Alicia Hulbert

Neoadjuvant chemoradiation therapy is beneficial for clinical stage T2 N0 esophageal cancer patients due to inaccurate preoperative staging.

BACKGROUND It remains unclear if patients with clinical stage T2 N0 (cT2 N0) esophageal cancer should be offered induction therapy vs surgical intervention alone. METHODS This was a retrospective cohort study of cT2 N0 patients undergoing induction therapy, followed by surgical resection, or resection alone, at the Johns Hopkins Hospital from 1989 to 2009. Kaplan-Meier analysis was used to compare all-cause mortality in cT2 N0 patients who had resection alone vs those who had induction chemoradiation therapy, followed by resection. RESULTS A study cohort of 69 patients was identified and divided into two groups: 55 patients (79.7%) received induction therapy and 14 (20.3%) did not. No statistically significant difference in 5-year survival rate was observed for the two groups: 49.5% for the resection-only group and 53.8% for the induction group. More than 50% of cT2 N0 patients were understaged. CONCLUSIONS For cT2 N0 esophageal cancer patients, the benefit of neoadjuvant therapy is still unclear. Induction therapy for cT2 N0 did not translate into a statistically significant improvement in survival. However, due to the significant understaging of T2 N0 patients, we recommend neoadjuvant therapy to all cT2N0 patients before operation.

Functional Identification of Cancer-Specific Methylation of CDO1, HOXA9, and TAC1 for the Diagnosis of Lung Cancer

Purpose: Non–small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer. Experimental Design: Following previously validated methods for the discovery of cancer-specific hypermethylation changes, we treated eight NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publicly available database and two independent cohorts of primary samples. Results: We identified >300 candidate genes. Using The Cancer Genome Atlas (TCGA) and extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This three-gene panel is 100% specific, showing no methylation in 75 TCGA normal and seven primary normal samples and is 83% to 99% sensitive for NSCLC depending on the cohort. Conclusion: This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this three-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC. Clin Cancer Res; 20(7); 1856–64. ©2014 AACR.

Prospective CT Screening for Lung Cancer in a High-Risk Population: HIV-Positive Smokers

Background: Epidemiological evidence suggests that HIV-infected individuals are at increased risk of lung cancer, but no data exist because large computed tomography (CT) screening trials routinely exclude HIV-infected participants. Methods: From 2006 to 2013, we conducted the worlds first lung cancer screening trial of 224 HIV-infected current/former smokers to assess the CT detection rates of lung cancer. We also used 130 HIV-infected patients with known lung cancer to determine radiographic markers of lung cancer risk using multivariate analysis. Results: Median age was 48 years with 34 pack-years smoked. During 678 person-years, one lung cancer was found on incident screening. Besides this lung cancer case, 18 deaths (8%) occurred, but none were cancer related. There were no interim diagnoses of lung or extrapulmonary cancers. None of the pulmonary nodules detected in 48 participants at baseline were diagnosed as cancer by study end. The heterogeneity of emphysema across the entire lung as measured by CT densitometry was significantly higher in HIV-infected subjects with lung cancer compared with the heterogeneity of emphysema in those without HIV (p ⩽ 0.01). On multivariate regression analysis, increased age, higher smoking pack-years, low CD4 nadir, and increased heterogeneity of emphysema on quantitative CT imaging were all significantly associated with lung cancer. Conclusions: Despite a high rate of active smoking among HIV-infected participants, only one lung cancer was detected in 678 patient-years. This was probably because of the young age of participants suggesting that CT screening of high-risk populations should strongly consider advanced age as a critical inclusion criterion. Future screening trials in urban American must also incorporate robust measures to ensure HIV patient compliance, adherence, and smoking cessation.

Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum.

Purpose: CT screening can reduce death from lung cancer. We sought to improve the diagnostic accuracy of lung cancer screening using ultrasensitive methods and a lung cancer–specific gene panel to detect DNA methylation in sputum and plasma. Experimental Design: This is a case–control study of subjects with suspicious nodules on CT imaging. Plasma and sputum were obtained preoperatively. Cases (n = 150) had pathologic confirmation of node-negative (stages I and IIA) non–small cell lung cancer. Controls (n = 60) had non-cancer diagnoses. We detected promoter methylation using quantitative methylation-specific real-time PCR and methylation-on-beads for cancer-specific genes (SOX17, TAC1, HOXA7, CDO1, HOXA9, and ZFP42). Results: DNA methylation was detected in plasma and sputum more frequently in people with cancer compared with controls (P < 0.001) for five of six genes. The sensitivity and specificity for lung cancer diagnosis using the best individual genes was 63% to 86% and 75% to 92% in sputum, respectively, and 65% to 76% and 74% to 84% in plasma, respectively. A three-gene combination of the best individual genes has sensitivity and specificity of 98% and 71% using sputum and 93% and 62% using plasma. Area under the receiver operating curve for this panel was 0.89 [95% confidence interval (CI), 0.80–0.98] in sputum and 0.77 (95% CI, 0.68–0.86) in plasma. Independent blinded random forest prediction models combining gene methylation with clinical information correctly predicted lung cancer in 91% of subjects using sputum detection and 85% of subjects using plasma detection. Conclusions: High diagnostic accuracy for early-stage lung cancer can be obtained using methylated promoter detection in sputum or plasma. Clin Cancer Res; 23(8); 1998–2005. ©2016 AACR.

