Committee on Surgical Combat Casualty Care position statement: Neurosurgical capability for the optimal management of traumatic brain injury during deployed operations.

BACKGROUND: Experiences over the last three decades of war have demonstrated a high incidence of traumatic brain injury (TBI) resulting in a persistent need for a neurosurgical capability within the deployed theater of operations. Despite this, no doctrinal requirement for a deployed neurosurgical capability exists. Through an iterative process, the Joint Trauma System Committee on Surgical Combat Casualty Care (CoSCCC) developed a position statement to inform medical and nonmedical military leaders about the risks of the lack of a specialized neurosurgical capability. METHODS: The need for deployed neurosurgical capability position statement was identified during the spring 2021 CoSCCC meeting. A triservice working group of experienced forward-deployed caregivers developed a preliminary statement. An extensive iterative review process was then conducted to ensure that the intended messaging was clear to senior medical leaders and operational commanders. To provide additional context and a civilian perspective, statement commentaries were solicited from civilian clinical experts including a recently retired military trauma surgeon boarded in neurocritical care, a trauma surgeon instrumental in developing the Brain Injury Guidelines, a practicing neurosurgeon with world-renowned expertise in TBI, and the chair of the Committee on Trauma. RESULTS: After multiple revisions, the position statement was finalized, and approved by the CoSCCC membership in February 2023. Challenges identified include (1) military neurosurgeon attrition, (2) the lack of a doctrinal neurosurgical capabilities requirement during deployed combat operations, and (3) the need for neurosurgical telemedicine capability and in-theater computed tomography scans to triage TBI casualties requiring neurosurgical care. CONCLUSION: Challenges identified regarding neurosurgical capabilities within the deployed trauma system include military neurosurgeon attrition and the lack of a doctrinal requirement for neurosurgical capability during deployed combat operations. To mitigate risk to the force in a future peer-peer conflict, several evidence-based recommendations are made. The solicited civilian commentaries strengthen these recommendations by putting them into the context of civilian TBI management. This neurosurgical capabilities position statement is intended to be a forcing function and a communication tool to inform operational commanders and military medical leaders on the use of these teams on current and future battlefields. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level V.

Relation of Vitamin D Level, BMI, and Location of Lower Extremity Stress Fractures in Military Trainees.

INTRODUCTION: Military trainees are at an increased risk of stress fractures. Vitamin D availability is known to play an important role in both fracture prevention and healing. The purpose of this investigation was to assess 25-hydroxy vitamin D (25(OH)D) levels in soldiers with confirmed lower extremity stress fractures and assess the predictors of fracture location. MATERIALS AND METHODS: Following Institutional Review Board approval, military trainees at a large training base presenting to the orthopedic clinic with a radiographically verified stress fracture were identified. Demographic data and 25(OH)D levels were collected. A descriptive analysis was performed in regard to patient age, body mass index (BMI), and 25(OH)D level. Interactions between variables were assessed using one-way analysis of variance for four fracture location groups (femoral neck, femoral shaft, tibial shaft, and foot and ankle). Bivariate correlations were examined between age, BMI, and vitamin D level. RESULTS: A total of 155 lower extremity stress fractures were identified in 144 males and 11 females over 30 months. The mean age was 22.7 ± 4.85 years. The majority (60.7%) of fractures were located in the femoral neck. The average 25(OH)D level was 26.8 ± 8.37 ng/mL. Overall, 26% (N = 41) of enrolled patients had normal 25(OH)D levels, 48% (N = 74) had insufficient 25(OH)D levels, and 26% (N = 40) had deficient 25(OH)D levels. Patients with femoral neck fractures and tibial shaft fractures had significantly lower BMI than patients with foot and ankle fractures (23.3 vs. 27.7, P < .001 and 24.2 vs. 27.7, P = .003, respectively). Patients with foot and ankle fractures had significantly lower 25(OH)D levels than patients with femoral shaft fractures (21.1 vs. 30.1, P = .02). There were no significant findings regarding age and fracture location. Age correlated positively (but weakly) with BMI (0.338, P < .001). There was no correlation between age and vitamin D level or BMI and vitamin D level. CONCLUSION: Overall, 74% of patients in military training with lower extremity stress fractures had insufficient or deficient levels of 25(OH)D, highlighting a persistent area of concern in this population. Patients with femoral neck and tibial shaft stress fractures had significantly lower BMI than patients with foot and ankle stress fractures. This suggests that in stress fracture-prone patients, BMI may play a role in predicting fracture location.

