A Phase 1, Open-Label Assessment of a Dengue Virus-1 Live Virus Human Challenge Strain.

BACKGROUND: Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics. METHODS: A phase 1 study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months. RESULTS: Twelve subjects received the challenge virus: 6 with 0.5 mL of 6.5 × 103 plaque-forming units (PFU)/mL (low-dose group) and 6 with 0.5 mL of 6.5 × 104 PFU/mL (mid-dose group). All except 1 in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5-9 days) and mean time of viremia was 6.8 days (range 3-9 days). Mean peak for all subjects was 1.6 × 107 genome equivalents (GE)/mL (range 4.6 × 103 to 5 × 107 GE/mL). There were no serious adverse events or long-term safety signals noted. CONCLUSIONS: We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing. CLINICAL TRIALS REGISTRATION: NCT02372175.

Next steps for adolescent and young adult oncology workshop: An update on progress and recommendations for the future.

Each year, 70,000 adolescents and young adults (AYAs) between ages 15 and 39 years in the United States are diagnosed with cancer. In 2006, a National Cancer Institute (NCI) Progress Review Group (PRG) examined the state of science associated with cancer among AYAs. To assess the impact of the PRG and examine the current state of AYA oncology research, the NCI, with support from the LIVESTRONG Foundation, sponsored a workshop entitled "Next Steps in Adolescent and Young Adult Oncology" on September 16 and 17, 2013, in Bethesda, Maryland. This report summarizes the findings from the workshop, opportunities to leverage existing data, and suggestions for future research priorities. Multidisciplinary teams that include basic scientists, epidemiologists, trialists, biostatisticians, clinicians, behavioral scientists, and health services researchers will be essential for future advances for AYAs with cancer.

Biologic and clinical characteristics of adolescent and young adult cancers: Acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma.

Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled "Next Steps in Adolescent and Young Adult Oncology" summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are whether there are mutational or signaling pathway differences (for example, between adult and AYA colorectal cancer) that can be clinically exploited to develop novel therapies for treating AYA cancers and to develop companion diagnostics.

Preemptive antiretroviral therapy modifications for the management of potential clinically significant drug interactions with direct acting hepatitis C therapies.

We report a case series of HIV/HCV co-infected patients who underwent preemptive antiretroviral therapy modifications to manage clinically significant drug interactions with HCV therapy. Among the 15 patients reviewed, all changed to a raltegravir-based regimen and none experienced a loss of virologic suppression or increase in HIV-RNA.

From genotype to phenotype: Are there imaging characteristics associated with lung adenocarcinomas harboring RET and ROS1 rearrangements?

INTRODUCTION: Recurrent gene rearrangements are important drivers of oncogenesis in non-small cell lung cancers. RET and ROS1 rearrangements are each found in 1-2% of lung adenocarcinomas and represent distinct molecular subsets. This study assessed the computed tomography (CT) imaging features of patients with RET- and ROS1-rearranged lung cancers. METHODS: Eligible patients included pathologically-confirmed lung adenocarcinomas of any stage with a RET or ROS1 rearrangement via fluorescence in-situ hybridization or next-generation sequencing, and available pre-treatment baseline imaging for review. A cohort of EGFR-mutant lung cancers was identified as a control group. CT features assessed included location, consistency, contour, presence of cavitation, and calcification of the primary tumor. Presence of an effusion, lung metastases, adenopathy and extrathoracic disease were recorded. The Wilcoxon rank-sum/Kruskal-Wallis and Fisher's exact tests were used to compare features between groups. RESULTS: 73 patients with lung adenocarcinomas were identified: 17 (23%) with ROS1 fusions, 25 (34%) with RET fusions and 31 (43%) with EGFR mutations. ROS1-rearranged lung cancers were more likely to present as peripheral tumors in comparison to EGFR-mutant lung cancers (32% vs. 65%, p=0.04). RET-rearranged lung cancers did not significantly differ from EGFR-mutant lung cancers radiographically. The consistency of the primary lesion for RET and ROS fusions and EGFR mutations were most frequently solid and spiculated. CONCLUSIONS: Lung adenocarcinomas with RET and ROS1 fusions share many radiographic features and those with ROS1 fusions are more likely to present as peripheral lesions in comparison to EGFR-mutant lung cancers.

Novel Poxvirus Infection in an Immune Suppressed Patient.

