Prospective, randomized, single-blinded, multi-center phase II trial of two HER2 peptide vaccines, GP2 and AE37, in breast cancer patients to prevent recurrence.

PURPOSE: AE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis. METHODS: In this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated. RESULTS: 456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275-1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499-1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114-1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142-0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG. CONCLUSIONS: This phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.

Peripheral Smear Review and Bone Marrow Biopsy Correlation.

INTRODUCTION: Peripheral Blood Smear (PBS) interpretation is a useful skill for Haematology/Oncology Clinicians (HOC). AIM: To explore practice patterns of PBS utilization for all benign haematology diagnosis in a non-simulated environment and to evaluate how it may guide the HOC in determining further work up and whether or not to perform a Bone Marrow Biopsy (BMB). MATERIALS AND METHODS: A retrospective review was conducted on 451 outpatient referrals for benign haematology diagnosis. Patient demographics and diagnostic tests were recorded. We further analysed cases in which a blood smear was ordered or reviewed. In cases with PBS review, we recorded testing ordered by the HOC. RESULTS: Records of 451 patients met inclusion criteria. The median age was 55 with males representing 51.9% of the cohort. Distribution of disorders were 50.6% (n = 228) erythrocyte (RBC), 25.5% (n = 114) leukocyte (WBC), 11.3% (n = 51) platelet (PLT), and 12.8% (n = 58) "other." A CBC was ordered in 82.7% of cases (373/451). A PBS was ordered in 47.4% of CBCs obtained (177/373, p<0.001). Of these, documentation occurred in 49.2% (87/177) which led to further testing 41.4% of cases (36/87). A BMB was performed in 11.5% (10/87) of cases in which a PBS was reviewed compared to 4.3% (16/373) of cases where BMB was performed without PBS review (p=.019). Of the 36 cases in which PBS review led to testing, 10 BMBs (27.8%) were performed-all of which led to specific haematologic diagnosis. A specific diagnosis was found in 43.8% (7/16) BMBs performed without prior PBS review. CONCLUSION: PBS interpretation is an important skill for HOCs. Haematology/Oncology (H/O) training programs should continue to teach this skill to increase proficiency in order to help guide diagnostic evaluation of various haematologic disorders.

Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence.

GP2 is a HER2-derived, HLA-A2+ restricted peptide. Phase I studies showed GP2 administered with GM-CSF to be safe and immunogenic. Here we report the primary analysis of a prospective, randomized, multicenter phase II adjuvant trial conducted to determine the vaccine's efficacy. The trial enrolled HLA-A2+, clinically disease-free, node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 (immunohistochemistry[IHC] 1+-3+). Patients were randomized to GP2+GM-CSF versus GM-CSF alone. Disease-free survival (DFS) was analyzed in intention-to-treat (ITT) and per-treatment cohorts; pre-specified subgroup analyses were performed for patients with IHC 3+ or FISH+ disease. The trial enrolled 180 patients; 89 received GP2+GM-CSF and 91 received GM-CSF alone. The groups were well-matched for clinicopathologic characteristics. Toxicities have been minimal. The Kaplan-Meier estimated 5-year DFS rate in the ITT analyses was 88% (95% CI:78-94%) in vaccinated vs. 81% (95% CI:69-89%) (P = 0.43) in control patients after a 34 month median follow-up. In the per-treatment analysis, the estimated 5-year DFS rates were 94% (95% CI:83-98%) and 85% (73-92%) (P = 0.17). In IHC 3+/FISH+ patients, the estimated 5-year DFS rate was 94% (82-98%) in vaccinated patients (n = 51) vs. 89% (71-96%) in control patients (n = 50), (P = 0.86) in the ITT analyses and 100% vs. 89% (71-96%) in vaccinated vs. control patients in the per-treatment analyses (P = 0.08). While the overall ITT analysis did not demonstrate benefit to vaccination, this trial confirmed that the GP2 vaccine is safe and suggests that vaccination may have clinical activity, particularly in patients with HER2 overexpression who received the full vaccine series (ie per-treatment group).

Efficacy of olanzapine for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV): a systematic review and meta-analysis.

