Perspective on reducing errors in research.

Efforts to ensure research integrity has mostly focused on research misconduct. However, the complexity of research operations and processes makes research work also prone to unintentional errors. To safeguard against errors and their consequences, strategies for error reduction, detection, and mitigation can be applied to research work. Nurturing a scientific culture that encourages error disclosure and rectification is essential to reduce the negative consequences of errors. Creating repositories where errors can be reported can enable learning from errors and creation of more robust research processes.

Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation.

BACKGROUND: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation. METHODS: We developed and optimized a DNA vaccine platform to target multiple neoantigens. The polyepitope DNA vaccine platform was first optimized using model antigens in vitro and in vivo. We then identified neoantigens in preclinical breast cancer models through genome sequencing and in silico neoantigen prediction pipelines. Optimized polyepitope neoantigen DNA vaccines specific for the murine breast tumor E0771 and 4T1 were designed and their immunogenicity was tested in vivo. We also tested an optimized polyepitope neoantigen DNA vaccine in a patient with metastatic pancreatic neuroendocrine tumor. RESULTS: Our data support an optimized polyepitope neoantigen DNA vaccine design encoding long (≥20-mer) epitopes with a mutant form of ubiquitin (Ubmut) fused to the N-terminus for antigen processing and presentation. Optimized polyepitope neoantigen DNA vaccines were immunogenic and generated robust neoantigen-specific immune responses in mice. The magnitude of immune responses generated by optimized polyepitope neoantigen DNA vaccines was similar to that of synthetic long peptide vaccines specific for the same neoantigens. When combined with immune checkpoint blockade therapy, optimized polyepitope neoantigen DNA vaccines were capable of inducing antitumor immunity in preclinical models. Immune monitoring data suggest that optimized polyepitope neoantigen DNA vaccines are capable of inducing neoantigen-specific T cell responses in a patient with metastatic pancreatic neuroendocrine tumor. CONCLUSIONS: We have developed and optimized a novel polyepitope neoantigen DNA vaccine platform that can target multiple neoantigens and induce antitumor immune responses in preclinical models and neoantigen-specific responses in clinical translation.

Effect of a Hospital-Initiated Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Patients Hospitalized With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

Importance: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life. Objective: To evaluate whether a hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers can improve outcomes. Design, Setting, and Participants: Single-site randomized clinical trial conducted in Baltimore, Maryland, with 240 participants. Participants were patients hospitalized due to COPD, randomized to intervention or usual care, and followed up for 6 months after hospital discharge. Enrollment occurred from March 2015 to May 2016; follow-up ended in December 2016. Interventions: The intervention (n = 120) involved a comprehensive 3-month program to help patients and their family caregivers with long-term self-management of COPD. It was delivered by nurses with special training on supporting patients with COPD using standardized tools. Usual care (n = 120) included transition support for 30 days after discharge to ensure adherence to discharge plan and connection to outpatient care. Main Outcomes and Measures: The primary outcome was number of COPD-related acute care events (hospitalizations and emergency department visits) per participant at 6 months. The co-primary outcome was change in participants' health-related quality of life measured by the St George's Respiratory Questionnaire (SGRQ) at 6 months after discharge (score, 0 [best] to 100 [worst]; 4-point difference is clinically meaningful). Results: Among 240 patients who were randomized (mean [SD] age, 64.9 [9.8] years; 61.7% women), 203 (85%) completed the study. The mean (SD) baseline SGRQ score was 62.3 (18.8) in the intervention group and 63.6 (17.4) in the usual care group. The mean number of COPD-related acute care events per participant at 6 months was 1.40 (95% CI, 1.01-1.79) in the intervention group vs 0.72 (95% CI, 0.45-0.97) in the usual care group (difference, 0.68 [95% CI, 0.22-1.15]; P = .004). The mean change in participants' SGRQ total score at 6 months was 2.81 in the intervention group and -2.69 in the usual care group (adjusted difference, 5.18 [95% CI, -2.15 to 12.51]; P = .11). During the study period, there were 15 deaths (intervention: 8; usual care: 7) and 339 hospitalizations (intervention: 202; usual care: 137). Conclusions and Relevance: In a single-site randomized clinical trial of patients hospitalized due to COPD, a 3-month program that combined transition and long-term self-management support resulted in significantly greater COPD-related hospitalizations and emergency department visits, without improvement in quality of life. Further research is needed to determine reasons for this unanticipated finding. Trial Registration: ClinicalTrials.gov Identifier: NCT02036294.

Effect of a Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Hospitalized Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.

