomics, 2015
The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in th... more The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4–5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.
Gut, 1994
The age at onset of non-polyposis colorectal cancer (CRC) was investigated in 49 families with at... more The age at onset of non-polyposis colorectal cancer (CRC) was investigated in 49 families with at least three relatives affected in two successive generations. Forty one of these families satisfy the accepted minimum criteria for hereditary non-polyposis CRC. The remaining eight families were distinguished by a late age of disease onset and, hence, could not be included in the group.
British journal of cancer, Jan 3, 2009
The aims of this study were to determine which consent procedure patients prefer for use of store... more The aims of this study were to determine which consent procedure patients prefer for use of stored tissue for research purposes and what the effects of consent procedures on actual consenting behaviour are. We offered 264 cancer patients three different consent procedures: 'one-time general consent' (asked written informed consent), 'opt-out plus' (had the opportunity to opt out by a form), or the standard hospital procedure (control group). The two intervention groups received a specific leaflet about research with residual tissue and verbal information. The control group only received a general hospital leaflet including opt-out information, which is the procedure currently in use. Subsequently, all patients received a questionnaire to examine their preferences for consent procedures. In all, 99% of patients consented to research with their residual tissue. In the 'one-time consent' group 85% sent back their consent form. Patients preferred 'opt-out plu...
Gastroenterology, 2015
Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to ga... more Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. These criteria are: families with 2 or more cases of diffuse-type gastric cancer (DGC), with at least 1 patient diagnosed before the age of 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in the Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate overall survival of patients with and without CDH1 mutations. In a cohort study in the Netherlands, the HDGC criteria identify individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, nor in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 y and 4% survived for 5 y; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 y and 13% survived for 5 y (P=.014 for comparative survival analysis between patients with and without a CDH1 mutation). All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.
Biomarker insights, 2008
Colorectal cancer (CRC) is the second most common cause of cancer-related death in Europe and its... more Colorectal cancer (CRC) is the second most common cause of cancer-related death in Europe and its prognosis is largely dependent on stage at diagnosis. Currently, there are no suitable tumour markers for early detection of CRC. In a retrospective study we previously found discriminative CRC serum protein profiles with surface enhanced laser desorption ionisation-time of flight mass spectrometry (SELDI-TOF MS). We now aimed at prospective validation of these profiles. Additionally, we assessed their applicability for follow-up after surgery and investigated tissue protein profiles of patients with CRC and adenomatous polyps (AP). Serum and tissue samples were collected from patients without known malignancy with an indication for colonoscopy and patients with AP and CRC during colonoscopy. Serum samples of controls (CON; n = 359), patients with AP (n = 177) and CRC (n = 73), as well as tissue samples from AP (n = 52) and CRC (n = 47) were analysed as described previously. Peak intens...
Analytical and Bioanalytical Chemistry, 2008
We present a highly sensitive method for the determination of platinum (Pt) in DNA extracts of pe... more We present a highly sensitive method for the determination of platinum (Pt) in DNA extracts of peripheral blood mononuclear cells (PBMCs) and tissue samples from patients treated with cisplatin. The method is based on the measurement of Pt by inductively coupled plasma mass spectrometry (ICP-MS) and allows quantification of Pt-DNA adducts in PBMCs isolated from 10 mL blood and 1 mg tissue. The lower limit of quantification is 0.75 pg Pt or 7.5 fg Pt μg(-1) DNA when using 100 μg DNA. The method proved to be accurate and precise. The results obtained using the ICP-MS method were in good agreement with results from the alternative (32)P-postlabelling assay. The ICP-MS method was, however, more sensitive and proved to be less laborious. The advantages of the presented ICP-MS technique were demonstrated by the analysis of PBMCs, normal gastric tissue, and gastric tumour tissue of patients treated with cisplatin.