PURPOSE: Olanzapine is a potent antipsychotic medication that inhibits a wide variety of receptors. It has been used in trials for the prophylaxis and rescue of chemotherapy-induced nausea and vomiting (CINV). This study systematically investigates the efficacy of olanzapine in relation to other antiemetics in the prophylaxis and rescue of CINV. METHODS: A literature search of Ovid MEDLINE, EMBASE, and CENTRAL was conducted to identify randomized controlled trials (RCTs) comparing olanzapine to other standard antiemetics for either prevention or rescue. The primary endpoints were the percentage of patients achieving no emesis or no nausea, in the acute, delayed, and overall phases. RESULTS: Ten RCTs in the preventative setting and three RCTs in the breakthrough setting were identified. Subgroup analysis demonstrated a similar degree of benefit from a 5- and 10-mg dose of olanzapine for the no emesis endpoint in the overall phase. In the prophylaxis setting, olanzapine was statistically superior in five of six endpoints and clinically superior in four of six endpoints. In the breakthrough setting, olanzapine was statistically and clinically superior in the only endpoint analyzed: no emesis. CONCLUSION: Olanzapine is more efficacious than other standard antiemetics for the rescue of CINV and its inclusion improves control in the prevention setting. Given the possible reduction in side effects, the use of a 5-mg dose of olanzapine should be considered. Future RCTs should compare the 5-mg versus the 10-mg dosages further and report on the efficacy and percentage of patients developing side effects. Further analyses should be done without the influence of corticosteroids.

Use of Milestones and Development of Entrustable Professional Activities in 2 Hematology/Oncology Training Programs.

BACKGROUND: The Next Accreditation System (NAS) increases the focus on educational outcomes and meaningful evaluation of learners. This requires that key clinical faculty develop new assessment formats such as entrustable professional activities (EPAs). OBJECTIVES: To build and develop milestone-based assessment tools supporting 5 EPAs for a hematology/oncology fellow continuity clinic, and to educate key clinical faculty regarding the Clinical Competency Committee (CCC) and the NAS. METHODS: Program directors from 2 hematology/oncology fellowship programs developed 5 EPAs for continuity clinic evaluation supported by milestone-based assessment. The program directors met to create a unified CCC charter. Key clinical faculty helped to develop a milestone-based evaluation of fellow continuity clinic through creation of 5 hematology/oncology-specific EPAs. Formal entrustment regarding EPAs was deliberated by the CCC. RESULTS: A total of 18 fellows were evaluated. Clinical Competency Committee deliberation at each institution took approximately 10 minutes per fellow for discussion and decision regarding entrustment for all 5 EPAs supporting continuity clinic. One-third of postgraduate year (PGY)-4s, 50% of PGY-5s, and 100% of PGY-6s were deemed competent in all 5 EPAs by the CCC. CONCLUSIONS: All hematology/oncology trainees in San Antonio were evaluated using milestone-based assessment for continuity clinic, and entrustment decisions regarding 5 EPAs were made by the CCC. This project may provide other programs with a sound basis for adoption and further development of the next generation of evaluation tools at their institutions. Entrustable professional activities that are rotation specific should be used as a starting point for linking to the competencies, subcompetencies, and the reporting milestones.

Current approaches and challenges in early detection of breast cancer recurrence.

Early detection of breast cancer recurrence is a key element of follow-up care and surveillance after completion of primary treatment. The goal is to improve survival by detecting and treating recurrent disease while potentially still curable assuming a more effective salvage surgery and treatment. In this review, we present the current guidelines for early detection of recurrent breast cancer in the adjuvant setting. Emphasis is placed on the multidisciplinary approach from surgery, medical oncology, and radiology with a discussion of the challenges faced within each setting.

Future directions for the early detection of recurrent breast cancer.

The main goal of follow-up care after breast cancer treatment is the early detection of disease recurrence. In this review, we emphasize the multidisciplinary approach to this continuity of care from surgery, medical oncology, and radiology. Challenges within each setting are briefly addressed as a means of discussion for the future directions of an effective and efficient surveillance plan of post-treatment breast cancer care.

Future directions for monitoring treatment responses in breast cancer.

In the prior review, we outlined the current standard of care for monitoring treatment responses in breast cancer and discussed the many challenges associated with these strategies. We described the challenges faced in common clinical settings such as the adjuvant setting, neoadjuvant setting, and the metastatic setting. In this review, we will expand upon future directions meant to overcome several of these current challenges. We will also explore several new and promising methods under investigation to enhance how we monitor treatment responses in breast cancer. Furthermore, we will highlight several new technologies and techniques for monitoring breast cancer treatment in the adjuvant, neoadjuvant and metastatic setting.

Current approaches and challenges in monitoring treatment responses in breast cancer.

