Phase 2 trial of a DNA vaccine (pTVG-HP) and nivolumab in patients with castration-sensitive non-metastatic (M0) prostate cancer.

PURPOSE: We have previously reported that a plasmid DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) had greater clinical activity when given in combination with pembrolizumab to patients with metastatic, castration-resistant prostate cancer. The current trial was conducted to evaluate vaccination with PD-1 blockade, using nivolumab, in patients with early, recurrent (M0) prostate cancer. METHODS: Patients with M0 prostate cancer were treated with pTVG-HP (100 µg administered intradermally) and nivolumab (240 mg intravenous infusion) every 2 weeks for 3 months, and then every 4 weeks for 1 year of total treatment. Patients were then followed for an additional year off treatment. The primary objectives were safety and complete prostate-specific antigen (PSA) response (PSA<0.2 ng/mL). RESULTS: 19 patients were enrolled. No patients met the primary endpoint of complete PSA response; however, 4/19 (21%) patients had a PSA decline >50%. Median PSA doubling times were 5.9 months pretreatment, 25.6 months on-treatment (p=0.001), and 9.0 months in the subsequent year off-treatment. The overall median radiographic progression-free survival was not reached. Grade 3 or 4 events included adrenal insufficiency, fatigue, lymphopenia, and increased amylase/lipase. 9/19 (47%) patients developed immune-related adverse effects (irAE). The development of irAE and increased CXCL9 were associated with increased PSA doubling time. Quantitative NaF PET/CT imaging showed the resolution of subclinical lesions along with the development of new lesions at each time point. CONCLUSIONS: In this population, combining nivolumab with pTVG-HP vaccination was safe, and immunologically active, prolonged the time to disease progression, but did not eradicate disease. Quantitative imaging suggested that additional treatments targeting mechanisms of resistance may be required to eliminate tumors. TRIAL REGISTRATION NUMBER: NCT03600350.

Analysis of statements in documents of gift for academic body donation programs in the United States, and recommendations for future practice.

In US anatomical gift law, the record on which a person consents to body donation after death is referred to as a document of gift (DG). Due to the lack of legal requirements around minimum information standards, enacted recommendations in the United States, and the unknown variation across extant DGs, a review of publicly-available DGs from US academic body donation programs were performed to benchmark existing statements and recommend specific foundational content for all US DGs. From 117 body donor programs identified, 93 DGs were downloaded (median length three pages, range 1-20). Statements within the DG were qualitatively categorized into 60 codes within eight themes (Communication, Eligibility, Terms of Use, Logistics, Legal References, Financials, Final Disposition, and Signatures), using existing recommendations of academics, ethicists, and professional associations to guide analysis. Of 60 codes, 12 had high disclosure rates (67%-100% of DGs included; e.g., donor personal information), 22 had moderate rates (34%-66%; e.g., discretion to decline a body), and 26 had low disclosure rates (1%-33%; e.g., testing bodies for disease). Some codes with the lowest disclosure frequency were those previously recommended as necessary. Findings highlighted substantial variation in DG statements, with a higher number of baseline disclosure statements than previously recommended. These results present an opportunity to better understand disclosures that have importance for programs and donors alike. Recommendations suggest minimum standards of informed consent practices for body donation programs in the United States. These include clarity around consent processes, consistency of language, and minimum operational standards for informed consent.

Flexible, short-duration outreach sessions in the human anatomy laboratory provide authentic, humanistic experiences.

