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OBJECTIVE: To describe retention in HIV care based on various definitions of retention in the modern treatment era. DESIGN: A cohort study of people enrolled in care at 7 mostly urban HIV clinics across the United States, 2010-2018. METHODS: We estimated retention based on missed visits, kept visits, kept encounters (clinical visits, CD4 counts, and viral loads), and HIV labs. We contrasted risk factors for retention by different definitions and estimated odds ratios for of viral suppression and hazard ratios for mortality in 2 years immediately following the year in which retention was defined (the study year). RESULTS: Across 108,171 person-years (N=21,481 people), in 71% of years people kept ≥75% of scheduled visits; in 78%, people kept ≥2 visits >90 days apart; in 74%, people had ≥2 HIV labs >90 days apart; and in 47%, people had no gaps >6 months in clinic visits. Missing >25% of scheduled visits despite attending ≥2 visits >90 days apart was associated with non-white non-Hispanic race/ethnicity, history of injection drug use, and prior AIDS diagnosis. In contrast, attending ≥75% of scheduled visits while not attending ≥2 visits >90 days apart was associated with male sex, white race, no injection drug use history, and no prior AIDS diagnosis. Subsequent viral non-suppression was more strongly associated with missed- than kept-visit measures of retention; 2-year mortality was only associated with failure to be retained by missed-visit measures. DISCUSSION: Missed and kept-visit definitions of retention capture different constructs. Missed-visit measures are more strongly associated with poor HIV outcomes.

BackgroundDuring the COVID-19 pandemic, patients experienced significant care disruptions, including lab monitoring. We investigated changes in the time between viral load (VL) checks for people with HIV associated with the pandemic.MethodsThis was an observational analysis of VLs of people with HIV in routine care at a large subspecialty clinic. At pandemic onset, the clinic temporarily closed its onsite laboratory. The exposure was time period (time-varying): pre-pandemic (January 1st 2019-March 15th, 2020); pandemic lab-closed (March 16th-July 12th, 2020); and pandemic lab-open (July 13th-December 31st, 2020). We estimated time from an index VL to a subsequent VL, stratified by whether the index VL was suppressed (≤200 copies/mL). We also calculated cumulative incidence of a non-suppressed VL following a suppressed index VL, and of re-suppression following a loss of viral suppression.ResultsCompared to pre-pandemic, hazard ratios for next VL check were: 0.34 (95% CI: 0.30, 0.37, lab-closed) and 0.73 (CI: 0.68, 0.78, lab-open) for suppressed patients; 0.56 (CI: 0.42, 0.79, lab-closed) and 0.92 (95% CI: 0.76, 1.10, lab-open) for non-suppressed patients. The 12-month cumulative incidence of loss of suppression was the same in the pandemic lab-open (4%) and pre-pandemic period (4%). The hazard of re-suppression following loss of suppression was lower during the pandemic lab-open versus the pre-pandemic period (hazard ratio: 0.68, 95% CI: 0.50, 0.92).ConclusionsEarly pandemic restrictions and lab closure significantly delayed VL monitoring. Once the lab re-opened, non-suppressed patients resumed normal monitoring. Suppressed patients still had a delay, but no significant loss of suppression.SummaryDuring the early COVID-19 pandemic, people with HIV experienced disruptions in viral load monitoring due to lab closure and pandemic restrictions. Loosening restrictions resolved delays for non-suppressed, but not suppressed patients. Delays did not significantly increase proportion of non-suppressed patients.

Supplementary Figures 1-7 and Supplementary Table 1

Purpose:Using standard-of-care CT images obtained from patients with a diagnosis of non–small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity of tumors to nivolumab, docetaxel, and gefitinib.Experimental Design:Data were collected prospectively and analyzed retrospectively across multicenter clinical trials [nivolumab, n = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); docetaxel, n = 50, CheckMate017; gefitinib, n = 46, (NCT00588445)]. Patients were randomized to training or validation cohorts using either a 4:1 ratio (nivolumab: 72T:20V) or a 2:1 ratio (docetaxel: 32T:18V; gefitinib: 31T:15V) to ensure an adequate sample size in the validation set. Radiomics signatures were derived from quantitative analysis of early tumor changes from baseline to first on-treatment assessment. For each patient, 1,160 radiomics features were extracted from the largest measurable lung lesion. Tumors were classified as treatment sensitive or insensitive; reference standard was median progression-free survival (NCT01642004, NCT01721759) or surgery (NCT00588445). Machine learning was implemented to select up to four features to develop a radiomics signature in the training datasets and applied to each patient in the validation datasets to classify treatment sensitivity.Results:The radiomics signatures predicted treatment sensitivity in the validation dataset of each study group with AUC (95 confidence interval): nivolumab, 0.77 (0.55–1.00); docetaxel, 0.67 (0.37–0.96); and gefitinib, 0.82 (0.53–0.97). Using serial radiographic measurements, the magnitude of exponential increase in signature features deciphering tumor volume, invasion of tumor boundaries, or tumor spatial heterogeneity was associated with shorter overall survival.Conclusions:Radiomics signatures predicted tumor sensitivity to treatment in patients with NSCLC, offering an approach that could enhance clinical decision-making to continue systemic therapies and forecast overall survival.

Supplement

Supplemental Figure 1. Mc Nemar´s test cross tabulations comparing identified (positive)/non identified (negative) lesions of [68Ga]-DOTATATE to [18F]-FDG, [18F]-FDOPA, [18F]-FDA PET/CT, and CT/MRI.

Purpose: Patients with succinate dehydrogenase subunit B(SDHB) mutation–related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited, but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison with the currently recommended functional imaging modalities [18F]-fluorodopamine ([18F]-FDA), [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-d-glucose ([18F]- FDG) PET/CT as well as CT/MRI.Experimental Design: [68Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [18F]-FDG PET/CT and CT/MRI, with 16 of the 17 patients also receiving [18F]-FDOPA and [18F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator.Results: [68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% [95% confidence interval (CI), 96.5%–99.5%], [18F]-FDG, [18F]-FDOPA, [18F]-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI, 81.3%–89.4%; P < 0.01), 61.4% (CI, 55.6%–66.9%; P < 0.01), 51.9% (CI, 46.1%–57.7%; P < 0.01), and 84.8% (CI, 80.0%–88.5%; P < 0.01), respectively.Conclusions: [68Ga]-DOTATATE PET/CT showed a significantly superior detection rate to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL. Clin Cancer Res; 21(17); 3888–95. ©2015 AACR.See related commentary by Hofman and Hicks, p. 3815