BACKGROUND: Human and animal poxvirus infections are being reported with increasing frequency. We describe a challenging case history and treatment of a previously unknown poxvirus rash illness in a renal transplant patient. METHODS: A combination of classical microbiology techniques, including viral culture and electron microscopy, were used to provide initial clinical diagnosis. Subsequent standard polymerase chain reaction assays available in 2001 were noncontributory. Next generation sequencing was used to provide definitive diagnosis. RESULTS: Retrospectively, next generation sequencing methods were used to ultimately provide the definitive diagnosis of a novel poxvirus infection initially identified by electron microscopy. The closest relative of this poxvirus, identified in North America, is a poxvirus collected from a mosquito pool from Central Africa in 1972. CONCLUSIONS: This diagnostic quandary was ultimately solved using next generation DNA sequencing. This article describes the use of classical and next generation diagnostic strategies to identify etiologic agents of emerging infectious diseases and once again demonstrates the susceptibility of immunossupressed patients to novel pathogens. The virus identified is closely related to Yoka virus; these viruses appear to have independently diverged from a common ancestor of all known orthopoxviruses.

The tale of infective endocarditis: fatal then curable but rarely preventable.

The story of infective endocarditis (IE) is a miracle of medical progress. In retrospect, it seems as a logical and orderly progression of remarkable events leading to the nearly complete conquest of the disease. IE was almost uniformly fatal until the 1st cures by surgery, followed by frequent cures with antibiotics, further improved when combined with valve surgery. Most recently, it has become almost a new disease with a change in the offending organisms, a change in the type of afflicted patients and the infection of implanted medical devices. Despite therapeutic success, prevention of IE has been elusive. In this review, the authors tell the story by highlighting major events, illustrating interconnections among branches of science that brought the authors to their present state and describing some well-known patients. For this summary, the authors are indebted to the more detailed descriptions of the IE history readily available for interested readers.

Imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

OBJECTIVE: The objective of the study was to describe the imaging appearances of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) on computed tomography (CT). MATERIALS AND METHODS: Electronic medical records were searched for patients with pathology-proven DIPNECH who had a CT available for review. Eleven patients were included. RESULTS: The most common finding on CT was small pulmonary nodules which were present in all patients and were multiple (≥5) in 7/11 patients. Other CT findings included mosaic pattern attenuation and bronchial wall thickening/bronchiectasis. CONCLUSION: DIPNECH should be considered as a diagnostic possibility when multiple small pulmonary nodules are identified on CT, particularly if there is an associated carcinoid tumor.

A mouse strain defective in both T cells and NK cells has enhanced sensitivity to tumor induction by plasmid DNA expressing both activated H-Ras and c-Myc.

As part of safety studies to evaluate the risk of residual cellular DNA in vaccines manufactured in tumorigenic cells, we have been developing in vivo assays to detect and quantify the oncogenic activity of DNA. We generated a plasmid expressing both an activated human H-ras gene and murine c-myc gene and showed that 1 µg of this plasmid, pMSV-T24-H-ras/MSV-c-myc, was capable of inducing tumors in newborn NIH Swiss mice. However, to be able to detect the oncogenicity of dominant activated oncogenes in cellular DNA, a more sensitive system was needed. In this paper, we demonstrate that the newborn CD3 epsilon transgenic mouse, which is defective in both T-cell and NK-cell functions, can detect the oncogenic activity of 25 ng of the circular form of pMSV-T24-H-ras/MSV-c-myc. When this plasmid was inoculated as linear DNA, amounts of DNA as low as 800 pg were capable of inducing tumors. Animals were found that had multiple tumors, and these tumors were independent and likely clonal. These results demonstrate that the newborn CD3 epsilon mouse is highly sensitive for the detection of oncogenic activity of DNA. To determine whether it can detect the oncogenic activity of cellular DNA derived from four human tumor-cell lines (HeLa, A549, HT-1080, and CEM), DNA (100 µg) was inoculated into newborn CD3 epsilon mice both in the presence of 1 µg of linear pMSV-T24-H-ras/MSV-c-myc as positive control and in its absence. While tumors were induced in 100% of mice with the positive-control plasmid, no tumors were induced in mice receiving any of the tumor DNAs alone. These results demonstrate that detection of oncogenes in cellular DNA derived from four human tumor-derived cell lines in this mouse system was not possible; the results also show the importance of including a positive-control plasmid to detect inhibitory effects of the cellular DNA.

Oncolytic viruses targeting tumor stem cells.

A workshop "Targeting Oncolytic Viruses to Tumor Stem Cells," organized by the Division of Cancer Biology, NCI, NIH, was held on September 6, 2013 in Rockville, MD. Seventeen invited experts presented an overview of their current research in this area and discussed the state of current research on the use of oncolytic viruses targeted to stem cells as a potential cancer therapy. The goal was to evaluate the evidence that this approach might increase the efficacy of oncolytic virus therapy and to identify gaps in knowledge that have retarded progress in this area.

Thigh Abscess Caused by Yersinia enterocolitica in an Immunocompetent Host.