Anatomy laboratories can provide rich opportunities for outreach to K-12 and college students interested in pursuing careers in health, medicine, or science. At the University of Missouri, the Department of Pathology and Anatomical Sciences has designed flexible, one-hour interactive sessions that typically cover basic anatomical concepts using whole-body donors. In order to evaluate whether short-duration programs were impactful in increasing enthusiasm for anatomy and the health professions sciences, we used mixed methods to study participant experience covering three topics: (1) enthusiasm for anatomy, (2) interest in pursuing a career in healthcare professions, and (3) perception of the importance of whole-body donation. The same questions were asked pre- and post-session, and the post-session survey had additional questions related to student satisfaction. Quantitative analyses showed an increased interest in anatomy and appreciation for whole-body donation following the session. Students also perceived that they had a better understanding of the body and what it would be like to attend a health professions school. Thematic analysis revealed an appreciation for contextualizing the size, position, and hands-on feel of anatomical structures, and emphasized that students felt that they understood the body better after having seen a donor's anatomy. This work shows that short-duration, flexible outreach sessions involving whole-body donors can provide students with a rare opportunity to confirm their contextual understanding of anatomy, and provide students with an authentic, and humanistic experience.

Phase 2 trial of T-cell activation using MVI-816 and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC).

BACKGROUND: We previously reported a trial using a DNA vaccine encoding prostatic acid phosphatase (MVI-816, pTVG-HP), given over 12 weeks concurrently or sequentially with pembrolizumab, in patients with mCRPC. We report the final analysis of this trial following two additional treatment arms in which patients with mCRPC continued concurrent treatment until progression. MATERIALS AND METHODS: Patients with mCRPC were treated with MVI-816 and pembrolizumab every 3 weeks (arm 3, n=20) or MVI-816 every 2 weeks and pembrolizumab every 4 weeks (arm 4, n=20). The primary objectives were safety, 6-month progression-free survival (PFS), median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations. RESULTS: In 25 patients with measurable disease, there were no complete response and one confirmed partial response in a patient who subsequently found to have an MSIhi tumor. 4/40 patients (10%) had a prostate-specific antigen decline >50%. The estimated overall radiographic PFS rate at 6 months was 47.2% (44.4% arm 3, 61.5% arm 4). Accounting for all off-study events, overall median time on treatment was 5.6 months (95% CI: 5.4 to 10.8 months), 5.6 months for arm 3 and 8.1 months for arm 4 (p=0.64). Thirty-two per cent of patients remained on trial beyond 6 months without progression. Median overall survival was 22.9 (95% CI: 16.2 to 25.6) months. One grade 4 event (hyperglycemia) was observed. Immune-related adverse events (irAEs) >grade 1 were observed in 42% of patients overall. Interferon-γ and/or granzyme B immune response to prostatic acid phosphatase was detected in 2/20 patients in arm 3 and 6/20 patients in arm 4. Plasma cytokines associated with immune activation and CD8+ T-cell recruitment were augmented at weeks 6 and 12. The development of irAE was significantly associated with a prolonged time on treatment (HR=0.42, p=0.003). Baseline DNA homologous recombination repair mutations were not associated with longer time to progression. CONCLUSIONS: Findings here demonstrate that combining programmed cell death 1 blockade with MVI-816 is safe, can augment tumor-specific T cells, and can result in a favorable 6-month disease control rate. Correlative studies suggest T-cell activation by vaccination is critical to the mechanism of action of this combination. Future randomized clinical trials are needed to validate these findings. TRIAL REGISTRATION NUMBER: NCT02499835.

Treatment Combinations with DNA Vaccines for the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC).

Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease to treat, with poor outcomes for patients. One antitumor vaccine, sipuleucel-T, has been approved as a treatment for mCRPC. DNA vaccines are another form of immunotherapy under investigation. DNA immunizations elicit antigen-specific T cells that cause tumor cell lysis, which should translate to meaningful clinical responses. They are easily amenable to design alterations, scalable for large-scale manufacturing, and thermo-stable for easy transport and distribution. Hence, they offer advantages over other vaccine formulations. However, clinical trials with DNA vaccines as a monotherapy have shown only modest clinical effects against tumors. Standard therapies for CRPC including androgen-targeted therapies, radiation therapy and chemotherapy all have immunomodulatory effects, which combined with immunotherapies such as DNA vaccines, could potentially improve treatment. In addition, many investigational drugs are being developed which can augment antitumor immunity, and together with DNA vaccines can further enhance antitumor responses in preclinical models. We reviewed the literature available prior to July 2020 exploring the use of DNA vaccines in the treatment of prostate cancer. We also examined various approved and experimental therapies that could be combined with DNA vaccines to potentially improve their antitumor efficacy as treatments for mCRPC.

