The impact of HER2/neu expression level on response to the E75 vaccine: from U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

PURPOSE: HER2/neu, a source of immunogenic peptides, is expressed in >75% of breast cancer patients. We have conducted clinical trials with the HER2/neu E75 peptide vaccine in breast cancer patients with varying levels of HER2/neu expression. Vaccine response based on HER2/neu expression level was analyzed. EXPERIMENTAL DESIGN: Patients were stratified by HER2/neu expression. Low expressors (n = 100) were defined as HER2/neu immunohistochemistry (IHC) 1(+) to 2(+) or fluorescence in situ hybridization < 2.0. Overexpressors (n = 51) were defined as IHC 3(+) or fluorescence in situ hybridization > or = 2.0. Additional analyses were done stratifying by IHC status (0-3(+)). Standard clinocopathlogic factors, immunologic response (in vivo delayed-type hypersensitivity reactions; ex vivo human leukocyte antigen A2:immunoglobulin G dimer assay), and clinical responses (recurrence; mortality) were assessed. RESULTS: Low-expressor (control, 44; vaccinated, 56) versus overexpressor patients (control, 22; vaccinated, 29) were assessed. Low expressors, overexpressors, and most IHC-status vaccinated groups responded immunologically. Vaccinated low-expressor patients had larger maximum immunologic responses compared with overexpressor patients (P = 0.04), and vaccinated IHC 1(+) patients had increased long-term immune response (P = 0.08). More importantly, compared with controls, low-expressor patients had a mortality reduction (P = 0.08). The largest decrease in mortality was seen in IHC 1(+) patients (P = 0.05). In addition, a subset of overexpressor patients (n = 7) received trastuzumab before vaccination, and this combination seems safe and immunologically beneficial. CONCLUSIONS: Most patients with various levels of HER2/neu expression responded immunologically and seemed to benefit from vaccination. The low expressors, specifically IHC 1(+) patients, had more robust immunologic responses and may derive the greatest clinical benefit from the E75 vaccine.

Optimal dose and schedule of an HER-2/neu (E75) peptide vaccine to prevent breast cancer recurrence: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

BACKGROUND: E75, a HER-2/neu-derived peptide, was administered as a preventive vaccine with granulocyte-macrophage-colony-stimulating factor (GM-CSF) in disease-free lymph node-positive (NP) and lymph node-negative (NN) breast cancer (BCa) patients. The optimal biologic dose (OBD) was determined based on toxicity and immunologic response. METHODS: Patients were vaccinated over 6 months (3, 4, or 6 times) with different doses of E75 plus GM-CSF. Toxicities were graded per National Cancer Institute Common Terminology Criteria. GM-CSF was reduced for significant toxicity. Immunologic response was measured by delayed type hypersensitivity test (DTH), and E75-specific CD8+ T-cells were quantified with human leukocyte antigen-A2:immunoglobulin G dimer and flow cytometry. RESULTS: Ninety-nine patients (48 NP and 51 NN) were vaccinated in 7 dose groups. The OBD was 1000 microg E75 plus 250 microg GM-CSF monthly x 6. The optimal dose group (ODG, n = 29) experienced similar toxicities to the suboptimal dose group (SDG, n = 70), which was comprised of the remaining 6 groups. The ODG demonstrated a trend toward an increase in the average postvaccine dimer (0.87 +/- 0.10% vs 0.67 +/- 0.05%; P = .07), a significantly larger DTH response (21.5 +/- 2.5 mm vs 11.3 +/- 1.3 mm; P = .0002), and a trend toward decreased recurrences (3.4% vs 12.9%; P = .27). Compared with the SDG, the ODG had larger tumors (percentage > or =T2: 55% vs 23%; P = .004), more positive lymph nodes (percentage NP: 76% vs 37%; P = .001), and higher grade tumors (percentage grade 3: 52% vs 30%; P = .07), but a shorter median follow-up time (20 months vs 32 months; P < .001). CONCLUSIONS: Compared with suboptimally dosed patients, the optimally dosed E75 vaccine in disease-free BCa patients had similar toxicity but enhanced HER-2/neu-specific immunity that may lead to decreased recurrences with additional follow-up.

Results of the first phase I clinical trial of the novel II-key hybrid preventive HER-2/neu peptide (AE37) vaccine.

PURPOSE: HER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4(+) T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four-amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients. PATIENTS AND METHODS: The dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 microg, 500 microg, 1,000 microg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 microg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [(3)H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790). RESULTS: All 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 microg; GM-CSF, 250 microg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36. CONCLUSION: The hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu-specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.