OBJECTIVES: Telemedicine became the primary mode of delivering care during the COVID-19 pandemic. We describe the impact of telemedicine on access to care for people with HIV (PWH) by comparing the proportion of PWH engaged in care prior to and during the COVID-19 pandemic. DESIGN AND METHODS: We conducted an observational analysis of patients enrolled in the Johns Hopkins HIV Clinical Cohort, a single-center cohort of patients at an urban HIV subspecialty clinic affiliated with an academic center. Due to the COVID-19 pandemic, the clinic transitioned from in-person to mostly telemedicine visits. We compared patients receiving care in two time periods. The pre-pandemic period included 2,010 people with ≥1 visit scheduled between September 1(st) 2019 and March 15(th) 2020. The pandemic period included 1,929 people with ≥1 visit scheduled between March 16(th) 2020 and September 30(th) 2020. We determined the proportion of patients completing ≥1 of their scheduled visits during each period. RESULTS: Visit completion increased significantly from 88% pre-pandemic to 91% during the pandemic (p=0.008). Visit completion improved significantly for patients age 20–39 (82% to 92%, p

Background Global progress towards reducing tuberculosis (TB) incidence and mortality has consistently lagged behind the World Health Organization targets leading to a perception that large reductions in TB burden cannot be achieved. However, several recent and historical trials suggest that intervention efforts that are comprehensive and intensive can have a substantial epidemiological impact. We aimed to quantify the potential epidemiological impact of an intensive but realistic, community-wide campaign utilizing existing tools and designed to achieve a “step change” in the TB burden. Methods We developed a compartmental model that resembled TB transmission and epidemiology of a mid-sized city in India, the country with the greatest absolute TB burden worldwide. We modeled the impact of a one-time, community-wide screening campaign, with treatment for TB disease and preventive therapy for latent TB infection (LTBI). This one-time intervention was followed by the strengthening of the tuberculosis-related health system, potentially facilitated by leveraging the one-time campaign. We estimated the tuberculosis cases and deaths that could be averted over 10 years using this comprehensive approach and assessed the contributions of individual components of the intervention. Results A campaign that successfully screened 70% of the adult population for active and latent tuberculosis and subsequently reduced diagnostic and treatment delays and unsuccessful treatment outcomes by 50% was projected to avert 7800 (95% range 5450–10,200) cases and 1710 (1290–2180) tuberculosis-related deaths per 1 million population over 10 years. Of the total averted deaths, 33.5% (28.2–38.3) were attributable to the inclusion of preventive therapy and 52.9% (48.4–56.9) to health system strengthening. Conclusions A one-time, community-wide mass campaign, comprehensively designed to detect, treat, and prevent tuberculosis with currently existing tools can have a meaningful and long-lasting epidemiological impact. Successful treatment of LTBI is critical to achieving this result. Health system strengthening is essential to any effort to transform the TB response.

Irreversible electroporation (IRE) expands the surgical options for patients with unresectable pancreatic cancer. This study evaluated for differences in survival stratified by type of IRE and receipt of adjuvant chemotherapy.Patients with locally advanced pancreatic cancer treated by IRE (2012-2020) were retrospectively included. Overall survival (OS) and recurrence-free survival (RFS) were compared by type of IRE (in situ for local tumor control or IRE of potentially positive margins with resection) and by receipt of adjuvant chemotherapy.Thirty-nine patients had IRE in situ, 61 had IRE for margin extension, and 19 received adjuvant chemotherapy. Most (97.00%) underwent induction chemotherapy. OS was 28.71 months (interquartile range [IQR] 19.17, 51.19) from diagnosis, with no difference by IRE type (hazard ratio [HR] 1.05 for margin extension [p = 0.85]) or adjuvant chemotherapy (HR 1.14 [p = 0.639]). RFS was 8.51 months (IQR 4.95, 20.17) with no difference by IRE type (HR 0.90 for margin extension [p = 0.694]) or adjuvant chemotherapy (HR 0.90 [p = 0.711]).These findings suggest that adjuvant therapy may have limited benefit for patients treated with induction chemotherapy followed by local control with IRE for unresectable pancreatic cancer. Further study of the duration and timing of systemic therapy is warranted to maximize benefit and limit toxicity.

Direct-acting antivirals (DAA) are highly effective against hepatitis C virus (HCV) infection among persons with human immunodeficiency virus (PWH). However, alcohol use post-DAA treatment poses a continued threat to the liver. Whether the focus on liver health alone during HCV treatment can impact alcohol consumption is unclear. Therefore, we examined the change in alcohol use among HCV-coinfected PWH who received DAA therapy by non-addiction medical providers.In our longitudinal clinical cohort study, we identified HCV-coinfected PWH who received interferon-free DAA therapy between January 2014 and June 2019 in the Centers for AIDS Research Network of Integrated Clinical Systems. The Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) was the alcohol screening instrument. We used mixed-effects logistic regression models to estimate the longitudinal change in alcohol use upon DAA therapy.Among 738 HCV-coinfected PWH, 339 (46 %) reported any alcohol use at the end of HCV treatment, including 113 (15 %) with high-risk use (i.e., AUDIT-C ≥3 for women, ≥4 for men). Concurrently, 280 (38 %) PWH noted active drug use, and 357 (48 %) were currently smoking. We observed no changes in the odds of any alcohol or high-risk alcohol use over time with DAA therapy. Findings were similar in the PWH subgroup with a history of alcohol use before DAA treatment.For PWH with HCV, alcohol use did not change following interferon-free DAA treatment by non-addiction medical providers. Thus, clinicians should consider integrating targeted alcohol use interventions into HCV care to motivate reduced alcohol consumption and safeguard future liver health.

Background Opioid use is prevalent among people living with human immunodeficiency virus (HIV; PLWH) and adversely affects HIV outcomes. We assessed the effect of buprenorphine (BUP) initiation on subsequent HIV viral loads. Methods We identified PLWH from the Johns Hopkins HIV Clinical Cohort who initiated BUP between 2002 and 2017. Poisson regression with robust variance was used to estimate the prevalence of viral suppression ( Results We identified 279 PLWH who initiated BUP. After BUP initiation, PLWH were more likely to be virally suppressed (prevalence ratio [PR], 1.19; 95% confidence interval [CI], 1.03–1.37). After matching PLWH who initiated BUP to controls and accounting for measured and unmeasured confounders, BUP initiation increased viral suppression for both those on antiretroviral therapy (ART) at baseline (PERR PR, 1.08; 95% CI, 1.00–1.18) and those not on ART at baseline (PR, 1.31; 95% CI, 1.10–1.61). Conclusions Our results indicate that the initiation of BUP results in an increase in the probability of being virally suppressed after accounting for both measured and unmeasured confounders. Persons with opioid use disorder should initiate BUP to not only treat substance use but also to increase viral suppression allowing for treatment as prevention.

