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Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.

Background The lapatinib–taxane combination led to shorter PFS than trastuzumab–taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum HER2, CAIX, and TIMP-1. Methods MA.31 accrued 652 patients; 537 (82%) were centrally confirmed HER2+. Biomarkers were categorized for univariate and multivariable predictive investigations with a median cut-point, ULN cut-points (15 ng/ml for HER2; 506 pg/ml for CAIX; 454 pg/ml for TIMP-1), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariable analysis examined continuous and categorical effects of biomarkers on PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. Results Serum was banked for 472 (72%) of 652 patients. Higher serum HER2 (>median; >15; >30; or >100 ng/ml; p  = 0.05–0.002); higher CAIX (>median; >506 pg/ml; p  = 0.02; p  = 0.001); and higher TIMP-1 (> median; > 454 pg/ml; p  = 0.001; p  = 0.02) had shorter univariate PFS. In multivariable analysis, higher continuous TIMP-1 was associated with significantly shorter PFS: HR = 1.001 (95% CI = 1.00–01.002; p  = 0.004). Continuous serum HER2 and CAIX were not significantly associated with PFS. HER2 of 15 ng/ml or higher had shorter PFS ( p  = 0.02); higher categorical CAIX had shorter PFS ( p  = 0.01–0.08). Interaction terms of HER2, CAIX, and TIMP-1 with treatment were not significant; the predictive test power was low. Conclusions Higher levels of serum TIMP-1, CAIX, and HER2 were significant prognostic biomarkers of shorter PFS. We found no significant interaction between serum biomarkers and response to lapatinib versus trastuzumab. Evaluation of TIMP-1 and CAIX-targeted therapy in addition to HER2-targeted therapy appears warranted in patients with elevated serum levels of these biomarkers.

Pharmaceutical companies have developed targeted therapies such as trastuzumab and lapatinib for human epidermal growth factor receptor (HER)2/neu-positive tumors, while others have developed antiepidermal growth factor receptor (EGFR) therapies, such as tarceva and erbitux for EGFR-positive tumors. A drug called rencarex is targeted to an oncoprotein designated carbonic anhydrase IX (CAIX), which is being evaluated in renal cell carcinoma patients. Based on these targeted therapeutic approaches, this review describes clinical research studies performed with enzyme-linked immunosorbent assays specific for the circulating oncoproteins, HER2/neu, EGFR and CAIX. These circulating biomarkers have the potential to be used in conjunction with the specific targeted therapies for patient selection, monitoring and management. With the variety of new therapeutic options, the major challenge ahead will be to select the appropriate therapy or combinations of therapies for each patient. Specific biomarker tests, either alone or in panels, will be needed at the appropriate time in the course of disease to ensure that patients receive the right drug at the right time. These tests will also be valuable in monitoring the efficacy of the targeted therapies. A circulating biomarker such as serum HER2/neu may be able to specifically identify patients with progressing HER2/neu-positive disease and provide the information needed by physicians to choose from the variety of HER2/neu-targeted therapies that will soon be available to cancer patients.

Background: The HER-2/neu oncogene and its p185 receptor protein are indicators of a more aggressive form of breast cancer. HER-2/neu status guides Herceptin therapy, specifically directed to the extracellular domain (ECD) of the HER-2/neu oncoprotein. The HER-2/neu ECD is shed from cancer cells into the circulation and is measurable by immunoassay. Methods: We performed a systematic review of the peer-reviewed literature on circulating ECD with respect to prevalence, prognosis, prediction of response to therapy, and monitoring of breast cancer. Results: The prevalence of increased ECD in patients with primary breast cancer varied between 0% and 38% (mean, 18.5%), whereas in metastatic disease the range was from 23% to 80% (mean, 43%). Some women with HER-2/neu-negative tumors by tissue testing develop increased ECD concentrations in metastatic disease. Increased ECD has been correlated with indicators of poor prognosis, e.g., overall survival and disease-free survival. Increased ECD predicts a poor response to hormone therapy and some chemotherapy regimens but can predict improved response to combinations of Herceptin and chemotherapy. Many studies support the value of monitoring ECD during breast cancer progression because serial increases precede the appearance of metastases and longitudinal ECD changes parallel the clinical course of disease. Conclusions: The monitoring of circulating HER-2/neu ECD provides a tool for assessing prognosis, for predicting response to therapy, and for earlier detection of disease progression and timely intervention with appropriate therapy.

Background Angiogenesis appears to play an important role in ovarian cancer. Vascular endothelial growth factor (VEGF) has recently been implicated as a therapeutic target in ovarian cancer. The tissue inhibitor of metalloproteinase 1 (TIMP-1) is involved in tissue invasion and angiogenesis. The application of serum TIMP-1 and VEGF to monitor primary therapy and predict clinical outcome of patients with ovarian cancer is unclear. Methods Patients with epithelial ovarian cancer who presented for primary surgery were included in this study. A total of 148 serum samples from 37 patients were analyzed. Samples were prospectively collected at 4 predefined time points: 1. before radical debulking surgery, 2. after surgery and before platinum/taxane based chemotherapy, 3. during chemotherapy, 4. after chemotherapy. Serum VEGF-165 and TIMP-1 as well as CA-125 were quantified by ELISA or ECLIA and correlation with response and long-term clinical outcome was analyzed. Results Serum levels of all markers changed substantially during first-line therapy. High CA-125 (p = 0.002), TIMP-1 (p = 0.007) and VEGF-165 (p = 0.02) after chemotherapy were associated with reduced overall survival. In addition, elevated CA-125 (p < 0.001) and VEGF-165 (p = 0.006) at this time point predicted poor progression-free survival. TIMP-1 and VEGF-165 were closely correlated at all time-points during therapy. Conclusions TIMP-1 and VEGF serum levels changed significantly during first-line therapy of ovarian cancer patients and predicted prognosis. These findings support the role of angiogenesis in ovarian cancer progression and the use of antiangiogenic therapy.