Oncology Letters, 2010
gastric cancer is a commonly diagnosed solid tumor which is associated with a dismal prognosis ma... more gastric cancer is a commonly diagnosed solid tumor which is associated with a dismal prognosis making early diagnosis essential. thus, this study aimed to identify novel biomarkers in gastric cancer. serum of patients with advanced gastric cancer was collected according to a predefined schedule: prior to first-line chemotherapy with epirubicin (50 mg/m 2 , day 1), cisplatin (60 mg/m 2 , day 1) and capecitabine (1,000 mg/m 2 , twice daily on days 1-14). the serum was collected serially before the treatment cycles and then analyzed by selDI-toF Ms. normal control subjects were matched according to age, gender and serum collection. serum proteomic mass spectrometry data of all subjects were processed using the tbimass r-package and compared. We analyzed i) whether proteomic profile changes were associated with a response to chemotherapy and survival, and ii) whether changes in proteomic profiles occurring during the time period of chemotherapy were associated with tumor response. In total, 82 patients with adenocarcinoma of the stomach (mean age 57 years, males 69.5%) were treated with a mean number of five chemotherapy cycles. The overall tumor response rate, complete and partial remission combined, was 37%, median time to progression was 7 months (95% cI, 6-8) and median overall survival 11 months (95% cI, 9.5-12). By comparing 77 serum samples of patients with normal matched controls, we identified 32 proteins which discriminated the two groups. By selecting the most differentiating proteins, we built a classification model that correctly categorized 81% of the gastric cancer patients and 90% of the normal controls. Furthermore, we found a statistically significant correlation between the pre-treatment intensity of serum amyloid-α (sAA) and overall survival in gastric cancer patients, whereby a low intensity of sAA predicted a longer patient survival. A classification model, based on the 32 most discriminating proteins differentiating gastric cancer from normal controls, correctly classified subjects with relatively high sensitivity and specificity.
Biomarkers in Medicine, 2008
Colorectal cancer (CRC) is the third most common cancer worldwide. Successful treatment is heavil... more Colorectal cancer (CRC) is the third most common cancer worldwide. Successful treatment is heavily dependent on tumor stage at the time of detection, but unfortunately CRC is often only detected in advanced stages. New biomarkers in the form of genes or proteins that can be used for diagnosis, prognostication, follow-up, and treatment selection and monitoring could be of great benefit for the management of CRC. Furthermore, proteins could prove valuable new targets for therapy. Therefore, clinical proteomics has gained a lot of scientific interest in this regard. To get an overall insight into the extent to which this research has contributed to a better management of CRC, we give a comprehensive overview of the results of proteomics research on CRC, focusing on expression proteomics, in other words, protein profiling studies. Furthermore, we evaluate the potential of the discriminating proteins identified in this research for clinical use as biomarkers for (early) diagnosis, progno...
Acta Medica Scandinavica, 1954
World Journal of Surgery, 2011
PROTEOMICS – CLINICAL APPLICATIONS, 2008
Oncology Reports, 2010
Colorectal cancer (CRC) is the second most common cause of cancer related death. Prognosis is hig... more Colorectal cancer (CRC) is the second most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early detection mandatory. This study aimed to identify novel disease specific biomarkers of CRC, validate our previously identified biomarkers of CRC and identify serum biomarkers predicting treatment response and for monitoring. Serum of patients with metastatic CRC was collected, according to a predefined schedule, prior to start of standard first-line chemotherapy with oxaliplatin and capecitabine and serially before each 3 weekly treatment cycle and analyzed for proteomic profile by standardized SELDI-TOF MS. Serum proteomic mass spectrometry data of all subjects were processed using the tbimass R-package and proteomic profiles of CRC patients were compared with those of matched normal control subjects. Furthermore, changes in proteomic profiles during the course of chemotherapy were recorded according to treatment response. In total, 42 patients with advanced CRC were treated and mean follow-up was 13.5 months. The response rate was 50% and the median overall survival 19.5 months (95% CI: 16-23). By comparing CRC patients and healthy controls we identified 13 potential biomarkers of CRC (m/z 2.0-31.9 kDa) whereas two proteins, m/z 14060 and 28100 Da (apolipoprotein A-I), were highly significant (p<0.0001). Comparison of responding and non-responding patients identified 6 proteins potentially predicting response, where of m/z 3330 Da was significant (p=0.007). Serial analysis identified 2 proteins, m/z 2022 and 28100 Da, that changed during chemotherapy in accordance with response. We identified 13 m/z values discriminating between CRC patients and healthy controls, including the previously identified apolipoprotein A-I as a candidate biomarker for CRC and treatment monitoring.