BackgroundTelemedicine use for the care of people with HIV (PWH) was widely expanded during the COVID-19 pandemic. During 2021, as on-site care was re-introduced, care was delivered through a mixture of in-person and telemedicine. We studied how different patient populations used telemedicine in this hybrid-care environment.MethodsUsing observational data from patients enrolled in the Johns Hopkins HIV Clinical Cohort, we analyzed all in-person and telemedicine HIV primary care visits completed in an HIV clinic from January 1st, 2021 to December 30th, 2021. We used log-binomial regression models to investigate the association between patient characteristics and the probability of completing a telemedicine versus in-person visit. A secondary analysis of telemedicine visits investigated the probably of completing a video versus telephone visit.ResultsA total of 5,518 visits were completed by 1,884 patients; 4,282 (77.6%) visits were in-person, 800 (14.5%) by phone, and 436 (7.9%) by video. The relative risk (RR) of completing telemedicine vs. in-person visits was 0.65 (95% Confidence Interval (CI): 0.47, 0.91) for patients age 65+ vs. age 20-39; 0.84 (95% CI: 0.72, 0.98) for males vs. females; 0.81 (95% CI: 0.66, 0.99) for Black vs. white patients; 0.62 (95% CI: 0.49, 0.79) for patients in the highest vs. lowest quartile of Area Deprivation Index; and 1.52 (95% CI: 1.26, 1.84) for patients >15 miles vs. ConclusionsIn the second year of the pandemic, overall in-person care was utilized more than telemedicine, and significant differences persist across subgroups in telemedicine uptake.

We estimated joint associations between having history of alcohol use disorder (AUD) (based on prior ICD-9/ICD-10 codes) and recent self-reported alcohol use and viral non-suppression (≥ 1 viral load measurement > 20 copies/mL in the same calendar year as alcohol consumption was reported) among patients on ART enrolled in routine care, 2014–2018, in an urban specialty clinic. Among 1690 patients, 26% had an AUD, 21% reported high-risk alcohol use, and 39% had viral non-suppression. Relative to person-years in which people without AUD reported not drinking, prevalence of viral non-suppression was higher in person-years when people with AUD reported drinking at any level; prevalence of viral non-suppression was not significantly higher in person-years when people with AUD reported not drinking or person-years when people without AUD reported drinking at any level. No level of alcohol use may be “safe” for people with a prior AUD with regard to maintaining viral suppression.

Background The Ending the HIV Epidemic (EHE) initiative aims to reduce incident HIV infections by 90% over a span of 10 years. The intensity of interventions needed to achieve this for local epidemics is unclear. Objective To estimate the effect of HIV interventions at the city level. Design A compartmental model of city-level HIV transmission stratified by age, race, sex, and HIV risk factor was developed and calibrated. Setting 32 priority metropolitan statistical areas (MSAs). Patients Simulated populations in each MSA. Intervention Combinations of HIV testing and preexposure prophylaxis (PrEP) coverage among those at risk for HIV, plus viral suppression in persons with diagnosed HIV infection. Measurements The primary outcome was the projected reduction in incident cases from 2020 to 2030. Results Absent intervention, HIV incidence was projected to decrease by 19% across all 32 MSAs. Modest increases in testing (1.25-fold per year), PrEP coverage (5 percentage points), and viral suppression (10 percentage points) across the population could achieve reductions of 34% to 67% by 2030. Twenty-five percent PrEP coverage, testing twice a year on average, and 90% viral suppression among young Black and Hispanic men who have sex with men (MSM) achieved similar reductions (13% to 68%). Including all MSM and persons who inject drugs could reduce incidence by 48% to 90%. Thirteen of 32 MSAs could achieve greater than 90% reductions in HIV incidence with large-scale interventions that include heterosexuals. A web application with location-specific results is publicly available (www.jheem.org). Limitation The COVID-19 pandemic was not represented. Conclusion Large reductions in HIV incidence are achievable with substantial investment, but the EHE goals will be difficult to achieve in most locations. An interactive model that can help policymakers maximize the effect in their local environments is presented. Primary funding source National Institutes of Health.

BackgroundThe COVID-19 pandemic disrupted the normal delivery of HIV care, altered social support networks, and caused economic insecurity. People with HIV (PWH) are vulnerable to such disruptions, particularly if they have a history of substance use. We describe engagement in care and adherence to antiretroviral therapy (ART) for PWH during the pandemic.MethodsFrom May 2020 to February 2021, 773 PWH enrolled in 6 existing cohorts completed 1495 surveys about substance use and engagement in HIV care during the COVID-19 pandemic. We described the prevalence and correlates of having missed a visit with an HIV provider in the past month and having missed a dose of ART in the past week.ResultsThirteen percent of people missed an HIV visit in the past month. Missing a visit was associated with unstable housing, food insecurity, anxiety, low resiliency, disruptions to mental health care, and substance use including cigarette smoking, hazardous alcohol use, cocaine, and cannabis use. Nineteen percent of people reported missing at least one dose of ART in the week prior to their survey. Missing a dose of ART was associated with being a man, low resiliency, disruptions to mental health care, cigarette smoking, hazardous alcohol use, cocaine, and cannabis use, and experiencing disruptions to substance use treatment.ConclusionsSocial determinants of health, substance use, and disruptions to mental health and substance use treatment were associated with poorer engagement in HIV care. Close attention to continuity of care during times of social disruption is especially critical for PWH.

BackgroundAlcohol use during the COVID-19 pandemic increased. People living with HIV or at risk for HIV acquisition often have psycho-social and structural barriers or co-occurring substance use making them vulnerable to the adverse effects of alcohol. We describe factors associated with alcohol use during the COVID-19 pandemic in this group.MethodsFrom May 2020 to February 2021, 1984 people enrolled in 6 existing cohort studies completed surveys about alcohol and other drug use during the COVID-19 pandemic. We describe the past-month prevalence of no alcohol use, low-risk use, and hazardous use. We use multinomial regression to describe factors associated with low-risk or hazardous alcohol use relative to no alcohol use.ResultsForty-five percent of participants reported no alcohol use, 33% low-risk use, and 22% hazardous use in the past 30 days. Cannabis and stimulant use were associated with a higher prevalence of low-risk use relative to no use. Tobacco, stimulant, cannabis use and recent overdose were associated with a higher prevalence of hazardous use relative to no use. Substance use treatment and living with HIV were associated with a lower prevalence of low-risk or hazardous use relative to no use.ConclusionsStimulant use was strongly associated with a higher prevalence of hazardous alcohol use while engagement in substance use treatment or living with HIV was associated with a lower prevalence. Ascertaining hazardous alcohol and other drug use, particularly stimulants, in clinical care could identify people at higher risk for adverse outcome and harm reduction counseling.

