Emily Chang

Immune Response and Mortality Risk Relate to Distinct Lung Microbiomes in Patients with HIV and Pneumonia

Rationale: The potential role of the airway microbiota in dictating immune responses and infection outcomes in HIV‐associated pneumonia is largely unknown. Objectives: To investigate whether microbiologically and immunologically distinct subsets of patients with HIV and pneumonia exist and are related to mortality. Methods: Bronchoalveolar lavage samples from Ugandan patients with HIV and pneumonia (n = 182) were obtained at study enrollment (following antibiotic treatment); patient demographics including 8‐ and 70‐day mortality were collected. Lower airway bacterial community composition was assessed via amplification and sequencing of the V4 region of the 16S ribosomal RNA gene. Host immune response gene expression profiles were generated by quantitative polymerase chain reaction using RNA extracted from bronchoalveolar lavage fluid. Liquid and gas chromatography mass spectrometry was used to profile serum metabolites. Measurements and Main Results: Based on airway microbiome composition, most patients segregated into three distinct groups, each of which were predicted to encode metagenomes capable of producing metabolites characteristically enriched in paired serum samples from these patients. These three groups also exhibited differences in mortality; those with the highest rate had increased ceftriaxone administration and culturable Aspergillus, and demonstrated significantly increased induction of airway T‐helper cell type 2 responses. The group with the lowest mortality was characterized by increased expression of T‐cell immunoglobulin and mucin domain 3, which down‐regulates T‐helper cell type 1 proinflammatory responses and is associated with chronic viral infection. Conclusions: These data provide evidence that compositionally and structurally distinct lower airway microbiomes are associated with discrete local host immune responses, peripheral metabolic reprogramming, and different rates of mortality.

Real-Time Transferrin-Based PET Detects MYC-Positive Prostate Cancer

Noninvasive biomarkers that detect the activity of important oncogenic drivers could significantly improve cancer diagnosis and management of treatment. The goal of this study was to determine whether 68Ga-citrate (which avidly binds to circulating transferrin) can detect MYC-positive prostate cancer tumors, as the transferrin receptor is a direct MYC target gene. PET imaging paired with 68Ga-citrate and molecular analysis of preclinical models, human cell-free DNA (cfDNA), and clinical biopsies were conducted to determine whether 68Ga-citrate can detect MYC-positive prostate cancer. Importantly, 68Ga-citrate detected human prostate cancer models in a MYC-dependent fashion. In patients with castration-resistant prostate cancer, analysis of cfDNA revealed that all patients with 68Ga-citrate avid tumors had a gain of at least one MYC copy number. Moreover, biopsy of two PET avid metastases showed molecular or histologic features characteristic of MYC hyperactivity. These data demonstrate that 68Ga-citrate targets prostate cancer tumors with MYC hyperactivity. A larger prospective study is ongoing to demonstrate the specificity of 68Ga-citrate for tumors with hyperactive MYC. Implications: Noninvasive measurement of MYC activity with quantitative imaging modalities could substantially increase our understanding of the role of MYC signaling in clinical settings for which invasive techniques are challenging to implement or do not characterize the biology of all tumors in a patient. Moreover, measuring MYC activity noninvasively opens the opportunity to study changes in MYC signaling in patients under targeted therapeutic conditions thought to indirectly inhibit MYC. Mol Cancer Res; 15(9); 1221–9. ©2017 AACR.

A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone‐ and/or Enzalutamide‐Refractory Metastatic Castration‐Resistant Prostate Cancer

Abstract Lessons Learned. In abiraterone‐ and/or enzalutamide‐refractory metastatic castration‐resistant prostate cancer (mCRPC) patients, selinexor led to prostate‐specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication. Despite twice‐a‐week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second‐generation anti‐androgen therapies, limiting further clinical development in this patient population. This study highlights the challenge of primary endpoint selection for phase II studies in the post‐abiraterone and/or post‐enzalutamide mCRPC space. Background. Selinexor is a first‐in‐class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin‐1 (XPO‐1), leading to nuclear accumulation of tumor suppressor proteins. Methods. This phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration‐resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide. Results. Fourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow‐up of 4 months, two patients (14%) had ≥50% prostate‐specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment‐related grade 3–4 AEs. The most common drug‐related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability. Conclusion. Selinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second‐line anti‐androgenic agents.