Yersinia enterocolitica is primarily a gastrointestinal tract pathogen known to cause gastroenteritis, although it may produce extra-intestinal infections like sepsis and its sequelae. However, primary cutaneous infections are extremely rare. We present a case of Y. enterocolitica thigh abscess in an immunocompetent adult. The portal of entry is unclear in this case. He did many outdoor activities that involved skin injuries and exposure to soil and contaminated water. Hence, direct inoculation as a result of exposure to contaminated water is postulated in the absence of evidence for a gastrointestinal route of infection.

Actinomyces meyeri infection: case report and review of the literature.

Actinomyces meyeri is an uncommon cause of actinomycosis. We present a patient with pneumonia and empyema due to A. meyeri. The patient underwent open thoracotomy with decortication and was discharged home on a twelve-month course of oral penicillin. Review of the English literature revealed thirty-two cases of infection due to A. meyeri. The majority of patients were male, and a significant number had poor dental hygiene and a history of alcoholism. More than other Actinomyces species, A. meyeri causes pulmonary infection and has a predilection for dissemination. Prognosis is favorable with prolonged penicillin therapy combined with surgical debridement, if needed.

What HIV-positive MSM want from sexual risk reduction interventions: findings from a qualitative study.

To facilitate the development of a tailored intervention that meets the needs of HIV-positive men who have sex with men (HIV-positive MSM), we conducted formative research with 52 HIV-positive MSM. We sought to (a) identify major barriers to consistent condom use, (b) characterize their interest in sexual risk reduction interventions, and (c) elicit feedback regarding optimal intervention format. Men identified several key barriers to consistent condom use, including treatment optimism, lessened support for safer sex in the broader gay community, challenges communicating with partners, and concerns about stigmatization following serostatus disclosure. Many men expressed an interest in health promotion programming, but did not want to participate in an intervention focusing exclusively on safer sex. Instead, they preferred a supportive group intervention that addresses other coping challenges as well as sexual risk reduction. Study results reveal important considerations for the development of appealing and efficacious risk reduction interventions for HIV-positive MSM.

Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer, and colon cancer.

Each year in the United States, nearly 70 000 individuals between the ages of 15 and 40 years are diagnosed with cancer. Although overall cancer survival rates among pediatric and older adult patients have increased in recent decades, there has been little improvement in survival of adolescent and young adult (AYA) cancer patients since 1975 when collected data became adequate to evaluate this issue. In 2006, the AYA Oncology Progress Review Group made recommendations for addressing the needs of this population that were later implemented by the LIVESTRONG Young Adult Alliance. One of their overriding questions was whether the cancers seen in AYA patients were biologically different than the same cancers in adult and/or pediatric patients. On June 9-10, 2009, the National Cancer Institute (NCI) and the Lance Armstrong Foundation (LAF) convened a workshop in Bethesda, MD, entitled "Unique Characteristics of AYA Cancers: Focus on Acute Lymphocytic Leukemia (ALL), Breast Cancer and Colon Cancer" that aimed to examine the current state of basic and translational research on these cancers and to discuss the next steps to improve their prognosis and treatment.

Medication adherence in HIV-infected smokers: the mediating role of depressive symptoms.

Strict medication adherence is integral to the success of highly active antiretroviral therapies (HAART) in patients with HIV. Research has examined several predictors of adherence, but few studies have examined the association between current smoking, which is highly prevalent among people living with HIV, and medication adherence; moreover, no study has examined the mediating role of depressive symptoms, which may influence both smoking and adherence. Therefore, we recruited 168 patients who were prescribed HAART and assessed viral load, CD4+ count, cigarette smoking, past week and 3-month medication adherence, and depressive symptoms. Results showed that 70% smoked at least one cigarette per day. As predicted, smoking was associated with poorer past week and 3-month adherence, and more depressive symptoms. Regression analyses provided partial support for the hypothesis that depressive symptoms mediated nonadherence among smokers. We conclude that future smoking cessation interventions with this population should target medical adherence and depression as intervention components.

Oncogenicity of DNA in vivo: tumor induction with expression plasmids for activated H-ras and c-myc.

All vaccines and other biological products contain contaminating residual DNA derived from the production cell substrate. Whether this residual cell-substrate DNA can induce tumors in vaccine recipients and thus represent a risk factor has been debated for over 50 years without resolution. As a first step in resolving this issue, we have generated expression plasmids for the activated human H-ras oncogene and for the murine c-myc proto-oncogene. Their oncogenic activity was confirmed in vitro using the focus-formation transformation assay. Two strains of adult and newborn immune-competent mice were inoculated with different amounts of either plasmid alone or with a combination of the H-ras and c-myc plasmids. Tumors developed only in mice inoculated with both plasmids and only at the highest amount of DNA (12.5 microg of each plasmid). The NIH Swiss mouse was more sensitive than the C57BL/6 mouse, and newborn animals were more sensitive than adults. Cell lines were established from the tumors. PCR and Southern hybridization analyses demonstrated that both inoculated oncogenes were present in all of the tumor-derived cell lines and that the cells in the tumors were clonal. Western analysis demonstrated that both oncoproteins were expressed in these cell lines. These results demonstrate that cellular oncogenes can induce tumors following subcutaneous inoculation. Such information provides a possible way of evaluating and estimating the theoretical oncogenic risk posed by residual cell-substrate DNA in vaccines.