The Journal of Thoracic and Cardiovascular Surgery, 2010
Journal of Proteome Research, 2010
Many proteins have been proposed as potential biomarkers for breast cancer. Yet, validation of th... more Many proteins have been proposed as potential biomarkers for breast cancer. Yet, validation of their discriminative value using quantitative methods has scarcely been performed. In this study, we investigated the discriminative value of six peptides that were previously proposed to be generated by breast cancer specific exoproteases: bradykinin, des-Arg(9)-bradykinin, Hyp(3)-bradykinin, and fragments of fibrinogen alpha-chain (Fib-alpha ([605-629])), complement component 4a (C4a ([1337-1350])), and interalpha trypsin inhibitor heavy chain 4 (ITIH4 ([666-687])). Their absolute serum concentrations were measured with a completely validated liquid chromatography-tandem mass spectrometric assay (LC-MS/MS) and compared between 62 newly diagnosed breast cancer patients and 62 controls matched for age and sample storage duration. Both ITIH4 ([666-687]) and des-Arg(9)-bradykinin showed statistically significantly higher median concentrations in breast cancer samples than in matched control samples. Additionally, we analyzed serum samples collected after surgical removal of the tumor, in which median ITIH4 ([666-687]) and des-Arg(9)-bradykinin concentrations were significantly decreased and not statistically significantly different from concentrations in the controls anymore. In a combined analysis, ITIH4 (666-687]) and des-Arg(9)-bradykinin independently contributed to the discrimination between cases and controls. In this study, we confirmed that the exoprotease breakdown peptides, ITIH4 (666-687]) and des-Arg(9)-bradykinin, differed between breast cancer cases and controls, supporting the potential of degradome markers for the diagnosis of breast cancer.
Journal of Clinical Oncology, 2012
Purpose Skin toxicity in patients receiving cetuximab has been associated positively with clinica... more Purpose Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. Patients and Methods After 21 days of standard-dose cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m2 per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). Results The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 m...
Investigational New Drugs, 2008
Pharmacogenomics, 2015
The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in th... more The dihydropyrimidine dehydrogenase enzyme (DPD, encoded by the gene DPYD) plays a key role in the metabolism of fluoropyrimidines. DPD deficiency occurs in 4–5% of the population and is associated with severe fluoropyrimidine-related toxicity. Several SNPs in DPYD have been described that lead to absent or reduced enzyme activity, including DPYD*2A, DPYD*13, c.2846A>T and c.1236G>A/haplotype B3. Since these SNPs differ in their effect on DPD enzyme activity, a differentiated dose adaption is recommended. We propose the gene activity score for translating DPYD genotype into phenotype, accounting for differences in functionality of SNPs. This method can be used to standardize individualized fluoropyrimidine dose adjustments, resulting in optimal safety and effectiveness.
Gut, 1994
The age at onset of non-polyposis colorectal cancer (CRC) was investigated in 49 families with at... more The age at onset of non-polyposis colorectal cancer (CRC) was investigated in 49 families with at least three relatives affected in two successive generations. Forty one of these families satisfy the accepted minimum criteria for hereditary non-polyposis CRC. The remaining eight families were distinguished by a late age of disease onset and, hence, could not be included in the group.
British journal of cancer, Jan 3, 2009
The aims of this study were to determine which consent procedure patients prefer for use of store... more The aims of this study were to determine which consent procedure patients prefer for use of stored tissue for research purposes and what the effects of consent procedures on actual consenting behaviour are. We offered 264 cancer patients three different consent procedures: 'one-time general consent' (asked written informed consent), 'opt-out plus' (had the opportunity to opt out by a form), or the standard hospital procedure (control group). The two intervention groups received a specific leaflet about research with residual tissue and verbal information. The control group only received a general hospital leaflet including opt-out information, which is the procedure currently in use. Subsequently, all patients received a questionnaire to examine their preferences for consent procedures. In all, 99% of patients consented to research with their residual tissue. In the 'one-time consent' group 85% sent back their consent form. Patients preferred 'opt-out plu...
Gastroenterology, 2015
Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to ga... more Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. These criteria are: families with 2 or more cases of diffuse-type gastric cancer (DGC), with at least 1 patient diagnosed before the age of 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in the Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate overall survival of patients with and without CDH1 mutations. In a cohort study in the Netherlands, the HDGC criteria identify individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, nor in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 y and 4% survived for 5 y; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 y and 13% survived for 5 y (P=.014 for comparative survival analysis between patients with and without a CDH1 mutation). All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.