Assessment of immunologic response and recurrence patterns among patients with clinical recurrence after vaccination with a preventive HER2/neu peptide vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

BACKGROUND: E75, a HER2/neu immunogenic peptide, is expressed in breast cancer (BCa). We have performed clinical trials of E75 + GM-CSF vaccine in disease-free, node-positive and node-negative BCa patients at high recurrence risk and recurrences were noted in both control and vaccine groups. METHODS: Among the 186 BCa patients enrolled, 177 completed the study. Patients were HLA typed; the HLA-A2(+)/A3(+) patients were vaccinated; HLA-A2(-)/A3(-) patients were followed as controls. Standard clinicopathological factors, immunologic response to the vaccine, and recurrences were collected and assessed. RESULTS: The control group recurrence rate was 14.8 and 8.3% in the vaccinated group (P = 0.17). Comparing the 8 vaccinated recurrences (V-R) to the 88 vaccinated nonrecurrent patients (V-NR), the V-R group had higher nodal stage (> or = N2: 75 vs. 5%, P = 0.0001) and higher grade tumors (%grade 3: 88 vs. 31%, P = 0.003). The V-R group did not fail to respond immunologically as noted by equivalent dimer responses and post-DTH responses. Compared to control recurrent patients (C-R), V-R patients trended toward higher-grade tumors and hormone-receptor negativity. C-R patients had 50% bone-only recurrences, compared to V-R patients with no bone-only recurrences (P = 0.05). Lastly, V-R mortality rate was 12.5% compared with 41.7% for the C-R group (P = 0.3). CONCLUSIONS: The vaccinated patients who recurred had more aggressive disease compared to V-NR patients. V-R patients had no difference in immune response to the vaccine either in vitro or in vivo. V-R patients, when compared to C-R patients, trended towards more aggressive disease, decreased recurrence rates, decreased mortality, and no bone-only recurrences.

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.

Systematic review on embracing cultural diversity for developing and sustaining a healthy work environment in healthcare.

Objectives The objective of this review was to evaluate evidence on the structures and processes that support development of effective culturally competent practices and a healthy work environment. Culturally competent practices are a congruent set of workforce behaviours, management practices and institutional policies within a practice setting resulting in an organisational environment that is inclusive of cultural and other forms of diversity. Inclusion criteria This review included quantitative and qualitative evidence, with a particular emphasis on identifying systematic reviews and randomised controlled trials. For quantitative evidence, other controlled, and descriptive designs were also included. For qualitative evidence, all methodologies were considered. Participants were staff, patients, and systems or policies that were involved or affected by concepts of cultural competence in the nursing workforce in a healthcare environment. Types of interventions included any strategy that had a cultural competence component, which influenced the work environment, and/or patient and nursing staff in the environment. The types of outcomes of interest to this review included nursing staff outcomes, patient outcomes, organisational outcomes and systems level outcomes. Search strategy The search sought both published and unpublished literature written in the English language. A comprehensive three-step search strategy was used, first to identify appropriate key words, second to combine all optimal key words into a comprehensive search strategy for each database and finally to review the reference lists of all included reviews and research reports. The databases searched were CINAHL, Medline, Current Contents, the Database of Abstracts of Reviews of Effectiveness, The Cochrane Library, PsycINFO, Embase, Sociological Abstracts, Econ lit, ABI/Inform, ERIC and PubMed. The search for unpublished literature used Dissertation Abstracts International. Methodological quality Methodological quality was independently established by two reviewers, using standardised techniques from the Joanna Briggs Institute (JBI) System for the Unified Management, Assessment and Review of Information (SUMARI) package. Discussion with a third reviewer was initiated where a low level of agreement was identified for a particular paper. Following inclusion, data extraction was conducted using standardised data extraction tools from the JBI SUMARI suite for quantitative and qualitative research. Data synthesis was performed using the JBI Qualitative Assessment and Review Instrument and JBI Narrative, Opinion and Text Assessment and Review Instrument software to aggregate findings by identifying commonalities across texts. Quantitative data were presented in narrative summary, as statistical pooling was not appropriate with the included studies. Results Of the 659 identified papers, 45 were selected for full paper retrieval, and 19 were considered to meet the inclusion criteria for this review. The results identified a number of processes that would contribute to the development of a culturally competent workforce. Appropriate and competent linguistic services, and intercultural staff training and education, were identified as key findings in this review. Conclusions The review recommends that health provider agencies establish links with organisations that can address needs of culturally diverse groups of patients, include cultural competence in decision support systems and staff education as well as embed them in patient brochures and educational materials. The review also concluded that staff in-service programs consider the skills needed to foster a culturally competent workforce, and recruitment strategies that also explicitly address this need.