Evaluation of antibody responses to panels of M. tuberculosis antigens as a screening tool for active tuberculosis in Uganda

Background Improved systematic screening of high-risk groups is a key component of the tuberculosis (TB) elimination strategy endorsed by the World Health Organization (WHO). We used a multiplex microbead immunoassay to measure antibody responses to 28 M. tuberculosis (M.tb) antigens, and assessed whether combinations of antibody responses achieve accuracy thresholds required for a TB screening test. Methods A random selection of plasma samples obtained from consecutive HIV-negative adults who were admitted to Mulago Hospital in Kampala, Uganda with cough ≥2 weeks’ but <6 months’ duration were analyzed for serological response to 28 M.tb antigens using an in-house multiplex microbead immunoassay. We compared the median difference of the antibody response to each antigen between patients with and without culture-confirmed TB, ranked each antigen according to variable importance (VIM), and assessed the sensitivity and specificity of combinations of antibody responses using an advanced classification algorithm, SuperLearner. Results Among the 237 patients included in the analysis, 119 (50%) were female, median age was 32 years (IQR 25, 46), and 113 (48%) had TB. Median antibody levels to eight antigens were significantly different between patients with and without TB. A panel including eight of the top ranked antigens had a sensitivity of 90.6% (95% CI 89.4, 93.8) and a specificity of 88.6% (95% CI 78.2, 97.6) (Ag85B, Ag85A, Ag85C, Rv0934-P38, Rv3881, BfrB, Rv3873, and Rv2878c). With sensitivity constrained to be >90%, specificity remained close to 70% with as few as 3 antigens included in the panels. Conclusions Measuring antibody responses to combinations of antigens could facilitate TB screening and should be further evaluated in populations being targeted for systematic screening.

Clinical Variables Associated With Overall Survival in Metastatic Castration-Resistant Prostate Cancer Patients Treated With Sipuleucel-T Immunotherapy

&NA; Sipuleucel‐T remains the only Food and Drug Administration–approved immunotherapy for metastatic castration‐resistant prostate cancer (mCRPC). However, limited data are available to guide patient selection and the timing of therapy. In the present retrospective study during the era of androgen signaling inhibitors, the baseline Eastern Cooperative Oncology Group performance status, prostate‐specific antigen doubling time, and abiraterone and/or enzalutamide use before sipuleucel‐T were associated with poorer overall survival in mCRPC patients treated with sipuleucel‐T. Background: Sipuleucel‐T is an autologous cell‐based cancer immunotherapy for men with asymptomatic or minimally symptomatic metastatic castration‐resistant prostate cancer (mCRPC). Its approval by the Food and Drug Administration was based on demonstration of an overall survival (OS) benefit in randomized placebo‐controlled phase III trials. However, treatment was associated with a prostate‐specific antigen (PSA) decline in only a small minority of patients. Understanding the clinical factors that are associated with OS could help guide treatment decisions, including patient selection and the timing of sipuleucel‐T relative to other therapies. Patients and Methods: We retrospectively identified 94 mCRPC patients treated with sipuleucel‐T from April 2010 to April 2016. The Kaplan‐Meier method was used to estimate the distribution of OS. Univariate and multivariate Cox proportional hazard modeling was used to identify the prognostic factors for OS. Results: With a median follow‐up of 24.9 months, the median OS was 34.9 months. On multivariate analysis, Eastern Cooperative Oncology Group performance status, pretreatment PSA doubling time, and previous abiraterone and/or enzalutamide were significant prognostic factors for OS. Conclusion: A poorer baseline performance status, faster disease pace measured by the PSA doubling time, and previous novel androgen signaling inhibitor exposure could be important prognostic considerations for the treatment of mCRPC patients with sipuleucel‐T. Further studies are needed to validate these findings.

Use of Oropharyngeal Washes to Diagnose and Genotype Pneumocystis jirovecii

Pneumocystis is an important opportunistic pathogen in immunocompromised patients. Molecular epidemiology studies are needed to understand transmission. This article evaluates non-invasive sampling and a new strain typing tool, both of which could be used for this purpose.

Diagnostic performance of blood inflammatory markers for tuberculosis screening in people living with HIV

Background Approaches to screening for active tuberculosis (TB) among people living with HIV are inadequate, leading to missed diagnoses and poor implementation of preventive therapy. Methods Consecutive HIV-infected adults hospitalized at Mulago Hospital (Kampala, Uganda) between June 2011 and July 2013 with a cough ≥ 2 weeks were enrolled. Patients underwent extensive evaluation for pulmonary TB. Concentrations of 43 cytokines/chemokines were measured at the same time point as C-reactive protein (CRP) in banked plasma samples using commercially-available multiplex kits. Advanced classification algorithms were used to rank cytokines/chemokines for their ability to identify TB, and to model the specificity of the top-ranked cytokines/chemokines individually and in combination with sensitivity constrained to ≥ 90% as recommended for TB screening. Results The median plasma level of 5 biomarkers (IL-6, INF-γ, MIG, CRP, IL-18) was significantly different between patients with and without TB. With sensitivity constrained to 90%, all had low specificity with IL-6 showing the highest specificity (44%; 95% CI 37.4–49.5). Biomarker panels were found to be more valuable than any biomarker alone. A panel combining IFN-γ and IL-6 had the highest specificity (50%; 95% CI 46.7–53.3). Sensitivity remained high (>85%) for all panels among sputum smear-negative TB patients. Conclusions Direct measurement of unstimulated plasma cytokines/chemokines in peripheral blood is a promising approach to TB screening. Cytokine/chemokine panels retained high sensitivity for smear-negative TB and achieved improved specificity compared to individual cytokines/chemokines. These markers should be further evaluated in outpatient settings where most TB screening occurs and where other illnesses associated with systematic inflammation are less common.