Biomarker insights, 2008
Colorectal cancer (CRC) is the second most common cause of cancer-related death in Europe and its... more Colorectal cancer (CRC) is the second most common cause of cancer-related death in Europe and its prognosis is largely dependent on stage at diagnosis. Currently, there are no suitable tumour markers for early detection of CRC. In a retrospective study we previously found discriminative CRC serum protein profiles with surface enhanced laser desorption ionisation-time of flight mass spectrometry (SELDI-TOF MS). We now aimed at prospective validation of these profiles. Additionally, we assessed their applicability for follow-up after surgery and investigated tissue protein profiles of patients with CRC and adenomatous polyps (AP). Serum and tissue samples were collected from patients without known malignancy with an indication for colonoscopy and patients with AP and CRC during colonoscopy. Serum samples of controls (CON; n = 359), patients with AP (n = 177) and CRC (n = 73), as well as tissue samples from AP (n = 52) and CRC (n = 47) were analysed as described previously. Peak intens...
Analytical and Bioanalytical Chemistry, 2008
We present a highly sensitive method for the determination of platinum (Pt) in DNA extracts of pe... more We present a highly sensitive method for the determination of platinum (Pt) in DNA extracts of peripheral blood mononuclear cells (PBMCs) and tissue samples from patients treated with cisplatin. The method is based on the measurement of Pt by inductively coupled plasma mass spectrometry (ICP-MS) and allows quantification of Pt-DNA adducts in PBMCs isolated from 10 mL blood and 1 mg tissue. The lower limit of quantification is 0.75 pg Pt or 7.5 fg Pt μg(-1) DNA when using 100 μg DNA. The method proved to be accurate and precise. The results obtained using the ICP-MS method were in good agreement with results from the alternative (32)P-postlabelling assay. The ICP-MS method was, however, more sensitive and proved to be less laborious. The advantages of the presented ICP-MS technique were demonstrated by the analysis of PBMCs, normal gastric tissue, and gastric tumour tissue of patients treated with cisplatin.
Oncology Letters, 2010
gastric cancer is a commonly diagnosed solid tumor which is associated with a dismal prognosis ma... more gastric cancer is a commonly diagnosed solid tumor which is associated with a dismal prognosis making early diagnosis essential. thus, this study aimed to identify novel biomarkers in gastric cancer. serum of patients with advanced gastric cancer was collected according to a predefined schedule: prior to first-line chemotherapy with epirubicin (50 mg/m 2 , day 1), cisplatin (60 mg/m 2 , day 1) and capecitabine (1,000 mg/m 2 , twice daily on days 1-14). the serum was collected serially before the treatment cycles and then analyzed by selDI-toF Ms. normal control subjects were matched according to age, gender and serum collection. serum proteomic mass spectrometry data of all subjects were processed using the tbimass r-package and compared. We analyzed i) whether proteomic profile changes were associated with a response to chemotherapy and survival, and ii) whether changes in proteomic profiles occurring during the time period of chemotherapy were associated with tumor response. In total, 82 patients with adenocarcinoma of the stomach (mean age 57 years, males 69.5%) were treated with a mean number of five chemotherapy cycles. The overall tumor response rate, complete and partial remission combined, was 37%, median time to progression was 7 months (95% cI, 6-8) and median overall survival 11 months (95% cI, 9.5-12). By comparing 77 serum samples of patients with normal matched controls, we identified 32 proteins which discriminated the two groups. By selecting the most differentiating proteins, we built a classification model that correctly categorized 81% of the gastric cancer patients and 90% of the normal controls. Furthermore, we found a statistically significant correlation between the pre-treatment intensity of serum amyloid-α (sAA) and overall survival in gastric cancer patients, whereby a low intensity of sAA predicted a longer patient survival. A classification model, based on the 32 most discriminating proteins differentiating gastric cancer from normal controls, correctly classified subjects with relatively high sensitivity and specificity.
Biomarkers in Medicine, 2008
Colorectal cancer (CRC) is the third most common cancer worldwide. Successful treatment is heavil... more Colorectal cancer (CRC) is the third most common cancer worldwide. Successful treatment is heavily dependent on tumor stage at the time of detection, but unfortunately CRC is often only detected in advanced stages. New biomarkers in the form of genes or proteins that can be used for diagnosis, prognostication, follow-up, and treatment selection and monitoring could be of great benefit for the management of CRC. Furthermore, proteins could prove valuable new targets for therapy. Therefore, clinical proteomics has gained a lot of scientific interest in this regard. To get an overall insight into the extent to which this research has contributed to a better management of CRC, we give a comprehensive overview of the results of proteomics research on CRC, focusing on expression proteomics, in other words, protein profiling studies. Furthermore, we evaluate the potential of the discriminating proteins identified in this research for clinical use as biomarkers for (early) diagnosis, progno...