Systematic review on embracing cultural diversity for developing and sustaining a healthy work environment in healthcare.

OBJECTIVES: The objective of this review was to evaluate evidence on the structures and processes that support development of effective culturally competent practices and a healthy work environment. Culturally competent practices are a congruent set of workforce behaviours, management practices and institutional policies within a practice setting resulting in an organisational environment that is inclusive of cultural and other forms of diversity. INCLUSION CRITERIA: This review included quantitative and qualitative evidence, with a particular emphasis on identifying systematic reviews and randomised controlled trials. For quantitative evidence, other controlled, and descriptive designs were also included. For qualitative evidence, all methodologies were considered. Participants were staff, patients, and systems or policies that were involved or affected by concepts of cultural competence in the nursing workforce in a healthcare environment. Types of interventions included any strategy that had a cultural competence component, which influenced the work environment, and/or patient and nursing staff in the environment. The types of outcomes of interest to this review included nursing staff outcomes, patient outcomes, organisational outcomes and systems level outcomes. SEARCH STRATEGY: The search sought both published and unpublished literature written in the English language. A comprehensive three-step search strategy was used, first to identify appropriate key words, second to combine all optimal key words into a comprehensive search strategy for each database and finally to review the reference lists of all included reviews and research reports. The databases searched were CINAHL, Medline, Current Contents, the Database of Abstracts of Reviews of Effectiveness, The Cochrane Library, PsycINFO, Embase, Sociological Abstracts, Econ lit, ABI/Inform, ERIC and PubMed. The search for unpublished literature used Dissertation Abstracts International. METHODOLOGICAL QUALITY: Methodological quality was independently established by two reviewers, using standardised techniques from the Joanna Briggs Institute (JBI) System for the Unified Management, Assessment and Review of Information (SUMARI) package. Discussion with a third reviewer was initiated where a low level of agreement was identified for a particular paper. Following inclusion, data extraction was conducted using standardised data extraction tools from the JBI SUMARI suite for quantitative and qualitative research. Data synthesis was performed using the JBI Qualitative Assessment and Review Instrument and JBI Narrative, Opinion and Text Assessment and Review Instrument software to aggregate findings by identifying commonalities across texts. Quantitative data were presented in narrative summary, as statistical pooling was not appropriate with the included studies. RESULTS: Of the 659 identified papers, 45 were selected for full paper retrieval, and 19 were considered to meet the inclusion criteria for this review. The results identified a number of processes that would contribute to the development of a culturally competent workforce. Appropriate and competent linguistic services, and intercultural staff training and education, were identified as key findings in this review. CONCLUSIONS: The review recommends that health provider agencies establish links with organisations that can address needs of culturally diverse groups of patients, include cultural competence in decision support systems and staff education as well as embed them in patient brochures and educational materials. The review also concluded that staff in-service programs consider the skills needed to foster a culturally competent workforce, and recruitment strategies that also explicitly address this need.

A comprehensive systematic review of evidence on the structure, process, characteristics and composition of a nursing team that fosters a healthy work environment.

Objectives The overall aim of this comprehensive systematic review was to identify the best available evidence on the effect of team characteristics, processes, structure and composition within the context of collaborative practice among nursing teams that create a healthy work environment. Search strategy The search strategy sought to find both published and unpublished studies and papers written in the English language. An initial limited search of Medline and CINAHL databases was undertaken to identify optimal search terms. A second extensive search using all identified keywords and index terms was then undertaken. Methodological quality Two independent reviewers assessed the methodological quality of retrieved papers using the corresponding checklist from the System for the Unified Management, Assessment and Review of Information (SUMARI) package. Results The papers included in the review included nine experimental or quasi-experimental studies, 11 descriptive studies and four qualitative studies. A variety of different team structures such as interdisciplinary teams, primary nursing, team nursing, multidisciplinary models of care delivery and the use of a Partner in Patient Care model were investigated. Team characteristics should include accountability, commitment, enthusiasm and motivation. Social support within a team from a supervisor or colleague increased satisfaction levels of staff. Conclusion The results of the review lead to the development of a number of recommendations for practice that could assist with creating a health work environment.