OBJECTIVE The aim of this study was to describe the risk of viral nonsuppression across the depression care cascade. DESIGN A clinical cohort study. METHODS We used depressive symptoms (PHQ-8 ≥ 10) self-reported on computer-assisted surveys, clinical diagnoses of depression in the medical record in the prior year and pharmacologic (any prescription for an antidepressant) and psychologic treatments for depression (attendance at at least two mental health visits in the prior year) to classify patients into groups: no history of depression; prior depression diagnosis; current indication for depression treatment (symptoms or clinical diagnosis); and treated depression (stratified by presence of persistent symptoms). We associated position in the depression care cascade with viral nonsuppression (>200 copies/ml) 7 days before to 6 months after the index self-report of depressive symptoms. RESULTS History of depression [adjusted risk difference (aRD) relative to no history = 5.9%, 95% confidence interval (95% CI): 1.5-10.3] and current depression (symptoms or diagnosis) in the absence of treatment (aRD relative to no current depression or depression treatment = 4.8%, 95% CI: 1.8-7.8) were associated with a higher risk of viral nonsuppression than no history of depression. Depression treatment mitigated this association (aRD = -0.4%, 95% CI: -2.5 to 1.7). CONCLUSION The relationship between depression care cascade and viral suppression is complex. Untreated depression and clinically unrecognized depressive symptoms were both related to viral nonsuppression. Treated depression was not associated with viral nonsuppression; however, a high proportion of treated patients still had depressive symptoms. Depression treatment should be titrated if patients' symptoms are not responsive and patients with a history of depression should be monitored for ART adherence.

Learning health systems use data to generate knowledge that informs clinical care, but few studies have evaluated how to leverage patient-reported mental health symptoms and substance use data to make patient-specific predictions. We developed a general Bayesian prediction algorithm that uses self-reported psychiatric symptoms and substance use within a population to predict future symptoms and substance use for individuals in that population. We validated our approach in 2444 participants from two clinical cohorts - the National Network of Depression Centers and the Johns Hopkins HIV Clinical Cohort - by predicting symptoms of depression, anxiety, and mania as well as alcohol, heroin, and cocaine use and comparing our predictions to observed symptoms and substance use. When we dichotomized mental health symptoms as moderate-severe vs. none-mild, individual predictions yielded areas under the ROC curve (AUCs) of 0.84 [95% confidence interval 0.80-0.88] and 0.85 [0.82-0.88] for symptoms of depression in the two cohorts, AUCs of 0.84 [0.79-0.88] and 0.85 [0.82-0.88] for symptoms of anxiety, and an AUC of 0.77 [0.72-0.82] for manic symptoms. Predictions of substance use yielded an AUC of 0.92 [0.88-0.97] for heroin use, 0.90 [0.82-0.97] for cocaine use, and 0.90 [0.88-092] for alcohol misuse. This rigorous, mathematically grounded approach could provide patient-specific predictions at the point of care. It can be applied to other psychiatric symptoms and substance use indicators, and is customizable to specific health systems. Such approaches can realize the potential of a learning health system to transform ever-increasing quantities of data into tangible guidance for patient care.

PURPOSE: A comparison of stage at cancer diagnosis and cancer treatment rates between people with HIV (PWH) and the general US population is needed to identify any disparities by HIV status. METHODS: We compared 236 PWH in clinical care diagnosed with cancer from 1997 to 2014 to a sample from NCI’s Surveillance, Epidemiology and End Results (SEER) Program, presumed to be HIV negative. We performed G-computation using random forest methods to estimate stage and treatment percent differences (PD) by HIV. We conducted sensitivity analyses among non-AIDS-defining cancers (NADC), by sex and by CD4 ≤ 200 or > 200 cells/mm(3). RESULTS: PWH were less likely to be diagnosed at localized stage (PD = − 16%; 95% CI − 21, − 11) and more likely to be diagnosed at regional stage (PD = 14%; 95% CI 8, 19) than those in SEER. Cancer treatment rates were 13% lower among PWH as compared to SEER (95% CI − 18, − 8). The difference in percent receiving cancer treatment was more pronounced for those with lower CD4 at cancer diagnosis (PD −15%; 95% CI − 27, − 6). Lower treatment rates were observed among NADC, males, and women with CD4 ≤ 200. CONCLUSION: Cancer care for PWH could be improved by diagnosis at earlier stages and increasing rates of cancer treatment.

INTRODUCTION: Few studies examine how depression and substance use interact to affect HIV control. METHODS: In 14,380 persons with HIV (PWH), we used logistic regression and generalized estimating equations to evaluate how symptoms of depression interact with alcohol, cocaine, opioid, and methamphetamine use to affect subsequent retention in care, maintaining an active prescription for ART, and consistent virologic suppression. RESULTS: Among PWH with no or mild depressive symptoms, heavy alcohol use had no association with virologic suppression (OR 1.00 [0.95–1.06]); among those with moderate or severe symptoms, it was associated with reduced viral suppression (OR 0.80 [0.74–0.87]). We found no interactions with heavy alcohol use on retention in care or maintaining ART prescription or with other substances for any outcome. DISCUSSION: These results highlight the importance of treating moderate or severe depression in PWH, especially with comorbid heavy alcohol use, and support multifaceted interventions targeting alcohol use and depression.

Accurate, routine measurement of recent illicit substance use is challenging. The Johns Hopkins Human Immunodeficiency Virus Clinical Cohort (Baltimore, Maryland) collects 2 imperfect but routine measurements of recent substance use: medical record review and self-interview. We used Bayesian latent class modeling to estimate sensitivity and specificity of each measurement as well as prevalence of substance use among 2,064 patients engaged in care during 2007-2015. Sensitivity of medical record review was higher than sensitivity of self-interview for cocaine and heroin use; posterior estimates ranged from 44% to 76% for cocaine use and from 39% to 67% for heroin use, depending on model assumptions and priors. In contrast, sensitivity of self-interview was higher than sensitivity of medical record review for any alcohol use, hazardous alcohol use, and cigarette smoking. Posterior estimates of sensitivity of self-interview were generally above 80%, 85%, and 87% for each substance, respectively. Specificity was high for all measurements. From one model, we estimated prevalence of substance use in the cohort to be 12.5% for cocaine, 9.3% for heroin, 48.5% for alcohol, 21.4% for hazardous alcohol, and 55.4% for cigarettes. Prevalence estimates from other models were generally comparable. Measurement error of substance use is nontrivial and should be accounted for in subsequent analyses.

A total of 236 people with HIV (PWH) with cancer diagnosed between 1997 and 2014 in the Johns Hopkins HIV Clinical Cohort (JHHCC) were compared with a sample from NCI's Surveillance, Epidemiology, and End Results (SEER) Program, presumed to be HIV negative. Using G-computation with random survival forest methods, we estimated 5-year restricted mean survival time (RMST) differences by HIV status. Sensitivity analyses were performed among non-AIDS defining cancers, males, females, and stratifying PWH by CD4 ≤ 200 or >200 cells/mm(3) at cancer diagnosis. PWH with CD4 ≤ 200 cells/mm(3) had decreased survival compared with those in SEER (−7 months; 95% CI = −13 to −2). Women with HIV and CD4 ≤ 200 cells/mm(3) at cancer diagnosis had lower survival than SEER women (−10 months; 95% CI = −18 to −2). In the total population, there was no significant difference in 5-year RMST; however, women with HIV and low CD4 had higher mortality despite accounting for stage at diagnosis and first course of cancer treatment.