At What Cost to Clinical Trial Enrollment? A Retrospective Study of Patient Travel Burden in Cancer Clinical Trials

BACKGROUND Recent literature suggests that living in a rural setting may be associated with adverse cancer outcomes. This study examines the burden of travel from home to cancer center for clinical trial (CT) enrollees. MATERIALS AND METHODS Patients from the University of California San Francisco Clinical Trial Management System database who enrolled in a cancer CT for a breast, genitourinary, or gastrointestinal malignancy between 1993 and 2014 were included. Cancer type, household zip code, race/ethnicity, phase of study, study sponsor, and year of signed consent were exported. Distance traveled from home to center was calculated using a GoogleMaps application programming interface. The relationships of distance with phase of CT, household income, and race/ethnicity were examined. RESULTS A total of 1,600 patients were enrolled in breast (55.8%), genitourinary (29.4%), or gastrointestinal (14.9%) cancer CTs. The overall median unidirectional distance traveled from home to study site was 25.8 miles (interquartile range [IQR] 11.5-75.3). Of the trial sponsors examined, principal investigator (56.4%), industry (22.2%), cooperative group (11.6%), and National Institutes of Health (NIH; 9.8%), the longest distance traveled was for NIH-sponsored trials, with a median of 39.4 miles (p < .001). Phase I (8.4%) studies had the longest distance traveled, with a median of 41.2 miles (IQR 14.5-101.0 miles; p = .001). White patients (83%) traveled longer compared with black patients (4.4%), with median distances of 29.9 and 13.9 miles, respectively (p < .001). Patients from lower-income areas (n = 799) traveled longer distances compared with patients from higher-income areas (n = 773; 58.3 vs. 17.8 miles, respectively; p < .001). A multivariable linear model where log10 (distance) was the outcome and adjusting for the exported variables and income revealed that cancer type, year of consent, race/ethnicity, and income were significantly associated with distance traveled. CONCLUSION This study found that the burden of travel is highest among patients enrolled in NIH-sponsored trials, phase I studies, or living in low-income areas. These data suggest that travel burden for cancer CT participants may be significant. IMPLICATIONS FOR PRACTICE This study is one of the first to measure travel distance for patients in cancer clinical trials using a real-world GoogleMaps calculator. Out-of-pocket expenses such as travel are not typically covered by health care payers; therefore, patients may face considerable cost to attend each study visit. Using a single-center clinical trials enrollment database, this study found that the burden of travel is highest for patients enrolled in National Institutes of Health-sponsored trials and phase I studies, as well as for patients living in low-income areas. Results suggest that a significant proportion of patients enrolled in clinical trials face a substantial travel burden.

Effects of clinical and environmental factors on bronchoalveolar antibody responses to Pneumocystis jirovecii: A prospective cohort study of HIV+ patients

Background Humoral immunity plays an important role against Pneumocystis jirovecii infection, yet clinical and environmental factors that impact bronchoalveolar antibody responses to P. jirovecii remain uncertain. Methods From October 2008—December 2011 we enrolled consecutive HIV-infected adults admitted to San Francisco General Hospital (SFGH) who underwent bronchoscopy for suspected Pneumocystis pneumonia (PCP). We used local air quality monitoring data to assign ozone, nitrogen dioxide, and fine particulate matter exposures within 14 days prior to hospital admission. We quantified serum and bronchoalveolar lavage fluid (BALF) antibody responses to P. jirovecii major surface glycoprotein (Msg) recombinant constructs using ELISA. We then fit linear regression models to determine whether PCP and ambient air pollutants were associated with bronchoalveolar antibody responses to Msg. Results Of 81 HIV-infected patients enrolled, 47 (58%) were diagnosed with current PCP and 9 (11%) had a prior history of PCP. The median CD4+ count was 51 cells/μl (IQR 15–129) and 44% were current smokers. Serum antibody responses to Msg were statistically significantly predictive of BALF antibody responses, with the exception of IgG responses to MsgC8 and MsgC9. Prior PCP was associated with increased BALF IgA responses to Msg and current PCP was associated with decreased IgA responses. For instance, among patients without current PCP, those with prior PCP had a median 73.2 U (IQR 19.2–169) IgA response to MsgC1 compared to a 5.00 U (3.52–12.6) response among those without prior PCP. Additionally, current PCP predicted a 22.5 U (95%CI -39.2, -5.82) lower IgA response to MsgC1. Ambient ozone within the two weeks prior to hospital admission was associated with decreased BALF IgA responses to Msg while nitrogen dioxide was associated with increased IgA responses. Conclusions PCP and ambient air pollutants were associated with BALF IgA responses to P. jirovecii in HIV-infected patients evaluated for suspected PCP.

Clinical variables associated with overall survival in metastatic castration resistant prostate cancer (mCRPC) patients treated with sipuleucel-T immunotherapy.

e16565Background: Sipuleucel-T (Sip-T) is a cellular-based cancer immunotherapy for men with asymptomatic or minimally symptomatic mCRPC. Its approval was based on overall survival (OS) benefit in ...