Increased indoleamine 2,3-dioxygenase activity and expression in prostate cancer following targeted immunotherapy.

BACKGROUND: We previously found that PD-L1 expression is increased on tumor cells following vaccination treatments that lead to increased tumor-specific T cells that secrete IFNγ. Indoleamine 2,3-dioxygenase (IDO) is another IFNγ inducible gene that has potent immunosuppressive effects. There have been reports of IDO expression in prostate cancer; however, it is unknown whether IDO expression might similarly increase in prostate tumors following T-cell-based immunotherapy. METHODS: Blood samples from normal male blood donors (n = 12) and patients with different stages of prostate cancer (n = 89), including patients with metastatic, castration-resistant prostate cancer treated with a DNA vaccine and/or pembrolizumab, were evaluated for IDO activity by kynurenine and tryptophan levels. Metastatic tissue biopsies obtained pre- and post-treatments were evaluated for IDO expression. IDO suppression of vaccine-induced T-cell function was assessed by ELISPOT. RESULTS: Overall, IDO activity was increased in patients with more advanced prostate cancer. This activity, and IDO expression as detected immunohistochemically, increased following treatment with either a DNA vaccine encoding the prostatic acid phosphatase (PAP) tumor antigen or PD-1 blockade with pembrolizumab. Increased IDO activity after treatment was associated with the absence of clinical effect, as assessed by lack of PSA decline following treatment. Increased antigen-specific T-cell response, as measured by IFNγ release, to the vaccine target antigen was detected following in vitro stimulation of peripheral blood cells with 1-methyltryptophan. CONCLUSIONS: These findings suggest that IDO expression is a mechanism of immune evasion used by prostate cancer and that future clinical trials using T-cell-based immune strategies might best include IDO inhibition.

Phase II Trial of a DNA Vaccine Encoding Prostatic Acid Phosphatase (pTVG-HP [MVI-816]) in Patients With Progressive, Nonmetastatic, Castration-Sensitive Prostate Cancer.

PURPOSE: We previously reported the safety and immunologic effects of a DNA vaccine (pTVG-HP [MVI-816]) encoding prostatic acid phosphatase (PAP) in patients with recurrent, nonmetastatic prostate cancer. The current trial evaluated the effects of this vaccine on metastatic progression. PATIENTS AND METHODS: Ninety-nine patients with castration-sensitive prostate cancer and prostate-specific antigen (PSA) doubling time (DT) of less than 12 months were randomly assigned to treatment with either pTVG-HP co-administered intradermally with 200 µg granulocyte-macrophage colony-stimulating factor (GM-CSF) adjuvant or 200 µg GM-CSF alone six times at 14-day intervals and then quarterly for 2 years. The primary end point was 2-year metastasis-free survival (MFS). Secondary and exploratory end points were median MFS, changes in PSA DT, immunologic effects, and changes in quantitative 18F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) imaging. RESULTS: Two-year MFS was not different between study arms (41.8% vaccine v 42.3%; P = .97). Changes in PSA DT and median MFS were not different between study arms (18.9 v 18.3 months; hazard ratio [HR], 1.6; P = .13). Preplanned subset analysis identified longer MFS in vaccine-treated patients with rapid (< 3 months) pretreatment PSA DT (12.0 v 6.1 months; n = 21; HR, 4.4; P = .03). PAP-specific T cells were detected in both cohorts, including multifunctional PAP-specific T-helper 1-biased T cells. Changes in total activity (total standardized uptake value) on 18F-NaF PET/CT from months 3 to 6 increased 50% in patients treated with GM-CSF alone and decreased 23% in patients treated with pTVG-HP (n = 31; P = .07). CONCLUSION: pTVG-HP treatment did not demonstrate an overall increase in 2-year MFS in patients with castration-sensitive prostate cancer, with the possible exception of a subgroup with rapidly progressive disease. Prespecified 18F-NaF PET/CT imaging conducted in a subset of patients suggests that vaccination had detectable effects on micrometastatic bone disease. Additional trials using pTVG-HP in combination with PD-1 blockade are under way.