We estimated 10-year (2020–2030) trajectories for human immunodeficiency virus incidence in 6 US cities. Estimated incidence will only decrease in 2 of 6 cities, with the overall population-weighted incidence decreasing 3.1% (95% credible interval [CrI], ˗1.0% to 8.5%) by 2025, and 4.3% (95% CrI, ˗2.6% to 12.7%) by 2030 across cities. Targeted, context-specific combination implementation strategies will be necessary to meet the newly established national targets.

The prevalence of tobacco smoking among people with HIV (PWH) ranges from 40% to 70%. Additionally, tobacco smoking is higher among low-income individuals, yet few studies have examined tobacco smoking in low socioeconomic status PWH. Using data from a cohort of PWH receiving care in an urban HIV clinic, we characterized factors associated with current and former smoking and with initiation/re-initiation and cessation of tobacco use. Among a study sample of 1,607 PWH, the prevalence of current smoking was 46.6% among men and 46.0% among women. Current smoking in men and women was associated with Medicaid insurance status, substance use, and panic symptoms. In women, but not men, hazardous alcohol use decreased the likelihood of quitting smoking and increased the risk of initiation/re-initiation. Smoking interventions for low-income, urban PWH may need to be tailored to address mental health and substance use comorbidities.

Importance Immunologic decline associated with cancer treatment in people with HIV is not well characterized. Quantifying excess mortality associated with cancer treatment–related immunosuppression may help inform cancer treatment guidelines for persons with HIV. Objective To estimate the association between cancer treatment and CD4 count and HIV RNA level in persons with HIV and between posttreatment CD4 count and HIV RNA trajectories and all-cause mortality. Design, Setting, and Participants This observational cohort study included 196 adults with HIV who had an incident first cancer and available cancer treatment data while in the care of The Johns Hopkins HIV Clinic from January 1, 1997, through March 1, 2016. The study hypothesized that chemotherapy and/or radiotherapy in people with HIV would increase HIV RNA levels owing to treatment tolerability issues and would be associated with a larger initial decline in CD4 count and slower CD4 recovery compared with surgery or other treatment. An additional hypothesis was that these CD4 count declines would be associated with higher mortality independent of baseline CD4 count, antiretroviral therapy use, and risk due to the underlying cancer. Data were analyzed from December 1, 2017, through April 1, 2018. Exposures Initial cancer treatment category (chemotherapy and/or radiotherapy vs surgery or other treatment). Main Outcomes and Measures Post–cancer treatment longitudinal CD4 count, longitudinal HIV RNA level, and all-cause mortality. Results Among the 196 participants (135 [68.9%] male; median age, 50 [interquartile range, 43-55] years), chemotherapy and/or radiotherapy decreased initial CD4 count by 203 cells/μL (95% CI, 92-306 cells/μL) among those with a baseline CD4 count of greater than 500 cells/μL. The decline for those with a baseline CD4 count of no greater than 350 cells/μL was 45 cells/μL (interaction estimate, 158 cells/μL; 95% CI, 31-276 cells/μL). Chemotherapy and/or radiotherapy had no detrimental association with HIV RNA levels. After initial cancer treatment, every 100 cells/μL decrease in CD4 count resulted in a 27% increase in mortality (hazard ratio, 1.27; 95% CI, 1.08-1.53), adjusting for HIV RNA level. No significant increase in mortality was associated with a unit increase in log10HIV RNA after adjusting for CD4 count (hazard ratio, 1.24; 95% CI, 0.94-1.65). Conclusions and Relevance In this study, chemotherapy and/or radiotherapy was associated with significantly reduced initial CD4 count in adults with HIV compared with surgery or other treatment. Lower CD4 count after cancer treatment was associated with an increased hazard of mortality. Further research is necessary on the immunosuppressive effects of cancer treatment in adults with HIV and whether health care professionals must consider the balance of cancer treatment efficacy against the potential cost of further immunosuppression. Monitoring of immune status may also be helpful given the decrease in CD4 count after treatment and the already immunocompromised state of patients with HIV.

Among persons with human immunodeficiency virus (HIV) infection, illegal drug use and hazardous alcohol use are hypothesized to be strong risk factors for failure to achieve or maintain a suppressed HIV viral load, but accurate quantification of this association is difficult because of challenges involved in measuring substance use as part of routine clinical care. We estimated the associations of recent cocaine use, opioid/heroin use, and hazardous alcohol use with unsuppressed viral load among 1,554 persons receiving care at the John G. Bartlett Specialty Practice (Baltimore, Maryland) between 2013 and 2017. We accounted for measurement error in substance use using Bayesian models and prior estimates of the sensitivity and specificity of 2 imperfect measures of substance use derived from a previous analysis in this cohort. The prevalence difference for unsuppressed viral load associated with recent cocaine use was 11.3% (95% credible interval (CrI): 6.4, 17.0); that associated with recent opioid/heroin use was 13.2% (95% CrI: 6.6, 20.7); and that associated with recent hazardous alcohol use was 8.5% (95% CrI: 3.2, 14.4). Failure to account for measurement error resulted in clinically meaningful underestimates of the prevalence difference. Time-varying substance use is prevalent and difficult to measure in routine care; here we demonstrate a method that improves the utility of imperfect data by accounting for measurement error.

Summary Background After steady decline since the 1990s, tuberculosis incidence in New York City and throughout the USA has plateaued. We aimed to explore the major drivers of the flattening of tuberculosis incidence in New York City and to project the future trajectory of the tuberculosis epidemic in the absence of any additional intervention. Methods We developed a compartmental transmission model of tuberculosis in New York City. The model was parameterised with detailed epidemiological data and stratified by age and nativity (US-born vs foreign-born). We ran the model under five alternative scenarios representing different explanations for recent declines in tuberculosis incidence. We evaluated the relative likelihood of each scenario by comparing its output with available data. We used the most likely scenarios to explore potential mechanisms underlying the recent declines in tuberculosis in New York City and to describe the reasonable range of future epidemic trajectories. Our primary outcome was the projected rate of decline in tuberculosis incidence from 2015 to 2025. Model calibration yielded estimates of future disease incidence and reductions in incidence with 95% credible intervals (CrIs). Findings Demographic changes and declining tuberculosis transmission alone were insufficient to explain recent trends in tuberculosis incidence in New York City. Only scenarios that assumed contemporary changes in tuberculosis dynamics among foreign-born individuals—a declining rate of reactivation or a decrease in imported subclinical tuberculosis—could accurately describe the trajectory of disease incidence since 2007. In those scenarios, the projected decline in incidence from 2015 to 2025 varied from minimal (2·0% per year [95% CrI 0·4–3·5]) to similar to 2005 to 2009 trends (4·4% per year [2·5–6·4]). The primary factor differentiating optimistic from pessimistic projections was the degree to which improvements in tuberculosis dynamics among the foreign-born population continued into the coming decade. Interpretation Further progress towards elimination of tuberculosis in New York City requires additional focus on the foreign-born population. Without additional intervention in this group, tuberculosis incidence might not decline further. Funding None.

