Surgical Critical Care for the Trauma Patient with Cardiac Disease.

The elderly population is rapidly increasing in number. Therefore, geriatric trauma is becoming more prevalent. All practitioners caring for geriatric trauma patients should be familiar with the structural and functional changes naturally occurring in the aging heart, as well as common preexisting cardiac diseases in the geriatric population. Identification of the shock state related to cardiac dysfunction and targeted assessment of perfusion and resuscitation are important when managing elderly patients. Finally, management of cardiac dysfunction in the trauma patient includes an appreciation of the inherent effects of trauma on cardiac function.

Longterm followup assessment of a HER2/neu peptide (E75) vaccine for prevention of recurrence in high-risk prostate cancer patients.

BACKGROUND: E75 is an immunogenic peptide from the HER2/neu protein that is expressed in prostate cancer. High-risk prostate cancer (HRPC) patients demonstrating varying levels of HER2/neu expression were vaccinated with E75 peptide plus granulocyte-macrophage colony-stimulating factor to prevent postprostatectomy PSA and clinical recurrences. STUDY DESIGN: Forty evaluable HRPC patients were prospectively identified using the validated Center for Prostate Disease Research/CaPSURE high-risk equation and enrolled. HLA-A2(+) patients (n = 21) were vaccinated, and HLA-A2(-) patients (n = 19) were followed as clinical controls. All patients were assessed for clinicopathologic factors, biochemical recurrence (consecutive PSA value >or= 0.2 ng/mL), clinical recurrence, and survival. RESULTS: Comparing the vaccinated and control groups, there were no statistical differences in clinicopathologic prognostic factors. At a median followup of 58.2 months (range 18.8 to 62.7 months), PSA recurrence rates were not different between vaccinated (29%) and control (26%) groups. Median time to recurrence from operation was 14.0 months (range 5.7 to 53.4 months) versus 8.5 months (range 4.7 to 34.1 months) (p = 0.7), respectively. Three vaccinated patients had PSA recurrences during the vaccine series. If these patients were excluded, median time to recurrence for the vaccinated group extends to 42.7 months (range 20.4 to 53.4 months) (p = 0.4). Study-wide, only one clinical recurrence and death occurred in a vaccinated patient that was early in the vaccine series. Subset analysis comparing vaccinated recurrent patients with control recurrences noted some statistical trends. CONCLUSIONS: The HER2/neu (E75) vaccine can prevent or delay recurrences in HRPC patients if completed before PSA recurrence. A larger randomized phase II trial in HLA-A2(+) patients will be required to confirm these findings.

Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high-risk breast cancer patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

PURPOSE: E75 is an immunogenic peptide from the HER2/neu protein, which is overexpressed in many breast cancer patients. We have conducted two overlapping E75 vaccine trials to prevent recurrence in node-positive (NP) and node-negative (NN) breast cancer patients. EXPERIMENTAL DESIGN: E75 (HER2/neu 369-377) + granulocyte macrophage colony-stimulating factor was given intradermally to previously treated, disease-free NP breast cancer patients in a dose escalation safety trial and to NN breast cancer patients in a dose optimization study. Local and systemic toxicity was monitored. Immunologic responses were assessed using in vitro assays and in vivo delayed-type hypersensitivity responses. Clinical recurrences were documented. RESULTS: One hundred and eighty-six patients were enrolled in the two studies (NP, 95; NN, 91). Human leucocyte antigen A2 (HLA-A2) and HLA-A3 patients were vaccinated (n = 101), whereas all others (n = 85) were followed prospectively as controls. Toxicities were minimal, and a dose-dependent immunologic response to the vaccine was shown. Planned primary analysis revealed a recurrence rate of 5.6% in vaccinated patients compared with 14.2% in the controls (P = 0.04) at a median of 20 months follow-up. As vaccine-specific immunity waned over time, the difference in recurrence lost significance at 26 months median follow-up (8.3% versus 14.8%); however, a significant difference in the pattern of recurrence persisted. CONCLUSIONS: E75 is safe and effective in raising a dose-dependent HER2/neu immunity in HLA-A2 and HLA-A3 NP and NN breast cancer patients. More importantly, E75 may reduce recurrences in disease-free, conventionally treated, high-risk breast cancer patients. These findings warrant a prospective, randomized phase III trial of the E75 vaccine with periodic booster to prevent breast cancer recurrences.

Phase I clinical trial of a HER-2/neu peptide (E75) vaccine for the prevention of prostate-specific antigen recurrence in high-risk prostate cancer patients.