Pitch control and speed limitation during overground deceleration in lemurid primates.

An animal's fitness is influenced by the ability to move safely through its environment. Recent models have shown that aspects of body geometry, for example, limb length and center of mass (COM) position, appear to set limits for pitch control in cursorial quadrupeds. Models of pitch control predict that the body shape of these and certain other primates, with short forelimbs and posteriorly positioned COM, should allow them to decelerate rapidly while minimizing the risk of pitching forward. We chose to test these models in two non-cursorial lemurs: Lemur catta, the highly terrestrial ring-tailed lemur, and Eulemur fulvus, the highly arboreal brown lemur. We modeled the effects of changes in limb length and COM position on maximum decelerative potential for both species, as well as collecting data on maximal decelerations across whole strides. In both species, maximum measured decelerations fell below the range of pitch-limited deceleration values predicted by the geometric model, with the ring-tailed lemur approaching its pitch limit more closely. Both lemurs showed decelerative potential equivalent to or higher than horses, the only comparative model currently available. These data reinforce the hypothesis that a relatively simple model of body geometry can predict aspects of maximum performance in animals. In this case, it appears that the body geometry of primates is skewed toward avoiding forward pitch in maximal decelerations.

Heterologous vaccination targeting prostatic acid phosphatase (PAP) using DNA and Listeria vaccines elicits superior anti-tumor immunity dependent on CD4+ T cells elicited by DNA priming.

Background. Sipuleucel T, an autologous cell-based vaccine targeting prostatic acid phosphatase (PAP), has demonstrated efficacy for the treatment of advanced prostate cancer. DNA vaccines encoding PAP and live attenuated Listeria vaccines have entered clinical trials for patients with prostate cancer, and have advantages in terms of eliciting predominantly Th1-biased immunity. In this study, we investigated whether the immunogenicity and anti-tumor efficacy of a DNA and Listeria vaccine, each encoding PAP, could be enhanced by using them in a heterologous prime/boost approach. Methods. Transgenic mice expressing HLA-A2.01 and HLA-DRB1*0101 were immunized alone or with a heterologous prime/boost strategy. Splenocytes were evaluated for MHC class I and II-restricted, PAP-specific immune responses by IFNγ ELISPOTs. Anti-tumor activity to a syngeneic, PAP-expressing tumor line was evaluated. Results. PAP-specific cellular immunity and anti-tumor activity were elicited in mice after immunization with DNA- or listeria-based vaccines. Greater CD4+ and CD8+ responses, and anti-tumor responses, were elicited when mice were immunized first with DNA and boosted with Listeria, but not when administered in the opposite order. This was found to be dependent on CD4+ T cells elicited with DNA priming, and was not due to inflammatory signals by Listeria itself or due to B cells serving as antigen-presenting cells for DNA during priming. Conclusions. Heterologous prime/boost vaccination using DNA priming with Listeria boosting may provide better anti-tumor immunity, similar to many reports evaluating DNA priming with vaccines targeting foreign microbial antigens. These findings have implications for the design of future clinical trials.

Prime-boost vaccination targeting prostatic acid phosphatase (PAP) in patients with metastatic castration-resistant prostate cancer (mCRPC) using Sipuleucel-T and a DNA vaccine.