In May, 2016, WHO endorsed a 9 month regimen for multidrug-resistant tuberculosis that is cheaper and potentially more effective than the conventional, longer (20-24 month) therapy. We aimed to investigate the population-level implications of scaling up this new regimen.In this population modelling analysis, we developed a dynamic transmission model to simulate the introduction of this short-course regimen as an instantaneous switch in 2016. We projected the corresponding percentage reduction in the incidence of multidrug-resistant tuberculosis by 2024 compared with continued use of longer therapy. In the primary analysis in a representative southeast Asian setting, we assumed that the short-course regimen would double treatment access (through savings in resources or capacity) and achieve long-term efficacy at levels seen in preliminary cohort studies. We then did extensive sensitivity analyses to explore a range of alternative scenarios.Under the optimistic assumptions in the primary analysis, the incidence of multidrug-resistant tuberculosis in 2024 would be 3·3 (95% uncertainty range 2·2-5·6) per 100 000 population with the short-course regimen and 4·3 (2·9-7·6) per 100 000 population with continued use of longer therapy-ie, the short-course regimen could reduce incidence by 23% (10-38). Incidence would be reduced by 14% (4-28) if the new regimen affected only treatment effectiveness and by 11% (3-24) if it affected only treatment availability. Under more pessimistic assumptions, the short-course regimen would have minimal effect and even potential for harm-eg, when 30% of patients are ineligible for the new regimen because of second-line drug resistance, we projected a change in incidence of -2% (-20 to +28). The new regimen's effect was greater in settings with more ongoing transmission of multidrug-resistant tuberculosis, but results were otherwise similar across settings with different levels of tuberculosis incidence and prevalence of multidrug resistance.The short-course regimen has potential to substantially lessen the multidrug-resistant tuberculosis epidemic, but this effect depends on its long-term efficacy, its ability to expand treatment access, and the role of second-line drug resistance.US National Institutes of Health and BillMelinda Gates Foundation.

Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluateTen patients with measurable BCBM received ANG1005 at a dose of 550 mg/mThirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was -17.5 % (n = 10 patients, lower, upper quartiles: -25.5, -4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUVANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and

Background Duty hour limits have shortened intern shifts without concurrent reductions in workload, creating work compression. Multiple admissions during shortened shifts can result in poor training experience and patient care. Objective To relieve work compression, improve resident satisfaction, and improve duty hour compliance in an academic internal medicine program. Methods In 2014, interns on general ward services were allotted 90 minutes per admission from 3 pm to 7 pm, when the rate of admissions was high. Additional admissions arriving during the protected period were directed to hospitalists. Resident teams received 2 patients admitted by the night float team to start the call day (front-fill). Results Of the 51 residents surveyed before and after the implementation of the intervention, 39 (77%) completed both surveys. Respondents reporting an unmanageable workload fell from 14 to 1 (P < .001), and the number of residents reporting that they felt unable to admit patients in a timely manner decreased from 14 to 2 (P < .001). Reports of adequate time with patients increased from 16 to 36 (P < .001), and residents indicating that they had time to learn from patients increased from 19 to 35 (P < .001). Reports of leaving on time after call days rose from 12 to 33 (P < .01), and overall satisfaction increased from 26 to 35 (P = .002). Results were similar when residents were resurveyed 6 months after the intervention. Conclusions Call day modifications improved resident perceptions of their workload and time for resident learning and patient care.

To determine the diagnostic usefulness of tuberculosis (TB) symptom screening to detect active pulmonary TB among human immunodeficiency virus (HIV) infected pregnant women in two PMTCT (prevention of mother-to-child transmission) clinics in western Kenya that are supported by the United States Agency for International Development-Academic Model Providing Access to Healthcare partnership.Cross-sectional study. Participants were interviewed for TB symptoms with a standardized questionnaire (cough2 weeks, fever, night sweats, weight loss or failure to gain weight). Those with cough submitted sputum specimens for smear microscopy for acid-fast bacilli and mycobacterial culture. Women at14 weeks gestation underwent shielded chest radiography (CXR).Of 187 HIV-infected women, 38 (20%) were symptom screen-positive. Of these, 21 had a cough for2 weeks, but all had negative sputum smears and mycobacterial cultures. CXRs were performed in 26 symptomatic women: three were suggestive of TB (1 miliary, 1 infiltrates and 1 cavitary). Of 149 women with a negative symptom screen, 100 had a CXR and seven had a CXR suggestive of TB (1 cavitary, 2 miliary and 4 infiltrates).This study did not support the utility of isolated symptom screening in identification of TB disease in our PMTCT setting. CXR was useful in identification of TB suspects in both symptomatic and asymptomatic women.Déterminer l’utilité diagnostique du dépistage des symptômes de la tuberculose (TB) pour la détection d’une TB pulmonaire active parmi les femmes enceintes séropositives pour le VIH dans deux polycliniques (PMTCT) de prévention de la transmission du VIH mère-à-enfant soutenues par le partenariat USAID–AMPATH dans l’ouest du Kenya.Étude transversale. Les participants ont été interviewés concernant les symptômes TB en utilisant un questionnaire standardisé (toux depuis2 semaines, sueurs nocturnes, perte ou échec de gain de poids). Les femmes qui toussaient ont donné deux échantillons de crachats pour l’examen microscopique des frottis à la recherche de bacilles acido-résistants et pour la culture. Les femmes enceintes de14 semaines ont subi un cliché thoracique (CXR) avec écran protecteur.Sur les 187 femmes séropositives pour le VIH, le dépistage des symptômes a été positif chez 38 (20%) ; parmi ces dernières, 21 toussaient depuis2 semaines mais chez toutes les frottis et les cultures mycobactériennes des crachats se sont révélés négatifs. On a réalisé un CXR chez 26 femmes symptomatiques ; chez trois d’entre elles, le cliché a suggéré une TB (miliaire 1, infiltrats 1 et creusement 1). Sur les 149 femmes chez qui le dépistage des symptômes s’est avéré négatif, 100 ont subi un CXR et chez sept d’entre elles, le cliché a suggéré une TB (creusement 1, miliaire 2 et infiltrats 4).Cette étude ne soutient pas l’utilité d’un dépistage isolé des symptômes pour l’identification d’une maladie TB dans le contexte du PMTCT. Le CXR s’est révélé utile pour l’identification des suspects de TB tant chez les femmes symptomatiques qu’asymptomatiques.Determinar la utilidad diagnóstica de la evaluación sistemática de los síntomas de tuberculosis (TB) con el fin de detectar la TB activa en las mujeres infectadas por el virus de la inmunodeficiencia humana (VIH) y embarazadas que acuden a dos consultorios de prevención de la transmisión maternoinfantil del VIH, financiados por la Alianza USAID–AMPATH en el occidente de Kenia.Fue este un estudio transversal, en el cual se administró a las participantes un cuestionario normalizado (tos de2 semanas de duración, fiebre, sudores nocturnos y pérdida de peso o imposibilidad de ganar peso). Las mujeres que refirieron tos aportaron muestras de esputo para baciloscopia y cultivo de micobacterias. Se practicó una radiografía de tórax (CXR) protegida a las mujeres con más de 14 semanas de gestación.En 38 de las 187 mujeres con infección por el VIH (20%), la detección de síntomas fue positiva. De estas mujeres, 21 refirieron tos de2 semanas de evolución, pero todos los resultados de las baciloscopias y los cultivos de micobacterias fueron negativos. Se practicaron CXR en 26 mujeres sintomáticas y tres de ellas presentaron imágenes indicativas de TB (un aspecto miliar, un infiltrado y un caso con cavernas). De las 149 mujeres con una detección sintomática negativa, en 100 se practicó la CXR y siete presentaron imágenes en favor del diagnóstico de TB (un caso con cavernas, dos aspectos miliares y cuatro con infiltrados).Los resultados del presente estudio no respaldan la utilidad de una detección exclusiva de los síntomas, con el fin de diagnosticar los casos de enfermedad TB en este contexto de la consulta de prevención de la transmisión maternoinfantil del VIH. La CXR se reveló útil en la detección de casos con presunción de TB en las mujeres sintomáticas y asintomáticas.