Monitoring response to treatment is a key element in the management of breast cancer that involves several different viewpoints from surgery, radiology, and medical oncology. In the adjuvant setting, appropriate surgical and pathological evaluation guides adjuvant treatment and follow up care focuses on detecting recurrent disease with the intention of improving long term survival. In the neoadjuvant setting, assessing response to chemotherapy prior to surgery to include evaluation for pathologic response can provide prognostic information to help guide follow up care. In the metastatic setting, for those undergoing treatment, it is crucial to determine responders versus non-responders in order to help guide treatment decisions. In this review, we present the current guidelines for monitoring treatment response in the adjuvant, neoadjuvant, and metastatic setting. In addition, we also discuss challenges that are faced in each setting.

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.

Drug-induced liver injury caused by the histrelin (Vantus) subcutaneous implant.

Drug-induced liver injury (DILI) is the leading cause of acute hepatic failure in the United States. Up to 13% of acute liver failure cases occur due to drugs other than acetaminophen. This clinical diagnosis, made after other causes of liver injury have been excluded, requires establishing a causal relationship between drug exposure and liver injury. The case of a patient with liver injury following a subcutaneous histrelin (Vantus) implant as therapy for advanced prostate cancer is presented.

Therapeutic breast cancer vaccines: a new strategy for early-stage disease.

Treatment of breast cancer in the adjuvant setting has changed rapidly over the last few years. In addition to improvements in chemotherapy, radiation, hormone manipulation, and surgery, immunotherapy has emerged as an effective adjunct for the treatment of breast cancer. Passive immunotherapeutic agents such as trastuzumab have been widely adopted as the standard of care for HER-2/neu overexpressing breast cancer. Vaccine therapy in the metastatic setting has yet to demonstrate clinical significance in a phase III testing. This may be due to the enhanced immunosuppressive effects demonstrated in the tumor microenvironment. Lack of co-stimulatory molecules, activation of the cytotoxic T-lymphocyte antigen-4 (CTLA-4), increased T regulatory cells as well as soluble immunosuppressive factors produced by the tumor contribute to the ineffectiveness of vaccine therapy. Based on these observations, there has been a shift towards treating patients with minimal residual disease and a high risk of relapse. In this adjuvant setting, immune mechanisms of tumor evasion are less formidable, and the use of vaccine therapy in these patients may offer a higher chance of clinical benefit. There are several different vaccine approaches, including the use of cell-based vaccines (autologous, allogeneic, or dendritic cell-based), tumor-associated peptide or protein vaccines, DNA vaccines, heat shock proteins, and recombinant technology using viral or bacterial vectors to enhance immunogenicity of vaccine preparations. This review summarizes principles involving vaccine formulation and antigen selection, followed by a brief synopsis of therapeutic vaccines given in the metastatic setting and possible reasons for their lack of efficacy. The current literature regarding vaccine development for the treatment of breast cancer in the adjuvant setting is also reviewed.

Resident run journal club: a model based on the adult learning theory.

BACKGROUND: Multiple formats of journal club exist but data is lacking regarding which model is most effective. Many residents are dissatisfied with their current format, which was the case at our institution. AIM: This article discusses a resident run model, residents' perceptions following its implementation, and recommendations for running a successful journal club. Practice points Journal club formats vary extensively without a clearly superior method. Defining goals is the first step to a successful journal club. Structured review instruments for articles enhance journal club. The presence of subspecialty staff may augment learning. Resident-run models of journal club can be successfully implemented. METHODS: A resident run model of journal club was developed based on Adult Learning Theory. A 30-question survey was created to assess residents' attitudes and satisfaction with the new model. RESULTS: All respondents preferred the new model compared to the old model. Residents reported the new model increased their medical knowledge (88%) and they were able to apply the methods learned in journal club to actual patients (82%). CONCLUSIONS: A resident run model of journal club may be a viable option for those attempting to start or improve their current club.

Presence and treatment of air hunger in severely ill patients.