Hypocalcemia in Military Casualties From Point of Injury to Surgical Teams in Afghanistan.

INTRODUCTION: Hypocalcemia is a known sequela of citrated blood product transfusion. Civilian data suggest hypocalcemia on hospital admission is associated with worse outcomes. Initial calcium levels in military casualties have not previously been analyzed. The objective of this retrospective review aimed to assess the initial calcium levels in military trauma casualties at different Forward Surgical Teams (FST) locations in Afghanistan and describe the effects of prehospital blood product administration on arrival calcium levels. MATERIALS AND METHODS: This is a retrospective cohort analysis of military casualties arriving from point of injury to one of two FSTs in Afghanistan from August 2018 to February 2019 split into four locations. The primary outcome was incidence of hypocalcemia (ionized calcium < 1.20 mmol/L). RESULTS: There were 101 patients included; 55 (54.5%) experienced hypocalcemia on arrival to the FST with a mean calcium of 1.16 mmol/L (95% confidence interval [CI], 1.14 to 1.18). The predominant mechanism of injury consisted of blast patterns, 46 (45.5%), which conferred an increased risk of hypocalcemia compared to all other patterns of injury (odds ratio = 2.42, P = .042). Thirty-eight (37.6%) patients required blood product transfusion. Thirty-three (86.8%) of the patients requiring blood product transfusion were hypocalcemic on arrival. Mean initial calcium of patients receiving blood product was 1.13 mmol/L (95% CI, 1.08 to 1.18), which was significantly lower than those who did not require transfusion (P = .01). Eight (7.9%) of the patients received blood products before arrival, with 6/8 (75%) presenting with hypocalcemia. CONCLUSIONS: Hypocalcemia develops rapidly in military casualties and is prevalent on admission even before transfusion of citrated blood products. Blast injuries may confer an increased risk of developing hypocalcemia. This data support earlier use of calcium supplementation during resuscitation.

The Golden Hour Offset Surgical Treatment Team Operational Concept: Experience of the 102nd Forward Surgical Team in Operation Freedom's Sentinel 2015-2016.

Theater Special Operations Force (SOF) medical planners have begun using Army Forward Surgical Teams (FSTs) to maintain a golden hour for U.S. SOF during Operation Freedom's Sentinel required adaptation in FST training, configuration, personnel, equipment, and employment to form Golden Hour Offset Surgical Treatment Teams (GHOST-Ts). This article describes one such FST's experience in Operation Freedom's Sentinel while deployed for 9 months in support of SOF in southern Afghanistan.

Surgical Instrument Sets for Special Operations Expeditionary Surgical Teams.

BACKGROUND: The deployment of surgical assets has been driven by mission demands throughout years of military operations in Iraq and Afghanistan. The transition to the highly expeditious Golden Hour Offset Surgical Transport Team (GHOST- T) now offers highly mobile surgical assets in nontraditional operating rooms; the content of the surgical instrument sets has also transformed to accommodate this change. METHODS: The 102nd Forward Surgical Team (FST) was attached to Special Operations assigned to southern Afghanistan from June 2015 to March 2016. The focus was to decrease overall size and weight of FST instrument sets without decreasing surgical capability of the GHOST-T. Each instrument set was evaluated and modified to include essential instruments to perform damage control surgery. RESULTS: The overall number of main instrument sets was decreased from eight to four; simplified augmentation sets have been added, which expand the capabilities of any main set. The overall size was decreased by 40% and overall weight decreased by 58%. The cardiothoracic, thoracotomy, and emergency thoracotomy trays were condensed to thoracic set. The orthopedic and amputation sets were replaced with an augmentation set of a prepackaged orthopedic external fixator set). An augmentation set to the major or minor basic sets, specifically for vascular injuries, was created. CONCLUSION: Through the reorganization of conventional FST surgical instrument sets to maintain damage control capabilities and mobility, the 102nd GHOST-T reduced surgical equipment volume and weight, providing a lesson learned for future surgical teams operating in austere environments.