PURPOSE: The E75 peptide is an immunogenic peptide from the HER-2/neu protein that is substantially expressed in prostate cancer. We are conducting a clinical trial of an E75/granulocyte macrophage colony-stimulating factor vaccine to prevent post-prostatectomy prostate-specific antigen (PSA) recurrences in high-risk prostate cancer (HRPC) patients. EXPERIMENTAL DESIGN: Prostate cancer patients at high risk for recurrence were prospectively evaluated and identified by the validated Center for Prostate Disease Research (CPDR)/CaPSURE high-risk equation. From these high-risk equation patients, 27 HER-2/neu-expressing prostate cancer patients were enrolled. HLA-A2+ patients (n = 17) were vaccinated, whereas HLA-A2- patients (n = 10) were followed as clinical controls. Local/systemic toxicities, immunologic responses, and time to recurrence were measured. RESULTS: This vaccine is safe with only minor toxicities observed. Additionally, the vaccine is immunogenic with all patients showing both in vivo and in vitro phenotypic and functional immune responses, although variable. HLA-A2+ patients were found to have larger tumors, higher postoperative Gleason scores, and more high-risk CPDR scores than HLA-A2- patients. Despite these differences, disease-free survival was not different between the vaccinated HLA-A2+ patients and the HLA-A2- controls at a median follow up of 23 months. Three of the four vaccinated patients that recurred had rising PSAs at the initiation of the trial. Ex vivo phenotypic assays were predictive of recurrences and correlated in general with functional assays. CONCLUSIONS: The E75 vaccine strategy is safe and effective in eliciting an immune response against the HER-2/neu protein in HRPC patients and may be useful as a preventive strategy against disease recurrence. Vaccination in response to a rising PSA may be too late.

Preclinical testing of a peptide-based, HER2/neu vaccine for prostate cancer.

The HER2/neu protein is over-expressed in multiple epithelial tumors and the source of immunogenic peptides currently under investigation in vaccine trials in ovarian and breast cancers. We sought to define the correlation between HER2/neu expression and risk for prostate cancer recurrence and then determine the potential efficacy of anti-HER2/neu vaccination in prostate cancer patients at risk for recurrence. The risk for prostate-specific antigen (PSA) recurrence in 95 patients undergoing prostatectomy at the Walter Reed Army Medical Center (WRAMC) was calculated and correlated to HER2/neu expression, as determined by immunohistochemical staining. Peripheral blood lymphocytes (PBL) were then isolated from six consecutive human leukocyte antigen (HLA) A2+ patients with HER2/neu+ prostate tumors. These PBL were grown in parallel cultures and stimulated either with no peptide, HER2/neu E75 peptide, or control peptide. The cultures were compared for stimulated proliferation, induced peptide-specific cytotoxicity and tumor-specific cytotoxicity. When assessed by risk group, 69% of the high risk patients' tumors over-expressed HER2/neu compared to 47% of the intermediate risk group (p<0.05). Evaluation of the in vitro immune response of PBL isolated from six consecutive prostate cancer patients revealed a statistically significant increase in E75-stimulated lymphocytic proliferation. E75-stimulated lymphocytes demonstrated an E75-specific cytolytic response in 6/6 prostate cancer patients that increased with successive stimulations. Moreover, these E75-specific lymphocytes also demonstrated tumor-specific lysis against HER2/neu-expressing prostate cancer cell lines. The majority of prostate cancer patients at high risk for recurrence have HER2/neu expressing tumors. Hence, HER2/neu is a viable target for immunotherapeutics such as preventative immunization strategies with HER2/neu peptide vaccines.

Direct measurement of peptide-specific CD8+ T cells using HLA-A2:Ig dimer for monitoring the in vivo immune response to a HER2/neu vaccine in breast and prostate cancer patients.

HER2/neu is a proto-oncogene and a member of the epidermal growth factor receptor family of proteins that is overexpressed in numerous types of human cancer. We are currently conducting clinical trials with the HER2/neu E75 peptide vaccine in breast and prostate cancer patients. We have evaluated the use of HLA-A2 dimer molecule for the immunological monitoring of cancer patients receiving the E75 peptide vaccine. Peripheral blood samples from patients receiving the vaccine were stained with HLA-A2 dimers containing the vaccine peptide E75 or control peptides and analyzed by flow cytometry. We compared the HLA-A2 dimer assay to standard methods of immunologic monitoring (IFN-gamma release, lymphocyte proliferation, and cytotoxicity). The HLA-A2 dimer assay was also compared with the HLA-A2 tetramer assay. E75 peptide-specific CD8 T cells were detected directly in the peripheral blood of patients by staining with E75-HLA-A2 dimers and CD8 antibodies. T cell cultures generated by repeated stimulations using E75 peptide-pulsed dendritic cells showed increased staining with E75-peptide loaded HLA-A2 dimers. Simultaneously analysis by the dimer assay and standard immunologic assays demonstrated that the dimer-staining assay correlated well with these methods of immunologic monitoring. A direct comparison using E75-specific HLA-A2 tetramers and HLA-A2 dimers for the detection of E75-specific CD8 T cells in peripheral blood showed comparable results with the two assays. Our findings indicate that the HLA-A2 dimer is a powerful new tool for directly quantifying and monitoring immune responses of antigen-specific T cells in peptide vaccine clinical trials.