Comparison of Outcomes of antibiotic Drugs and Appendectomy (CODA) trial: a protocol for the pragmatic randomised study of appendicitis treatment.

INTRODUCTION: Several European studies suggest that some patients with appendicitis can be treated safely with antibiotics. A portion of patients eventually undergo appendectomy within a year, with 10%-15% failing to respond in the initial period and a similar additional proportion with suspected recurrent episodes requiring appendectomy. Nearly all patients with appendicitis in the USA are still treated with surgery. A rigorous comparative effectiveness trial in the USA that is sufficiently large and pragmatic to incorporate usual variations in care and measures the patient experience is needed to determine whether antibiotics are as good as appendectomy. OBJECTIVES: The Comparing Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial for acute appendicitis aims to determine whether the antibiotic treatment strategy is non-inferior to appendectomy. METHODS/ANALYSIS: CODA is a randomised, pragmatic non-inferiority trial that aims to recruit 1552 English-speaking and Spanish-speaking adults with imaging-confirmed appendicitis. Participants are randomised to appendectomy or 10 days of antibiotics (including an option for complete outpatient therapy). A total of 500 patients who decline randomisation but consent to follow-up will be included in a parallel observational cohort. The primary analytic outcome is quality of life (measured by the EuroQol five dimension index) at 4 weeks. Clinical adverse events, rate of eventual appendectomy, decisional regret, return to work/school, work productivity and healthcare utilisation will be compared. Planned exploratory analyses will identify subpopulations that may have a differential risk of eventual appendectomy in the antibiotic treatment arm. ETHICS AND DISSEMINATION: This trial was approved by the University of Washington's Human Subjects Division. Results from this trial will be presented in international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT02800785.

The GP2 peptide: a HER2/neu-based breast cancer vaccine.

Preclinical studies suggest that GP2, a HER2/neu-derived peptide, is immunogenic. Subsequent phase I clinical trials demonstrated that GP2-based vaccines are safe and effective in stimulating peptide-specific immunity. A GP2 peptide vaccine is currently being evaluated in a phase II efficacy trial enrolling breast cancer patients. This article reviews initial studies characterizing GP2, clinical trials investigating GP2-based vaccines, and novel immunotherapy strategies incorporating GP2 in combination with other peptides or with the monoclonal antibody trastuzumab.

Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

BACKGROUND: The authors conducted exploratory phase 1-2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3-restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS). METHODS: These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3(+) ) expressing tumors. HLA-A2/A3(+) patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. RESULTS: Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred. CONCLUSIONS: The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.

AE37: a novel T-cell-eliciting vaccine for breast cancer.

INTRODUCTION: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combatting breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8(+) T-cell-eliciting vaccines. AE37 is a promising primarily CD4(+) T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials. AREAS COVERED: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine. EXPERT OPINION: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.

Colorectal, prostate, and skin cancer screening among Hispanic and White non-Hispanic men, 2000-2005.

BACKGROUND: Hispanic men have lower colorectal, prostate, and skin cancer screening rates than white non-Hispanic men. Programs designed to increase screening rates, including the national Screen for Life campaign specifically for promoting colorectal cancer (CRC) screening, regional educational/research programs, and state cancer control programs, have been launched. Screen for Life and some intervention programs included educational materials in Spanish as well as English. OBJECTIVE: To assess whether CRC as well as prostate and skin cancer screening rates among Hispanic and white non-Hispanic men changed between 2000 and 2005. METHODS: Cancer screening rates were compared between 2000 and 2005 using the National Health Interview Survey data. The age ranges of the study subjects and definitions of cancer screening were site specific and based on the American Cancer Society recommendations. RESULTS: Hispanic men were less likely to comply with cancer screening guidelines than white non-Hispanic men. However, significant increases in CRC endoscopic screening were observed in both ethnic groups. It increased 2.1-fold and 2.4-fold for Hispanics and white non-Hispanics, respectively (P < .05). In contrast, the use of home fecal occult blood tests decreased among white non-Hispanics but remained similar among Hispanics. Prostate-specific antigen screening remained stable, while the use of skin cancer screening tended to increase among both groups. CONCLUSION: Although cancer screening rates may be affected by multiple factors, our study suggested the intervention programs such as the Centers for Disease Control and Prevention's national Screen for Life campaign may have raised CRC screening awareness and may contributed to the increase in endoscopic screening rates among both ethnic groups.

Standardized pretreatment breast MRI--accuracy and influence on mastectomy decisions.

BACKGROUND AND OBJECTIVES: Routine pretreatment breast magnetic resonance imaging in newly diagnosed cancer patients remains controversial. We assess MRI accuracy and influence on mastectomy decisions after institution of standardized pretreatment MRI. METHODS: A prospectively collected database of 74 consecutive new invasive breast cancer patients with pretreatment breast MRI was reviewed for treatment choice, radiologic, and pathologic results. Thirty-eight of 72 patients with available surgical records underwent mastectomy. Mastectomy preoperative and operative electronic records were reviewed for treatment decision analysis. RESULTS: Seventeen of 72 (23.6%) invasive breast cancer patients were likely influenced to undergo mastectomy by new information from MRI. MRI reported that the multifocal/multicentric (MF/MC) rate was 20 of 72 (27.8%) versus 19 of 72 (26.4%) by surgical pathology. MRI sensitivity for MF/MC disease was 89.5% versus 11.8% for mammography. MRI specificity was 84.2%. All three false positives declined recommended preoperative biopsies. MRI MF/MC diagnosis highly correlated with pathology results, P < 0.001. CONCLUSIONS: Increased mastectomy rate from 29 to 52.8% after standardization of pre-treatment breast MRI for invasive cancer is largely due to MRI findings of increased extent of disease. These MRI findings correlate well with pathologic findings and appear to justify the performance of mastectomies in these patients.