Deployed skills training for whole blood collection by a special operations expeditionary surgical team.

BACKGROUND: Noncompressible hemorrhage is the leading cause of potentially preventable battlefield death. Combining casualty retrieval from the battlefield and damage control resuscitation (DCR) within the "golden hour" increases survival. However, transfusion requirements may exceed the current blood component stocks held by forward surgical teams. Warm fresh whole blood (WFWB) is an alternative. We report WFWB transfusion training developed by and delivered to a US Golden Hour Offset Surgical Treatment Team and the resulting improvement in confidence with WFWB transfusion. METHODS: A bespoke instructional package was derived from existing operational clinical guidelines. All Golden Hour Offset Surgical Treatment Team personnel completed initial training, reinforced through ongoing casualty simulations. A record of blood types and donor eligibility was established to facilitate rapid identification of potential WFWB donors. Self-reported confidence in seven aspects of the WFWB transfusion process was assessed before and after training using a five-point Likert scale. Personnel were analyzed by groups consisting of those whose operational role includes WFWB transfusion ("transfusers"), clinical personnel without such responsibilities ("nontransfusers") and nonclinical personnel (other). Comparisons within and between groups were made using appropriate nonparametric tests. RESULTS: Data were collected from 39 (89%) of 44 training participants: 24 (62%) transfusers, 12 (31%) nontransfusing clinicians, and 3 (8%) other personnel. Transfusers and nontransfusers reported increased comfort with all practical elements of WFWB transfusion. The confidence of other personnel also increased, but (likely due to small numbers) was not statistically significant. CONCLUSION: WFWB transfusion is an integral part of modern deployed military remote DCR. Our in-theater training program rapidly and reproducibly enhanced the comfort in WFWB transfusion in providers from a range of backgrounds and skill-mixes. This model has the potential to improve both safety and effectiveness of WFWB remote DCR in the far-forward deployed setting. LEVEL OF EVIDENCE: Therapeutic/care management study, level IV.

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.

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.

Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02.

BACKGROUND: The authors are conducting clinical trials of the HER-2/neu E75-peptide vaccine in clinically disease-free breast cancer (BC) patients. Their phase 1-2 trials revealed that the E75 + granulocyte-macrophage colony-stimulating factor (GM-CSF) vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8(+) T cells. They assessed the need for and response to a booster after completion of primary vaccination series. METHODS: BC patients enrolled in the E75 vaccine trials who were ≥6 months from completion of their primary vaccination series were offered boosters with E75 + GM-CSF. Patients were monitored for toxicity. E75-specific CD8(+) T cells were quantified using the human leukocyte antigen-A2:immunoglobulin G dimer before and after boosting. RESULTS: Fifty-three patients received the vaccine booster. Median time from primary vaccination series was 9 months (range, 6-35 months), and median residual E75-specific immunity was 0.70% (range, 0-3.49%) CD8(+) lymphocytes. Elevated residual immunity (ERI) (CD8(+) E75-specific T cells >0.5%) was seen in 94.4% of patients at 6 months from primary vaccination series versus 48% of patients at >6 months (P = .002). The booster was well tolerated, with only grade 1 and 2 toxicity observed. Local reactions were more robust in patients receiving the booster at 6 months from primary vaccination series compared with those at >6 months (99.4 ± 6.1 mm vs 81.8 ± 4.1 mm, P = .01). In patients lacking ERI, 85% had increased ERI after vaccination (P = .0014). CONCLUSIONS: The HER-2/neu E75 peptide vaccine E75 stimulates specific immunity in disease-free BC patients. However, immunity wanes with time. A vaccine booster is safe and effective in stimulating E75-specific immunity in those patients without ERI. These results suggest that the booster may be most effective at 6 months after completion of the primary vaccination series.

Circulating regulatory T cells (CD4+CD25+FOXP3+) decrease in breast cancer patients after vaccination with a modified MHC class II HER2/neu (AE37) peptide.