Air hunger at end-of-life poses challenges to providers who attempt to comfort while not diminishing mental capacities. We examined the presence, methods of assessment, and treatment of air hunger. This observational study prospectively screened 198 consecutive medicine admissions for increased risk of near-term death. These patients in turn were screened for dyspnea. Patients screening positive were assessed on admission and the next day with the Visual Analog Scale (VAS), modified Borg Scale, and the American Thoracic Society (ATS) Shortness of Breath Scale. Additionally, resident physician opinions of patient dyspnea level were assessed using the same tools. Treatments focused on alleviating air hunger were recorded. Thirty-nine percent of patients were at risk for near-term death and of these, 53% (95% CI: 41-65%) reported air hunger. All dyspnea scales improved to a statistically and clinically significant degree (Borg p=0.007, VAS p<0.0005, ATS p=0.008). There was statistically significant agreement between Borg-VAS and between Borg-ATS with a trend toward significance with ATS-VAS. Physician assessment of dyspnea showed poor agreement with patients. A median of three treatments were received by patients but dyspnea improvement did not correlate with the type, number, or specific combination of therapies. Dyspnea is common near end-of-life. Borg or VAS scales appear useful in assessing terminal dyspnea and can be employed in assessing terminal air hunger. No individual treatment or combination of treatments significantly improved patients' dyspnea. However, air hunger significantly improved with hospitalization.

Optical density values correlate with the clinical probability of heparin induced thrombocytopenia.

INTRODUCTION: Heparin induced thrombocytopenia is a clinicopathologic syndrome that may result in severe thrombotic sequelae without prompt diagnosis and treatment. A clinical scoring system to assess the pre-test probability of heparin-induced thrombocytopenia, the 4 T's, has been reported to correlate with the serotonin release assay. MATERIALS AND METHODS: We performed a single-center, retrospective study correlating the 4 T's score with the commercial heparin-PF4 ELISA. RESULTS: One hundred forty four cases were identified. The pre-test probability scores were: low probability 45.8%, moderate probability 41.0% and high probability 13.2%. The median optical density was 0.148, 0.223 and 0.470 for low probability, moderate probability and high probability, respectively (P < 0.0005). The frequencies of obtaining an optical density>1.00 for these probability scores were 1.5%, 6.8%, and 36.8%, respectively (P < 0.0005). CONCLUSIONS: Heparin-PF4 ELISA optical density values increase with increasing probability of heparin induced thrombocytopenia.

Case management study Walter Reed Army Medical Center. A 37-year-old soldier with right flank pain.

The objective of this study was to discuss the appropriate diagnostic and treatment approach to an active duty patient presenting with recurrent kidney stones. A 37-year-old active duty infantryman, stationed in Iraq, was evacuated by air to Waiter Reed Army Medical Center for workup of recurrent kidney stones and hypercalcemia. A diagnosis was made and the definitive treatment was performed. During this report, we will illustrate the various aspects of diagnosis that are involved with the workup of kidney stones and hypercalcemia as well as discuss the available treatment options. Relevant military issues include proceeding with the initial management regimen and recognition of appropriate reasons for initiation of referral consultation.

Treatment of excessive anticoagulation with phytonadione (vitamin K): a meta-analysis.

BACKGROUND: Patients taking oral anticoagulants with an international normalized ratio (INR) greater than 4.0 are at increased risk for bleeding. We performed a meta-analysis to determine the effectiveness of phytonadione (vitamin K) in treating excessive anticoagulation. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched (without language restrictions) for articles published between January 1985 and September 2004. Randomized controlled trials or prospective, nonrandomized trials that used vitamin K to treat patients without major hemorrhage with an INR greater than 4.0 due to oral anticoagulant use were included. The primary outcome was achievement of the target INR (1.8-4.0) at 24 hours after vitamin K administration. Summary estimates were calculated using a random effects model. RESULTS: Twenty-one studies (10 randomized and 11 prospective trials) were included. Among oral vitamin K treatment arms (4, n = 75), the proportion with a target INR at 24 hours was 82% (95% confidence interval [CI], 70%-93%), which was similar to intravenous vitamin K treatment arms (6, n = 69; target INR, 77%; 95% CI, 60%-95%). Treatment arms of subcutaneous vitamin K (3, n = 58; 31%; 95% CI, 7%-55%) and placebo/observation (2, n = 27; 20%; 95% CI, 0%-47%) were less likely to achieve target INR at 24 hours. Only 1 of 21 trials appropriately assessed for adverse events, so a summary estimate for bleeding risk could not be generated. CONCLUSIONS: Limited evidence suggests that oral and intravenous vitamin K are equivalent and more effective for excessive anticoagulation than simply withholding warfarin sodium. Subcutaneous vitamin K, however, is inferior to oral and intravenous vitamin K for this indication and is similar to placebo. Whether treatment with vitamin K decreases hemorrhagic events cannot be determined from the published literature.