The HER2 oncoprotein has emerged as an essential biomarker in the treatment of breast cancer patients. Once the primary breast cancer is removed, there is an increasing need to detect breast cancer recurrence as early as possible with the hope that earlier intervention with new anti-HER2 therapies will improve quality of life and increase overall survival. Numerous publications have shown that increasing blood levels of circulating HER2 is an early indicator of progression, particularly in HER2-positive patients and that the rise and fall parallels the clinical course of disease and independent of therapy. Many studies show that the HER2 status of the primary tumor may not fully and accurately reflect the HER2 status of recurrent cancer. Thus, elevated serum HER2 levels may be an early signal of the emergence of a HER2-positive metastatic tumor and therefore alert the physician to re-assess HER2 status using a tissue test.

In spite of the current explosion of interest in biomarker research, industry seems to be struggling to incorporate these advances into drug development and healthcare delivery. explored the issues with Dr Walter Carney, a pioneer in linking diagnostics with medicines to target therapies to stratified patient groups. Dr Carney and his colleagues were the first to discover the circulating human epidermal growth factor receptor (HER)2/neu oncoprotein in women with metastatic breast cancer. He has been granted numerous patents pertaining to the HER2/neu and ras oncoproteins, as well as having published extensively in this area. Dr Carney joined the DuPont Medical Products Department in 1982 where he held a variety of management positions in the Diagnostics Division. He was Vice President and General Manager of the Diagnostics and Research Products Division and in 1997 was appointed President of Oncogene Science. Dr Carney also held the position of Vice President of Proprietary Drug Development Programs for OSI Pharmaceuticals until Oncogene Science joined Bayer Diagnostics in late 1999. As part of Bayer HealthCare, Dr Carney continued as Head of the Oncogene Science business, which is a Center of Excellence for Oncology and is focused on the use of novel biomarker tests in linking diagnostics with pharmaceuticals. Oncogene Science is now part of the Global Siemens Medical Solutions Diagnostics, which is the first integrated diagnostics company and driving medical innovation by combining circulating biomarkers with imaging biomarkers.

In spite of the current explosion of interest in biomarker research, industry seems to be struggling to incorporate these advances into drug development and healthcare delivery. Biomarkers in Medicine explored the issues with Dr Walter Carney, a pioneer in linking diagnostics with medicines to target therapies to stratified patient groups. Dr Carney and his colleagues were the first to discover the circulating human epidermal growth factor receptor (HER)2/neu oncoprotein in women with metastatic breast cancer. He has been granted numerous patents pertaining to the HER2/neu and ras oncoproteins, as well as having published extensively in this area. Dr Carney joined the DuPont Medical Products Department in 1982 where he held a variety of management positions in the Diagnostics Division. He was Vice President and General Manager of the Diagnostics and Research Products Division and in 1997 was appointed President of Oncogene Science. Dr Carney also held the position of Vice President of Proprietary Drug Development Programs for OSI Pharmaceuticals until Oncogene Science joined Bayer Diagnostics in late 1999. As part of Bayer HealthCare, Dr Carney continued as Head of the Oncogene Science business, which is a Center of Excellence for Oncology and is focused on the use of novel biomarker tests in linking diagnostics with pharmaceuticals. Oncogene Science is now part of the Global Siemens Medical Solutions Diagnostics, which is the first integrated diagnostics company and driving medical innovation by combining circulating biomarkers with imaging biomarkers.

We compared levels of erbB-2 oncoprotein among three groups: Group I included 60 asymptomatic women; Group II had 51 women with benign breast biopsies; and Group III had 67 women with node-negative breast cancer. Serological levels of erbB-2 protein were measured in all participants; tumor levels were measured for Groups II and III. Forty-three percent of usable tumors (25/58), including three of seven lobular tumors, were erbB-2 positive. Tumor and blood oncoprotein levels were unrelated. Blood levels, however, were positively related to tumor volume, but only when the tumor had both a ductal carcinoma in situ (DCIS) component and an invasive component, suggesting a role for erbB-2 protein in progression of DCIS to invasive carcinoma. In Groups I and II serological levels of erbB-2 protein were directly related to age, and inversely related to having had a live birth. Therefore, a model that determined the threshold levels of serological erbB-2 positivity in Group III included age and nulliparity as independent variables. Only three of the 67 women (4.5%) in Group III were positive for serological erbB-2. In a multivariate model, with serological erbB-2 as the dependent variable, and in which the independent variables included Study Group, there was a statistical trend for younger women, in which Group III had the highest serological levels of erbB-2, followed by Group II, and then Group I. In women who were over the age of 50 years the trend was reversed; i.e., levels of erbB-2 tended to be lowest in Group III, followed by Group II, and finally Group I.

These studies were set up to determine whether those oncogenes participating in the initiation of mammary carcinogenesis (for example, ras oncogenes) play a direct role in the outcome of events associated with the late stages of tumor development such as loss of hormone dependency. Mammary carcinomas induced by a single carcinogenic insult in pubescent rats was selected as an in vivo model system with direct relevance to human breast cancer. Acquisition of hormone-independent growth in these carcinogen-induced tumors was found to be independent of the activation of ras oncogenes during the early stages of carcinogenesis. In agreement with these observations, introduction of a human ras oncogene into human MCF-7 breast carcinoma cells did not abrogate their hormonal dependency for growth in vivo. These findings suggest that those events responsible for the critical stages of breast cancer development occur independently and in an uncoordinated manner.