Acta Medica Scandinavica, 1954
World Journal of Surgery, 2011
PROTEOMICS – CLINICAL APPLICATIONS, 2008
Oncology Reports, 2010
Colorectal cancer (CRC) is the second most common cause of cancer related death. Prognosis is hig... more Colorectal cancer (CRC) is the second most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early detection mandatory. This study aimed to identify novel disease specific biomarkers of CRC, validate our previously identified biomarkers of CRC and identify serum biomarkers predicting treatment response and for monitoring. Serum of patients with metastatic CRC was collected, according to a predefined schedule, prior to start of standard first-line chemotherapy with oxaliplatin and capecitabine and serially before each 3 weekly treatment cycle and analyzed for proteomic profile by standardized SELDI-TOF MS. Serum proteomic mass spectrometry data of all subjects were processed using the tbimass R-package and proteomic profiles of CRC patients were compared with those of matched normal control subjects. Furthermore, changes in proteomic profiles during the course of chemotherapy were recorded according to treatment response. In total, 42 patients with advanced CRC were treated and mean follow-up was 13.5 months. The response rate was 50% and the median overall survival 19.5 months (95% CI: 16-23). By comparing CRC patients and healthy controls we identified 13 potential biomarkers of CRC (m/z 2.0-31.9 kDa) whereas two proteins, m/z 14060 and 28100 Da (apolipoprotein A-I), were highly significant (p<0.0001). Comparison of responding and non-responding patients identified 6 proteins potentially predicting response, where of m/z 3330 Da was significant (p=0.007). Serial analysis identified 2 proteins, m/z 2022 and 28100 Da, that changed during chemotherapy in accordance with response. We identified 13 m/z values discriminating between CRC patients and healthy controls, including the previously identified apolipoprotein A-I as a candidate biomarker for CRC and treatment monitoring.
The Journal of Thoracic and Cardiovascular Surgery, 2010
Journal of Proteome Research, 2010
Many proteins have been proposed as potential biomarkers for breast cancer. Yet, validation of th... more Many proteins have been proposed as potential biomarkers for breast cancer. Yet, validation of their discriminative value using quantitative methods has scarcely been performed. In this study, we investigated the discriminative value of six peptides that were previously proposed to be generated by breast cancer specific exoproteases: bradykinin, des-Arg(9)-bradykinin, Hyp(3)-bradykinin, and fragments of fibrinogen alpha-chain (Fib-alpha ([605-629])), complement component 4a (C4a ([1337-1350])), and interalpha trypsin inhibitor heavy chain 4 (ITIH4 ([666-687])). Their absolute serum concentrations were measured with a completely validated liquid chromatography-tandem mass spectrometric assay (LC-MS/MS) and compared between 62 newly diagnosed breast cancer patients and 62 controls matched for age and sample storage duration. Both ITIH4 ([666-687]) and des-Arg(9)-bradykinin showed statistically significantly higher median concentrations in breast cancer samples than in matched control samples. Additionally, we analyzed serum samples collected after surgical removal of the tumor, in which median ITIH4 ([666-687]) and des-Arg(9)-bradykinin concentrations were significantly decreased and not statistically significantly different from concentrations in the controls anymore. In a combined analysis, ITIH4 (666-687]) and des-Arg(9)-bradykinin independently contributed to the discrimination between cases and controls. In this study, we confirmed that the exoprotease breakdown peptides, ITIH4 (666-687]) and des-Arg(9)-bradykinin, differed between breast cancer cases and controls, supporting the potential of degradome markers for the diagnosis of breast cancer.
Journal of Clinical Oncology, 2012
Purpose Skin toxicity in patients receiving cetuximab has been associated positively with clinica... more Purpose Skin toxicity in patients receiving cetuximab has been associated positively with clinical outcome in several tumor types. This study investigated the effect of cetuximab dose escalation in patients with irinotecan-refractory metastatic colorectal cancer who had developed no or mild skin reactions after 21 days of treatment at the standard dose. This article reports clinical and pharmacokinetic (PK) data. Patients and Methods After 21 days of standard-dose cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week) plus irinotecan, patients with ≤ grade 1 skin reactions were randomly assigned to standard-dose (group A) or dose-escalated (to 500 mg/m2 per week; group B) cetuximab. Patients with ≥ grade 2 skin reactions continued on standard-dose cetuximab plus irinotecan (group C). Results The intent-to-treat population comprised 157 patients. PK profiles reflected the dose increase and were predictable across the dose range investigated. Weekly cetuximab doses of up to 500 m...
Investigational New Drugs, 2008