A systematic review of evidence on the professional practice of the nurse and developing and sustaining a healthy work environment in healthcare.

Objectives The overall aim of this systematic review was to identify the best available evidence on the relationship between the knowledge, competencies and behaviours of nurses exhibiting professional practice in their workplace; and the development of a healthy work environment. Search strategy The search strategy sought to find both published and unpublished studies written in the English language. An initial limited search of MEDLINE and CINAHL databases was undertaken to identify optimal search terms. A second extensive search using all identified key words and index terms was then undertaken. Methodological quality Two independent reviewers assessed the methodological quality of retrieved papers using the corresponding checklist from the System for the Unified Management, Assessment and Review of Information (SUMARI) package. Results Of the 4238 papers found in the search: 219 were selected for full paper retrieval; 19 of these papers were unable to be located; 200 full papers were assessed for methodological quality; 181 studies were excluded; and 19 were included in the review. Of these 19, four quantitative studies evaluated a professional nursing practice model and its impact on a variety of outcomes; five descriptive studies examined elements of nurses' professional practice and the impact these elements had on specified outcomes; and 10 qualitative papers examined varying behaviours, competencies and knowledge levels of nurses. Various methods were used, such as focus groups and open-ended interviews. Overall, the evidence suggests that professional practice has a positive impact on the work environment in terms of nurses' role satisfaction and patient outcomes. The evidence is, however, equivocal in many areas and the impact of the professional practice of the nurse requires further investigation. Conclusion The results of the review suggest a number of recommendations for practice and research on creating a healthy work environment.

A comprehensive systematic review of evidence on the structure, process, characteristics and composition of a nursing team that fosters a healthy work environment.

OBJECTIVES: The overall aim of this comprehensive systematic review was to identify the best available evidence on the effect of team characteristics, processes, structure and composition within the context of collaborative practice among nursing teams that create a healthy work environment. SEARCH STRATEGY: The search strategy sought to find both published and unpublished studies and papers written in the English language. An initial limited search of Medline and CINAHL databases was undertaken to identify optimal search terms. A second extensive search using all identified keywords and index terms was then undertaken. METHODOLOGICAL QUALITY: Two independent reviewers assessed the methodological quality of retrieved papers using the corresponding checklist from the System for the Unified Management, Assessment and Review of Information (SUMARI) package. RESULTS: The papers included in the review included nine experimental or quasi-experimental studies, 11 descriptive studies and four qualitative studies. A variety of different team structures such as interdisciplinary teams, primary nursing, team nursing, multidisciplinary models of care delivery and the use of a Partner in Patient Care model were investigated. Team characteristics should include accountability, commitment, enthusiasm and motivation. Social support within a team from a supervisor or colleague increased satisfaction levels of staff. CONCLUSION: The results of the review lead to the development of a number of recommendations for practice that could assist with creating a health work environment.

A systematic review of evidence on the professional practice of the nurse and developing and sustaining a healthy work environment in healthcare.

OBJECTIVES: The overall aim of this systematic review was to identify the best available evidence on the relationship between the knowledge, competencies and behaviours of nurses exhibiting professional practice in their workplace; and the development of a healthy work environment. SEARCH STRATEGY: The search strategy sought to find both published and unpublished studies written in the English language. An initial limited search of MEDLINE and CINAHL databases was undertaken to identify optimal search terms. A second extensive search using all identified key words and index terms was then undertaken. METHODOLOGICAL QUALITY: Two independent reviewers assessed the methodological quality of retrieved papers using the corresponding checklist from the System for the Unified Management, Assessment and Review of Information (SUMARI) package. RESULTS: Of the 4238 papers found in the search: 219 were selected for full paper retrieval; 19 of these papers were unable to be located; 200 full papers were assessed for methodological quality; 181 studies were excluded; and 19 were included in the review. Of these 19, four quantitative studies evaluated a professional nursing practice model and its impact on a variety of outcomes; five descriptive studies examined elements of nurses' professional practice and the impact these elements had on specified outcomes; and 10 qualitative papers examined varying behaviours, competencies and knowledge levels of nurses. Various methods were used, such as focus groups and open-ended interviews. Overall, the evidence suggests that professional practice has a positive impact on the work environment in terms of nurses' role satisfaction and patient outcomes. The evidence is, however, equivocal in many areas and the impact of the professional practice of the nurse requires further investigation. CONCLUSION: The results of the review suggest a number of recommendations for practice and research on creating a healthy work environment.