BACKGROUND: Prostatic acid phosphatase (PAP) is a prostate tumor antigen, and the target of the only FDA-approved anti-tumor vaccine, sipuleucel-T. We have previously reported in two clinical trials that a DNA vaccine encoding PAP (pTVG-HP) could elicit PAP-specific, Th1-biased T cells in patients with PSA-recurrent prostate cancer. In the current pilot trial we sought to evaluate whether this vaccine could augment PAP-specific immunity when used as a booster to immunization with sipuleucel-T in patients with metastatic, castration-resistant prostate cancer (mCRPC). METHODS: Eigthteen patients with mCRPC were randomized to receive sipuleucel-T alone or followed by intradermal immunization with pTVG-HP DNA vaccine. Patients were followed for time to progression, and immune monitoring was conducted at defined intervals. RESULTS: Overall, patients were followed for a median of 24 months. 11/18 patients completed treatments as per protocol. No treatment-associated events > grade 2 were observed. Th1-biased PAP-specific T-cell responses were detected in 11/18 individuals, and were not statistically different between study arms. Higher titer antibody responses to PAP were detectable in patients who received pTVG-HP booster immunizations. Median time to progression was less than 6 months and not statistically different between study arms. The median overall survival for all patients was 28 months. CONCLUSIONS: These findings suggest that prime-boost vaccination can augment and diversify the type of immunity elicited with anti-tumor vaccination in terms of T-cell and humoral immunity. Future studies will explore DNA as priming immunization rather than a booster immunization. TRIAL REGISTRATION: NCT01706458 .

Pretreatment antigen-specific immunity and regulation - association with subsequent immune response to anti-tumor DNA vaccination.

BACKGROUND: Immunotherapies have demonstrated clinical benefit for many types of cancers, however many patients do not respond, and treatment-related adverse effects can be severe. Hence many efforts are underway to identify treatment predictive biomarkers. We have reported the results of two phase I trials using a DNA vaccine encoding prostatic acid phosphatase (PAP) in patients with biochemically recurrent prostate cancer. In both trials, persistent PAP-specific Th1 immunity developed in some patients, and this was associated with favorable changes in serum PSA kinetics. In the current study, we sought to determine if measures of antigen-specific or antigen non-specific immunity were present prior to treatment, and associated with subsequent immune response, to identify possible predictive immune biomarkers. METHODS: Patients who developed persistent PAP-specific, IFNγ-secreting immune responses were defined as immune "responders." The frequency of peripheral T cell and B cell lymphocytes, natural killer cells, monocytes, dendritic cells, myeloid derived suppressor cells, and regulatory T cells were assessed by flow cytometry and clinical laboratory values. PAP-specific immune responses were evaluated by cytokine secretion in vitro, and by antigen-specific suppression of delayed-type hypersensitivity to a recall antigen in an in vivo SCID mouse model. RESULTS: The frequency of peripheral blood cell types did not differ between the immune responder and non-responder groups. Non-responder patients tended to have higher PAP-specific IL-10 production pre-vaccination (p = 0.09). Responder patients had greater preexisting PAP-specific bystander regulatory responses that suppressed DTH to a recall antigen (p = 0.016). CONCLUSIONS: While our study population was small (n = 38), these results suggest that different measures of antigen-specific tolerance or regulation might help predict immunological outcome from DNA vaccination. These will be prospectively evaluated in an ongoing randomized, phase II trial.

Trends of vaccine-preventable diseases in Afghanistan from the Disease Early Warning System, 2009-2015.

BACKGROUND: Afghanistan's public health system was neglected during decades of military and civil conflict, and trends in infectious disease occurrence remain poorly characterized. This study examines cyclical and long-term trends of six vaccine-preventable diseases: pneumonia, diarrhea, meningitis, typhoid, measles, and acute viral hepatitis. METHODS: Using weekly data collected between 2009 and 2015 through Afghanistan's Disease Early Warning System, we calculated monthly case counts, and fit a Poisson regression with a Fourier transformation for seasonal cycles and dummy variables for year. RESULTS: We found the greatest incidence of diarrhea and typhoid in the summer, pneumonia in the winter, and measles in the late spring. Meningitis and acute viral hepatitis did not demonstrate substantial seasonality. Rates of pneumonia and diarrhea were constant across years whereas rates of meningitis, typhoid, and acute viral hepatitis decreased. Measles incidence increased in 2015. CONCLUSIONS: Communicable disease reporting systems can guide public health operations-such as the implementation of new vaccines, and permit evaluation of health interventions. For example, measles supplementary immunization activities in Afghanistan have not slowed long-term transmission of the disease, but decreases in typhoid fever and acute viral hepatitis are probably tied to improvements in sanitation in the country.