The association of benefit finding to psychosocial and health behavior adaptation among HIV+ men and women.

Psychological and behavioral adaptation to HIV is integral to long-term survival. Although most research on coping with HIV has focused on factors associated with poor adaptation, recent research has expanded to include positive concomitants of adaptation, such as benefit finding. This study examined the occurrence of benefit finding among HIV+ men and women and evaluated the potential relevance of benefit finding to positive health behavior and psychosocial adaptation. HIV+ participants (N = 221) recruited during outpatient care completed self-report assessments of benefit finding, social support, depression, HAART adherence, substance use, and physical activity. In a series of multivariate analyses that controlled for demographic and health status variables, benefit finding was associated with lower depression scores, greater social support, and more physical activity, but showed no association to HAART adherence or substance use. The association of benefit finding to depression was partially mediated by differences in social support. Thus, benefit finding may improve psychological adjustment by motivating patients who experience stress-related growth to seek social support.

Cigarette smoking among HIV+ men and women: examining health, substance use, and psychosocial correlates across the smoking spectrum.

The prevalence of cigarette smoking among HIV+ individuals is greater than that found in the general population. However, factors related to smoking within this population are not well understood. This study examined the associations between smoking and demographic, medical, substance use, and psychosocial factors in a clinic-based sample of HIV+ men and women. Two hundred twelve participants completed self-report measures of tobacco use, HIV-related symptoms, viral load, CD4, alcohol and illicit drug use, depression, and social support. Multinomial logistic regression (MLR) analyses modeled the independent associations of the cross-sectional set of predictors with smoking status. Results indicated that 74% of the sample smoked at least one cigarette per day; using standard definitions, 23% of the sample were light smokers, 22% were moderate smokers, and 29% smoked heavily. Smoking was associated with more HIV-related symptoms, greater alcohol and marijuana use, and less social support. Light smoking was related to minority race/ethnicity and less income; moderate smoking was associated with less education; and heavy smoking was related to less education and younger age. Viral load, CD4 count, and depression were not associated with smoking status. Psychosocial interventions targeting this population should consider the relationships between biopsychosocial factors and smoking behavior.

A university hospital's 10-year experience with tuberculin testing: value of the 2-step tuberculin skin test.

BACKGROUND: The usefulness of the 2-step tuberculin skin test as a tool for monitoring tuberculosis exposure among health care workers is controversial. OBJECTIVES: We aimed to determine the cost-effectiveness and influence of initiation of a preemployment, 2-step tuberculin skin-testing program on the annual tuberculin skin conversion rate among a university hospital's health care workers. METHODS: The tuberculin skin test conversion rates among the recipients of 31,729 tuberculin skin tests over 10 years were retrospectively analyzed. Data from the first 6 years of this study were generated when a single preemployment tuberculin skin test was utilized. Data from the last 4 years were gathered after the advent of a preemployment 2-step program. A cost analysis of the 2-step tuberculin skin test process was performed to determine the annual cost of this program. RESULTS: Relative risk of a conversion was 8.43 times less during the 2-step period when compared with the years when a single tuberculin skin test was given at the start of employment (P < .001). A cost analysis showed that the annual added cost of the 2-step program was approximately 9,565 US dollars. CONCLUSION: A greater than 8-fold reduction in the number of annual tuberculin skin test conversion coincided with, but could not be attributed solely to, the initiation of a 2-step program in our hospital. The Infection Control Committee concluded that the 2-step testing program is essential to achieve the hospital's goal of a 0% annual tuberculin skin test conversion rate and that the annual cost is justified.

Impact of HIV-related stigma on health behaviors and psychological adjustment among HIV-positive men and women.

HIV-related stigmatization remains a potent stressor for HIV-positive people. This study examined the relationships among stigma-related experiences and depression, medication adherence, serostatus disclosure, and sexual risk among 221 HIV-positive men and women. In bivariate analyses that controlled for background characteristics, stigma was associated with depressive symptoms, receiving recent psychiatric care, and greater HIV-related symptoms. Stigma was also associated with poorer adherence and more frequent serostatus disclosure to people other than sexual partners, but showed no association to sexual risk behavior. In a multivariate analysis that controlled for all correlates, depression, poor adherence, and serostatus disclosure remained as independent correlates of stigma-related experiences. Findings confirm that stigma is associated with psychological adjustment and adherence difficulties and is experienced more commonly among people who disclose their HIV status to a broad range of social contacts. Stigma should be addressed in stress management, health promotion, and medication adherence interventions for HIV-positive people.