Importance: Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life. Objective: To evaluate a hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers. Design, Setting, and Participants: This single-site randomized clinical trial was conducted in Baltimore, Maryland, with 240 participants. Participants were patients hospitalized due to COPD, randomized to intervention or usual care, and followed up for 6 months after hospital discharge. Enrollment occurred from March 2015 to May 2016; follow-up ended in December 2016. Interventions: The intervention (n = 120) was a comprehensive 3-month program to help patients and their family caregivers with long-term self-management of COPD. It was delivered by COPD nurses (nurses with special training on supporting patients with COPD using standardized tools). Usual care (n = 120) included transition support for 30 days after discharge to ensure adherence to discharge plan and connection to outpatient care. Main Outcomes and Measures: The primary outcome was number of COPD-related acute care events (hospitalizations and emergency department visits) per participant at 6 months. The co-primary outcome was change in participants' health-related quality of life measured by the St George's Respiratory Questionnaire (SGRQ) at 6 months after discharge (score, 0 [best] to 100 [worst]; 4-point difference is clinically meaningful). Results: Among 240 patients who were randomized (mean [SD] age, 64.9 [9.8] years; females, 61.7%), 203 (85%) completed the study. The mean (SD) baseline SGRQ score was 63.1 (19.9) in the intervention group and 62.6 (19.3) in the usual care group. The mean number of COPD-related acute care events per participant at 6 months was 0.72 (95% CI, 0.45-0.97) in the intervention group vs 1.40 (95% CI, 1.01-1.79) in the usual care group (difference, 0.68 [95% CI, 0.22 to 1.15]; P = .004). The mean change in participants' SGRQ total score at 6 months was -1.53 in the intervention and +5.44 in the usual care group (adjusted difference, -6.69 [95% CI, -12.97 to -0.40]; P = .04). During the study period, there were 15 deaths (intervention: 7; usual care: 8) and 337 hospitalizations (intervention: 135; usual care: 202). Conclusions and Relevance: In a single-site randomized clinical trial of patients hospitalized due to COPD, a 3-month program that combined transition and long-term self-management support resulted in significantly fewer COPD-related hospitalizations and emergency department visits and better health-related quality of life at 6 months after discharge. Further research is needed to evaluate this intervention in other settings. Trial Registration: ClinicalTrials.gov Identifier: NCT02036294.

A Rare Adrenal Incidentaloma That Mimics Adrenocortical Carcinoma.

OBJECTIVE: We present a case of an adrenal hemangioma, an uncommon cause of an adrenal mass, and review the clinical presentation, work-up, and management of adrenal incidentalomas. BACKGROUND: A 64-year-old male was found to have a right adrenal incidentaloma during work-up for elevated liver transaminase levels, later found to be from hepatitis C. The mass was suspicious for adrenocortical carcinoma on CT imaging. Biochemical evaluation revealed no evidence of function. He underwent an open right adrenalectomy. The mass was found to be an adrenal hemangioma on histopathologic analysis. METHODS: This is a case report with pertinent review of the diagnosis and management of adrenal incidentalomas. RESULTS: Adrenal hemangiomas are rare, benign, nonfunctional tumors typically found during imaging for other reasons. As illustrated by this case, they appear similar to adrenocortical carcinoma on CT imaging. The diagnosis is usually not made prior to surgical resection. CONCLUSION: Adrenal hemangioma is a rare nonfunctional adrenal incidentaloma that displays atypical features on CT imaging. The suspicion for adrenocortical carcinoma usually prompts adrenalectomy.

Development of an adenovirus vector vaccine platform for targeting dendritic cells.

Adenoviral (Ad) vector vaccines represent one of the most promising modern vaccine platforms, and Ad vector vaccines are currently being investigated in human clinical trials for infectious disease and cancer. Our studies have shown that specific targeting of adenovirus to dendritic cells dramatically enhanced vaccine efficacy. However, this was achieved using a molecular adapter, thereby necessitating a two component vector approach. To address the mandates of clinical translation of our strategy, we here sought to accomplish the goal of DC targeting with a single-component adenovirus vector approach. To redirect the specificity of Ad vector vaccines, we replaced the Ad fiber knob with fiber-fibritin chimeras fused to DC1.8, a single-domain antibody (sdAb) specific for murine immature DC. We engineered a fiber-fibritin-sdAb chimeric molecule using the coding sequence for DC1.8, and then replaced the native Ad5 fiber knob sequence by homologous recombination. The resulting Ad5 virus, Ad5FF1.8, expresses the chimeric fiber-fibritin sdAb chimera. Infection with Ad5FF1.8 dramatically enhances transgene expression in DC2.4 dendritic cells compared with infection with native Ad5. Ad5FF1.8 infection of bone marrow-derived DC demonstrates that Ad5FF1.8 selectively infects immature DC consistent with the known specificity of DC1.8. Thus, sdAb can be used to selectively redirect the tropism of Ad5 vector vaccines, providing the opportunity to engineer Ad vector vaccines that are specifically targeted to DC, or specific DC subsets.

Mammaglobin-A is a target for breast cancer vaccination.

We recently completed a phase 1 clinical trial demonstrating the safety of a mammaglobin-A DNA vaccine in patients with metastatic breast cancer. We are currently enrolling patients with early stage breast cancer in a phase 1b clinical trial. The mammaglobin-A DNA vaccine will be administered concurrently with neoadjuvant endocrine therapy, providing a unique opportunity to examine the impact of vaccination in the tumor microenvironment.