Safety and Immunological Efficacy of a DNA Vaccine Encoding the Androgen Receptor Ligand-Binding Domain (AR-LBD).

BACKGROUND: The androgen receptor (AR) is a key oncogenic driver of prostate cancer, and has been the primary focus of prostate cancer treatment for several decades. We have previously demonstrated that the AR is also an immunological target antigen, recognized in patients with prostate cancer, and targetable by means of vaccines in rodent models with delays in prostate tumor growth. The current study was performed to determine the safety and immunological efficacy of a GMP-grade plasmid DNA vaccine encoding the ligand-binding domain (LBD) of the AR, pTVG-AR. METHODS: Groups of male mice (n = 6-10 per group) were evaluated after four or seven immunizations, using different schedules and inclusion of GM-CSF as a vaccine adjuvant. Animals were assessed for toxicity using gross observations, pathological analysis, and analysis of serum chemistries. Animals were analyzed for evidence of vaccine-augmented immunity by tetramer analysis. Survival studies using different immunization schedules and inclusion of GM-CSF were conducted in an autochthonous genetically engineered mouse model. RESULTS: No significant toxicities were observed in terms of animal weights, histopathology, hematological changes, or changes in serum chemistries, although there was a trend to lower serum glucose in animals treated with the vaccine. There was specifically no evidence of toxicity in other tissues that express AR, including liver, muscle, hematopoietic, and brain. Vaccination was found to elicit AR LBD-specific CD8+ T cells. In a subsequent study of tumor-bearing animals, animals treated with vaccine had prolonged survival compared with control-immunized mice. CONCLUSIONS: These studies demonstrate that, in immunocompetent mice expressing the target antigen, immunization with the pTVG-AR vaccine was both safe and effective in eliciting AR-specific cellular immune responses, and prolonged the survival of prostate tumor-bearing mice. These findings support the clinical evaluation of pTVG-AR in patients with recurrent prostate cancer. Prostate 77:812-821, 2017. © 2017 Wiley Periodicals, Inc.

Preclinical and clinical development of DNA vaccines for prostate cancer.

Prostate cancer is the most commonly diagnosed cancer in the United States. It is also the second leading cause of cancer-related death in men, making it one of the largest public health concerns today. Prostate cancer is an ideal disease for immunotherapies because of the generally slow progression, the dispensability of the target organ in the patient population, and the availability of several tissue-specific antigens. As such, several therapeutic vaccines have entered clinical trials, with one autologous cellular vaccine (sipuleucel-T) recently gaining Food and Drug Administration approval after demonstrating overall survival benefit in randomized phase III clinical trials. DNA-based vaccines are safe, economical, alternative "off-the-shelf" approaches that have undergone extensive evaluation in preclinical models. In fact, the first vaccine approved in the United States for the treatment of cancer was a DNA vaccine for canine melanoma. Several prostate cancer-specific DNA vaccines have been developed in the last decade and have shown promising results in early phase clinical trials. This review summarizes anticancer human DNA vaccine trials, with a focus on those conducted for prostate cancer. We conclude with an outline of special considerations important for the development and successful translation of DNA vaccines from the laboratory to the clinic.

Single-limb force data for two lemur species while vertically clinging.