Comparison of different HER2/neu vaccines in adjuvant breast cancer trials: implications for dosing of peptide vaccines.

We have performed multiple adjuvant clinical trials using immunogenic peptides from the HER2/neu protein (AE37/E75/GP2) plus (GM-CSF) given intradermally to breast cancer patients. Four trials were performed with similar dose-escalation design with increasing doses of peptide (AE37/E75/GP2) and varying amounts of GM-CSF. Dose reductions (DRs) were made for significant local and/or systemic toxicity by decreasing GM-CSF for subsequent inoculations. Ex vivo and in vivo immunologic responses were used to compare groups. Of 132 patients, 39 required DR (30 for robust local reactions [DR-L]). DR patients, particularly DR-L, had greater immune responses both ex vivo and in vivo. Postvaccine delayed-type hypersensitivity in DR-L patients compared with all others was larger for E75 (p = 0.001), AE37 (p = 0.077) and GP2 (p = 0.076). All three peptide vaccines were safe and well-tolerated. These findings have led to a clinically relevant optimal vaccine dosing strategy, which may be applicable to other peptide-based cancer vaccines.

Folate receptor α: a storied past and promising future in immunotherapy.

Folate receptor alpha (FR α) is a membrane-bound transport protein with several features which make it an attractive target for cancer immunotherapy. FR α is largely shielded from the immune system in normal tissue but exposed while expressed on a variety of malignancies; it is functionally active in cancer pathogenesis; and it is immunogenic. A variety of different immunotherapeutic methods targeting FR α are being explored to treat cancer. Passive immunotherapy includes monoclonal antibodies, antibodies modified to deliver treatments, and modified T cell therapy. Active immunotherapy has focused on using FR α to increase the immunogenicity of cancer or to generate active FR α-directed immunity through a range of vaccination techniques. We will review the rationale behind targeting immunotherapy to FR α and cover the various techniques designed to do this. Folate receptor alpha (FRα) is a unique tumor-associated antigen (TAA) with many characteristics that make it an attractive target for immunotherapy in cancer. Many different immunotherapeutic modalities utilizing FRα are being explored to treat cancer. The research is in various stages: some are just beyond conception, others have been tried and abandoned, and others still are progressing through human clinical trials. This review will cover immunotherapeutic methods, both active and passive, that target FRα.

Current US military operations and implications for military surgical training.

BACKGROUND: Since 2001, US military surgeons have deployed frequently, with many surgeons deploying within 1 year of graduating residency. The purpose of this study was to evaluate readiness of recent graduates to manage combat-related injuries and to make recommendations for improvements in training military surgeons. STUDY DESIGN: We reviewed casualties treated at the 31st Combat Support Hospital in Baghdad from December 2003 to November 2004. We identified 3,426 wounded patients; of these, 2,648 (77.3%) required an operative procedure. There were 2,788 patients (81.4%) who sustained penetrating injuries. The most common procedures performed were debridement of wounds (39%), skeletal fixation (14.7%), and exploratory laparotomy (11.4%). Common procedures were compared with 15 case logs from the ACGME database for our institution from 2005 to 2009. RESULTS: Graduating residents averaged 973 cases during residency (range 867 to 1,293, median 921). This included experience with most procedures encountered except nephrectomy (1.5 procedures per resident [PPR]), craniotomy (1.1 PPRs), inferior vena cava injury (1.1 PPRs), bladder repair (0.87 PPR), and duodenal injury (0.6 PPR). Residents had minimal experience with skeletal fixation and external genital trauma. CONCLUSIONS: Recent surgical residency graduates are prepared for deployment in support of US military operations for the majority of injuries encountered. However, familiarization with procedures that fall outside the traditional general surgical curriculum would improve their ability to treat these injuries. To enhance experience with rare injuries, cadaver studies and animal models may serve as training tools before deployment.

Use of GM-CSF as an adjuvant with cancer vaccines: beneficial or detrimental?

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been utilized in the clinical management of multiple disease processes. Most recently, GM-CSF has been incorporated into the treatment of malignancies as a sole therapy, as well as a vaccine adjuvant. While the benefits of GM-CSF in this arena have been promising, recent reports have suggested the potential for GM-CSF to induce immune suppression and, thus, negatively impact outcomes in the management of cancer patients. The purpose of this review is to critically evaluate these reports, while considering the most recent clinical data on immunotherapies. We aim to demonstrate the utility of this adjuvant, elucidate those instances in which GM-CSF may induce immune suppression and identify potential explanations for these recent findings.