Pituitary homeobox 1 (Ptx1/Pitx1) is a homeodomain-containing transcription factor present throughout pituitary development. Ptx1/Pitx1 interacts with steroidogenic factor 1 (SF-1) in the regulation of pituitary gene expression. SF-1 also plays a critical role in the transcription of enzymes involved in adrenal steroidogenesis. Therefore, we analyzed the presence and role of Ptx1/Pitx1 in human adrenal cortex. Both Ptx1/Pitx1 and SF-1 mRNA were expressed in the human adrenal gland, and immuno-electron microscopy demonstrated the presence of Ptx1/Pitx1 protein in the nucleus of adrenocortical cells. Computer analysis revealed the presence of Ptx1/Pitx1 signal sequences within the promoter region of human 11beta hydroxylase ( hCYP11B1). To examine the role of Ptx1/Pitx1 in the regulation of the genes, we prepared reporter constructs using the 5'-flanking DNA of the hCYP11B1 gene and transfected them into Y-1 mouse adrenocortical cells, HeLa and CV-1 cells. Ptx1/Pitx1 stimulation of hCYP11B1 reporter activity (3-fold over basal) in Y-1 cells was equal to that observed with SF-1. The hCYP11B1 promoter activity in Y-1 cells was not synergistically increased by co-transfection with both Ptx1/Pitx1 and SF-1. Both basal and ACTH-stimulated hCYP11B1 reporter activities in Y-1 cells were increased by co-transfection with either Ptx1/Pitx1 or SF-1 expression vectors. In contrast, co-transfection with both Ptx1/Pitx1 and SF-1 synergistically increased hCYP11B1 promoter activity in HeLa and CV-1 cells (5-fold and 20-fold over basal, respectively). In conclusion, this study represents the first demonstration for a role of Ptx1/Pitx1 in the regulation of transcription of enzymes involved in adrenal steroidogenesis.

A 95 kDa membrane protein (P-95) has been previously noted to be overexpressed in a doxorubicin-resistant subline of the MCF-7 breast cancer line and in clinical samples obtained from patients with solid tumours refractory to doxorubicin. We performed Western blotting on blast cell lysates from adults with acute myeloid leukaemia, using antisera to P-95. Concomitant flow cytometric assays measured daunorubicin accumulation and retention. Blasts from 16/46 patient samples had detectable P-95 and had reduced accumulation of daunorubicin compared with the negative marrows. Experiments with the P-95 positive MCF-7 multidrug-resistant subline demonstrated decreased daunorubicin accumulation and retention relative to the sensitive parent line. AML blast cells positive for P-95 also demonstrated greater overall in vitro survival in the presence of daunorubicin relative to the P-95-negative samples. The expression of P-95 did not correlate with failure to achieve an initial complete remission with daunorubicin and cytarabine induction chemotherapy. We conclude that the P-95 protein may possess an efflux transporter function, and may represent another mechanism responsible for anthracycline resistance in acute myeloid leukaemia. Images Figure 1

Three decades since the introduction of cisplatin into clinical cancer treatment, this drug and its second generation analogues, carboplatin and oxaliplatin, form an integral part of recent evolving achievements in the treatment of solid tumors. For example, landmark studies have established a role for cisplatin after resection in lung cancer, and improved survival from platinum-based chemoradiation in cancer of the uterine cervix and combination chemotherapy in mesothelioma, small cell lung, ovarian, and endometrial cancers. Colon cancer survival has improved with the addition of oxaliplatin to its treatment. Here we summarize how insights into the mechanism of action of platinum compounds and studies of their structure-activity relationships may identify platinums with unusual selectivity towards tumors such as melanoma, renal cell, and breast cancer and other cancers not usually treated with existing platinums. Both new drug development and mechanistic studies with established drugs should lead to the next generation of clinical studies with platinum compounds, and their integration with emerging 'targeted therapies'.

Some types of cancer respond far less favorably to treatment than do others. A quantitative estimate of this intuition can be obtained from the SEER (Surveillance, Epidemiology and End-Results) Cancer Statistics Review. Of particular interest, from a drug resistance perspective, are the five-year survival data for patients presenting with tumors that were diagnosed as "distant". A good correlation can be found between those numbers and an estimate of treatment successes obtained from a survey of current literature on chemotherapy applied to cancers originating from these various tissues. These two measures, considered together, define "the axis of intractability", a parameter that characterizes the (possibly) inherent, physiological basis of the tissue-by-tissue intractability of cancers. Exploring the basis of this intractability, it appears that factors other than the classical ABC transporter-based, multidrug resistance systems probably play a major role. An ineffective DNA repair system, coupled to reduced apoptosis, is the basis for the inherent tractability of testicular cancer. For other tissues, important contributions to resistance arise from cell adhesion-mediated drug resistance, which is overcome when cells are released from tissues during anoikis. Making a direct comparison between gene expression in solid tumors and their corresponding cell lines, genes controlling the extracellular matrix and cell-cell communication appear among the genes that are over-expressed in the solid tumors, while genes coding for the protein biosynthesis system are over-expressed in the cell lines. The more tractable cancers are closer to the cell lines in their expression profiles of these sets of genes.

We have designed and developed a Gene Ontology based navigation tool, GoMiner, which organizes lists of interesting genes from a microarray or a protein array experiment for biological interpretation. It provides quantitative and statistical output files and useful visualization (e.g., a tree -like structure) to map the list of genes to its biological functional categories. It also provides links to other resources such as pubmed, locuslink, and biological molecular interaction map and signaling pathway packages.