OBJECTIVES: Vertical clinging and climbing have been integral to hypotheses about primate origins, yet little is known about how an animal with nails instead of claws resists gravity while on large, vertical, and cylindrical substrates. Here we test models of how force is applied to maintain posture, predicting (1) the shear component force (Fs ) at the hands will be higher than the feet; (2) the normal component force (Fn ) at the feet will be relatively high compared to the hands; (3) the component force resisting gravity (Fg ) at the feet will be relatively high compared to the hands; (4) species with a high frequency of vertical clinging postures will have low Fg at the hands due to relatively short forelimbs. MATERIALS AND METHODS: Using a novel instrumented support, single-limb force data were collected during clinging postures for the hands and feet and compared across limbs and species for Propithecus verreauxi (N = 2), a habitual vertical clinger and leaper, and Varecia variegata (N = 3), a habitual above-branch arboreal quadruped. RESULTS: For both species, hand Fs were significantly higher than at the feet and Fn and Fg at the feet were significantly higher than at the hands. Between species, P. verreauxi has relatively low Fg at the hands and Fn at the feet than V. vareigata. DISCUSSION: These results support previous models and show that hindlimb loading dominance, characteristic of primate locomotion, is found during clinging behaviors and may allow the forelimbs to be used for foraging while clinging. These findings provide insight into selective pressures on force distribution in primates and primate locomotor evolution.

Comparative effectiveness of two catheter locking solutions to reduce catheter-related bloodstream infection in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Infection is the second leading cause of death in hemodialysis patients. Catheter-related bloodstream infection and infection-related mortality have not improved in this population over the past two decades. This study evaluated the impact of a prophylactic antibiotic lock solution on the incidence of catheter-related bloodstream infection and mortality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective, multicenter, observational cohort study compared the effectiveness of two catheter locking solutions (gentamicin/citrate versus heparin) in 555 hemodialysis patients dialyzing with a tunneled cuffed catheter between 2008 and 2011. The groups were not mutually exclusive. Rates of catheter-related bloodstream infection and mortality hazards were compared between groups. RESULTS: The study population (n=555 and 1350 catheters) had a median age of 62 years (interquartile range=41-83 years), with 50% men and 71% black. There were 427 patients evaluable in the heparin period (84,326 days) and 322 patients evaluable in the antibiotic lock period (71,192 days). Catheter-related bloodstream infection in the antibiotic lock period (0.45/1000 catheter days) was 73% lower than the heparin period (1.68/1000 catheter days; P=0.001). Antibiotic lock use was associated with a decreased risk of catheter-related bloodstream infection compared with heparin (risk ratio, 0.23; 95% confidence interval, 0.13 to 0.38 after multivariate adjustment). Cox proportional hazards modeling found that antibiotic lock was associated with a reduction in mortality (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58 in unadjusted analyses; hazard ratio, 0.32; 95% confidence interval, 0.14 to 0.75 after multivariate adjustment). The rate of gentamicin-resistant organisms decreased (0.40/1000 person-years to 0.22/1000 person-years) in the antibiotic lock period (P=0.01). CONCLUSIONS: The results of this study show that the use of a prophylactic, gentamicin/citrate lock was associated with a substantial reduction in catheter-related bloodstream infection and is the first to report a survival advantage of antibiotic lock in a population at high risk of infection-related morbidity and mortality.

Real-time immune monitoring to guide plasmid DNA vaccination schedule targeting prostatic acid phosphatase in patients with castration-resistant prostate cancer.

PURPOSE: We have previously reported that a DNA vaccine encoding prostatic acid phosphatase (PAP) could elicit PAP-specific T cells in patients with early recurrent prostate cancer. In the current pilot trial, we sought to evaluate whether prolonged immunization with regular booster immunizations, or "personalized" schedules of immunization determined using real-time immune monitoring, could elicit persistent, antigen-specific T cells, and whether treatment was associated with changes in PSA doubling time (PSA DT). EXPERIMENTAL DESIGN: Sixteen patients with castration-resistant, nonmetastatic prostate cancer received six immunizations at 2-week intervals and then either quarterly (arm 1) or as determined by multiparameter immune monitoring (arm 2). RESULTS: Patients were on study a median of 16 months; four received 24 vaccinations. Only one event associated with treatment >grade 2 was observed. Six of 16 (38%) remained metastasis-free at 2 years. PAP-specific T cells were elicited in 12 of 16 (75%), predominantly of a Th1 phenotype, which persisted in frequency and phenotype for at least 1 year. IFNγ-secreting T-cell responses measured by ELISPOT were detectable in 5 of 13 individuals at 1 year, and this was not statistically different between study arms. The overall median fold change in PSA DT from pretreatment to posttreatment was 1.6 (range, 0.6-7.0; P = 0.036). CONCLUSIONS: Repetitive immunization with a plasmid DNA vaccine was safe and elicited Th1-biased antigen-specific T cells that persisted over time. Modifications in the immunization schedule based on real-time immune monitoring did not increase the frequency of patients developing effector and memory T-cell responses with this DNA vaccine.