Regulatory T cells (T(Reg)), CD4(+)CD25(+)FOXP3(+), are implicated in suppressing tumor immune responses. We analyzed peripheral blood lymphocytes (PBL) from breast cancer patients receiving a modified HLA class II HER2/neu peptide (AE37) vaccine for T(Reg) cells and correlated their levels with vaccine-specific immune responses. The mean CD4(+)CD25(+)FOXP3(+) T(Reg) cells decreased in patients with vaccination with no significant difference in serum TGF-ß levels. IFN-γ ELISPOT and DTH increased after vaccination with a good correlation between T(Reg) cell reduction and size of DTH to AE37. The T(Reg) cell reduction and associated immune response suggest that AE37 may be clinically useful.

Results of the first phase 1 clinical trial of the HER-2/neu peptide (GP2) vaccine in disease-free breast cancer patients: United States Military Cancer Institute Clinical Trials Group Study I-04.

BACKGROUND: HER-2/neu, overexpressed in breast cancer, is a source of immunogenic peptides that include GP2 and E75. Phase 2 testing of E75 as an adjuvant vaccine has suggested a clinical benefit. GP2, derived from the transmembrane portion of HER-2/neu, has differing binding characteristics and may be more immunogenic than E75. Results of the first phase 1 trial of GP2 peptide vaccine are presented. METHODS: Disease-free, lymph node-negative, human leukocyte antigen (HLA)-A2(+) breast cancer patients were enrolled. This dose escalation trial included 4 groups to determine safety and optimal GP2 peptide/granulocyte-macrophage colony-stimulating factor (GM-CSF) dose. Toxicities were monitored. Immunologic response was assessed ex vivo via the HLA-A2:immunoglobulin dimer assay to detect GP2-specific CD8(+) T cells (and E75-specific CD8(+) T cells to assess epitope spreading) and in vivo via delayed type hypersensitivity (DTH) reaction (medians/ranges). RESULTS: Eighteen patients were enrolled. All toxicities were grade < or =2. Eight (88.9%) of 9 patients in the first 3 dose groups required GM-CSF dose reductions for local reactions > or =100 mm or grade > or =2 systemic toxicity. GM-CSF dose was reduced to 125 microg for the final dose group. All patients responded immunologically ex vivo (GP2-specific CD8(+) T cells from prevaccination to maximum, 0.4% [0.0%-2.0%] to 1.1% [0.4%-3.6%], P < .001) and in vivo (GP2 pre- to postvaccination DTH, 0 mm [0.0-19.5 mm] to 27.5 mm [0.0-114.5 mm, P < .001). E75-specific CD8(+) T cells also increased in response to GP2 from prevaccination to maximum (0.8% [0.0%-2.41%] to 1.6% [0.86%-3.72%], P < .001). CONCLUSIONS: The GP2 peptide vaccine appears safe and well tolerated with minimal local/systemic toxicity. GP2 elicited HER-2/neu-specific immune responses, including epitope spreading, in high-risk, lymph node-negative breast cancer patients. These findings support further investigation of the GP2 vaccine for the prevention of breast cancer recurrence.

Preoperative thyroid ultrasound in all patients undergoing parathyroidectomy?

BACKGROUND: Coexisting thyroid nodules are the most common cause of false positive localization by radioscintigraphy in the preoperative evaluation for MIPS in patients with primary hyperparathyroidism (pHPT). This false positive finding can prompt full neck exploration in the setting of an unanticipated and incompletely evaluated thyroid nodule. Therefore, we are studying prospectively the routine use of preoperative thyroid US in patients with pHPT to determine the prevalence of concurrent thyroid disease and to assess how frequently this added information could alter the surgical plan. MATERIALS AND METHODS: Twenty-four patients with biochemically confirmed pHPT were evaluated with thyroid US after localizing (99m)Tc-sestamibi scintigraphy prior to parathyroid operation. RESULTS: Of the 24 patients, 38% (n = 9) had their operations altered from a planned MIPS or four-gland exploration due to coexisting thyroid nodule(s). Of these, 33% (n = 3) had underlying thyroid malignancy (all papillary thyroid cancer) requiring thyroidectomy in addition to parathyroidectomy. All but one patient had parathyroid adenoma as the cause of pHPT. CONCLUSION: The routine use of preoperative thyroid US in patients with pHPT undergoing parathyroid surgery may aid in the timely diagnosis and treatment of coexisting thyroid disease. This added information secured before operation may avoid difficult intraoperative decision dilemmas and prevent the increased morbidity associated with a second neck exploration. A large scale prospective study is on-going.

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.

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.

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.