PSC 833 is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance (MDR). The authors conducted a Phase I study of orally administered PSC 833 in combination with vinblastine administered as a 5-day continuous infusion.Seventy-nine patients with advanced malignant disease were enrolled in the trial and treated with escalating doses of PSC 833. Pharmacokinetic interactions between PSC 833 and vinblastine were anticipated. Accordingly, when dose limiting toxicities were observed, the dose of vinblastine was reduced as PSC 833 was escalated. Three schedules and two formulations of PSC 833 were used in the study.The maximum tolerated doses of PSC 833 were 12.5 mg/kg orally every 12 hours for 8 days for the liquid formulation in combination with 0.9 mg/m(2) per day vinblastine as a continuous intravenous infusion (CIV) for 5 days; and 4 mg/kg orally every 6 hours for 8 days for the microemulsion formulation in combination with 0.6 mg/m(2) per day vinblastine CIV for 5 days. The principal toxicities for PSC 833 were ataxia and paresthesias and for the combination, constipation, fever. and neutropenia. Increased oral bioavailability and increased peak and trough concentrations were observed with the microemulsion formulation. Significant interpatient variability in pharmacokinetic parameters was observed. Ten patients studied at the MTD for PSC 833 (4 mg/kg orally every 6 hours for 8 days) had inhibition of rhodamine efflux from CD56 positive peripheral lymphocytes as a surrogate for Pgp antagonism. Among 43 evaluable patients with clear cell carcinoma of the kidney, 3 patients had complete responses, and 1 patient had a partial response.PSC 833 in combination with vinblastine can be administered safely to patients provided the vinblastine dose is adjusted for pharmacokinetic interactions. The high interpatient variability is a significant confounding factor. Surrogate studies with CD56 positive cells suggest that Pgp inhibition in the clinical setting is achievable. Improved methods for predicting pharmacokinetic interactions should improve future studies.

Microtubules (MTs) are cytoskeletal components whose structural integrity is mandatory for the execution of many basic cell functions. Utilizing parental and drug-resistant ovarian carcinoma cell lines that have acquired point mutations in beta-tubulin and p53, we studied the level of expression and modification of proteins involved in apoptosis and MT integrity. Extending previous results, we demonstrated phosphorylation of pro-survival Bcl-x(L) in an epothilone-A resistant cell line, correlating it with drug sensitivity to tubulin-active compounds. Furthermore, Mcl-1 protein turned over more rapidly following exposure to tubulin-modifying agents, the stability of Mcl-1 protein paralleling the drug sensitivity profile of the paclitaxel or epothilone-A resistant cell lines. The observed decreases in Mcl-1 were not a consequence of G(2)M arrest, as determined by flow cytometry analysis, which showed prominent levels of Mcl-1 in the absence of any drug treatment in populations enriched in mitotic cells. We also observed that a paclitaxel-resistant cell line expressed Bax at a much lower level than the sensitive parental line [A2780(1A9)], consistent with its mutant p53 status. MT-associated protein-4 (MAP4), whose phosphorylation during specific phases of the cell cycle reduces its MT-polymerizing and -stabilizing capabilities, was phosphorylated in response to drug challenge without a change in expression. Phosphorylation of MAP4 correlated with sensitivity to tubulin-binding drugs and with a dissociation from MTs. We propose that the tubulin mutations, which result in a compromised paclitaxel:tubulin or epothilone:tubulin interaction and paclitaxel or epothilone resistance, indirectly inhibit downstream events that lead to cell death, and this, in turn, may contribute to the drug-resistance phenotype

To understand resistance to topoisomerase II inhibitors, we used four cancer cell lines (ZR-75B, MDA-MB-231, T47D, and MCF-7) and performed a single-step selection process to isolate 50 clones resistant to topoisomerase II inhibitors. Of these, 26 were isolated with VP-16 and 24 with mAMSA. Sixteen of these isolates (four from each cell line; two selected with VP-16 and two with mAMSA) were further exposed to higher drug concentrations. Characterization of the resistant sublines revealed the adaptation that occurs with increasing drug concentration during in-vitro selections. Reduced topoisomerase IIalpha mRNA level was observed in the majority of the initial isolates. This reduction was accompanied by a decrease in topoisomerase II activity. Other isolates showed increased levels of multidrug resistance-associated protein (MRP). With advancing resistance, MRP expression was increased further, concomitantly with some recovery in topoisomerase IIalpha expression and topoisomerase II activity. In these sublines, high levels of resistance were attained as a result of synergism between the reduced topoisomerase IIalpha levels and MRP overexpression. These results extend previous studies demonstrating how cellular adaptation to increasing drug pressure utilizes more than one mechanism. Reduced expression of topoisomerase IIalpha occurs early in the selection process. MRP overexpression can occur early or can help to confer high levels of resistance. In the latter case, MRP overexpression allows some recovery of topoisomerase II activity without loss of high drug resistance.

The presence of coxsackie and adenovirus receptor (CAR) and alpha(v) integrin on cell surfaces is required for efficient adenovirus infection. Treatment of cells with the histone deacetylase inhibitor FR901228 (depsipeptide) increased CAR and alpha(v) integrin RNA levels in six cancer cell lines. Sodium butyrate and trichostatin A, other histone deacetylase inhibitors, caused similar increases. Cells treated with FR901228 prior to infection had a 4-10-fold increase in transgene expression from a beta-galactosidase-expressing adenoviral vector. These studies suggest that FR901228 increases the efficiency of adenoviral transgene expression and may be useful in cancer gene therapy.

Lack of selectivity in the killing of tumor and normal cells is a major obstacle in cancer therapy. By inhibiting normal but not autonomous cell growth, we exploited the differences in cell cycle regulation to achieve a selective protection of nonautonomous cells against paclitaxel and other microtubule-active drugs. Tubulin polymerization, a primary effect of paclitaxel, can be dissociated from Bcl-2 phosphorylation and cytotoxicity in HL-60 cells. Growth arrest prevented paclitaxel-induced Bcl-2 phosphorylation and apoptosis without affecting paclitaxel-induced tubulin polymerization. We abrogated the effects of paclitaxel on MCF-10A immortalized breast cells, while preserving its effects on MCF-7 cancer cells. Unlike MCF-7 cells, MCF-10A cells were arrested by epidermal growth factor withdrawal, precluding paclitaxel-induced Bcl-2 phosphorylation. Furthermore, the inhibition of the epidermal growth factor receptor kinase with low doses of AG1478 arrested growth of MCF-10A but not MCF-7 cells. Pretreatment with AG1478 did not affect paclitaxel-induced Bcl-2/Raf-1 phosphorylation in MCF-7 but abrogated such phosphorylation in MCF-10A. Exploitation of growth factor dependency may allow the protection of normal cells from microtubule-active drugs.