Major variation in MICs of tigecycline in Gram-negative bacilli as a function of testing method.

Tigecycline is one of the few remaining therapeutic options for extensively drug-resistant (XDR) Gram-negative bacilli (GNB). MICs of tigecycline to Acinetobacter baumannii have been reported to be elevated when determined by the Etest compared to determinations by the broth microdilution (BMD) method. The study aim was to compare the susceptibility of GNB to tigecycline by four different testing methods. GNB were collected from six health care systems (25 hospitals) in southeast Michigan from January 2010 to September 2011. Tigecycline MICs among A. baumannii, carbapenem-resistant Enterobacteriaceae (CRE), extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae, and susceptible Enterobacteriaceae isolates were determined by Etest, BMD, Vitek-2, and MicroScan. Nonsusceptibility was categorized as a tigecycline MIC of ≥4 µg/ml for both A. baumannii and Enterobacteriaceae. The study included 4,427 isolates: 2,065 ESBL-producing Enterobacteriaceae, 1,105 A. baumannii, 888 susceptible Enterobacteriaceae, and 369 CRE isolates. Tigecycline nonsusceptibility among A. baumannii isolates was significantly more common as determined by Etest compared to that determined by BMD (odds ratio [OR], 10.3; P<0.001), MicroScan (OR, 12.4; P<0.001), or Vitek-2 (OR, 9.4; P<0.001). These differences were not evident with the other pathogens. Tigecycline MICs varied greatly according to the in vitro testing methods among A. baumannii isolates. Etest should probably not be used by laboratories for tigecycline MIC testing of A. baumannii isolates, since MICs are significantly elevated with Etest compared to those determined by the three other methods.

Contact precautions: more is not necessarily better.

OBJECTIVE: To determine whether increases in contact isolation precautions are associated with decreased adherence to isolation practices among healthcare workers (HCWs). DESIGN: Prospective cohort study from February 2009 to October 2009. SETTING: Eleven teaching hospitals. PARTICIPANTS: HCWs. METHODS: One thousand thirteen observations conducted on HCWs. Additional data included the number of persons in isolation, types of HCWs, and hospital-specific contact precaution practices. Main outcome measures included compliance with individual components of contact isolation precautions (hand hygiene before and after patient encounter, donning of gown and glove upon entering a patient room, and doffing upon exiting) and overall compliance (all 5 measures together) during varying burdens of isolation. RESULTS: Compliance with hand hygiene was as follows: prior to donning gowns/gloves, 37.2%; gowning, 74.3%; gloving, 80.1%; doffing of gowns/gloves, 80.1%; after gown/glove removal, 61%. Compliance with all components was 28.9%. As the burden of isolation increased (20% or less to greater than 60%), a decrease in compliance with hand hygiene (43.6%-4.9%) and with all 5 components (31.5%-6.5%) was observed. In multivariable analysis, there was an increase in noncompliance with all 5 components of the contact isolation precautions bundle (odds ratio [OR], 6.6 [95% confidence interval (CI), 1.15-37.44]; P = .03) and in noncompliance with hand hygiene prior to donning gowns and gloves (OR, 10.1 [95% CI, 1.84-55.54]; P = .008) associated with increasing burden of isolation. CONCLUSIONS: As the proportion of patients in contact isolation increases, compliance with contact isolation precautions decreases. Placing 40% of patients under contact precautions represents a tipping point for noncompliance with contact isolation precautions measures.