Why are patients being readmitted after surgery for esophageal cancer

OBJECTIVE Readmission after surgery is an unwanted adverse event that is costly to the healthcare system. We sought to evaluate factors associated with increased risk of readmission and to characterize the nature of these readmissions in patients who have esophageal cancer. METHODS A retrospective cohort study was performed in 306 patients with esophageal carcinoma who underwent neoadjuvant chemoradiation followed by esophagectomy at Johns Hopkins Hospital between 1993 and 2011. Logistic regression was used to identify factors associated with 30-day readmission. Readmissions were defined as inpatient admissions to our institution within 30 days of discharge. RESULTS The median age at surgery was 61 years; the median postoperative length of stay was 9 days; and 48% of patients had ≥1 postoperative complication (POC). The 30-day readmission rate was 13.7% (42 of 306). In univariate analysis, length of stay and having ≥1 POC were significantly associated with readmission. In multivariate analysis, having ≥1 POC was significantly associated with a >2-fold increase in risk for 30-day readmission (odds ratio 2.35, with 95% confidence interval [1.08-5.09], P = .031) when controlling for age at diagnosis and length of stay. Of the 42 patients who were readmitted, 67% experienced POCs after surgery; 50% of patients who experienced POCs were readmitted for reasons related to their postoperative complication. The most common reasons for readmission were pulmonary issues (29%), anastomotic complications (20%), gastrointestinal concerns (17%), and venous thromboembolism (14%). CONCLUSIONS Complications not adequately managed before discharge may lead to readmission. Quality improvement efforts surrounding venous thromboembolism prophylaxis, and discharging patients nothing-by-mouth, may be warranted.

Correlates of Risky Injection Practices among Past-Year Injection Drug Users among the US General Population

BACKGROUND With an estimated 1 million active injection drug users (IDUs), injection drug use continues to be a public health concern in the United States. Risky injection practices have been associated with the transmission of HIV, Hepatitis B and C, as well as other skin and soft tissue infections. METHODS We used data from 463 respondents, aged 18 and older, who were past-year IDUs in the 2005-2008 National Survey of Drug Use and Health (NSDUH). We investigated correlates of risky injection behavior among these recent IDUs. RESULTS Older age (≥ 35 versus 18-25) was associated with reusing ones own needle at last injection (aOR=1.80 [1.02-3.17], as were past year heroin (aOR=2.59 [1.18-5.66]) and cocaine injection (aOR=2.17 [1.13-4.15]). Past year crack cocaine use was positively associated with not cleaning needles with bleach (aOR=2.18 [1.10-4.33]). Past year cocaine injection was associated with obtaining needles in a risky manner (aOR=2.29 [1.23-4.25]). Methamphetamine injection was associated with obtaining needles in less risky ways (aOR=0.41 [0.20-0.84]). CONCLUSION Our findings indicate that some IDUs are continuing to engage in high risk injection behaviors. The identification of potential at-risk populations of IDUs may have implications for harm reduction interventions and HIV prevention programs.

Human immunodeficiency virus infection as a prognostic factor in surgical patients with non-small cell lung cancer

BACKGROUND The purpose of this study was to assess the effect of human immunodeficiency virus (HIV) infection on postoperative survival among non-small cell lung cancer (NSCLC) patients. METHODS A retrospective cohort study compared 22 HIV-infected lung cancer patients to 2,430 lung cancer patients with HIV-unspecified status who underwent resection at Johns Hopkins Hospital from 1985 to 2009. Subcohort comparative analyses were performed using individual matching methods. RESULTS Thirty-day mortality rates did not differ between HIV-infected and HIV-unspecified patients. Survival rates for HIV-infected lung cancer patients were significantly shorter than for HIV-unspecified patients (median, 26 versus 48 months; p=0.001). After adjustment, the relative hazard of mortality among HIV-infected NSCLC patients was more than threefold that of HIV-unspecified patients (adjusted hazard ratio, 3.08; 95% confidence interval: 1.85 to 5.13). When additional surgical characteristics were modeled in a matched subcohort, the association remained statistically significant (adjusted hazard ratio, 2.31; 95% confidence interval: 1.11 to 4.81). Moreover, HIV-infected lung cancer patients with CD4 counts less than 200 cells/mm3 had shortened median survival compared with patients whose CD4 counts were 200 cells/mm3 or greater (8 versus 40 months; p=0.031). Postoperative pulmonary and infectious complications were also elevated in the HIV-infected group (p=0.001 and p<0.001, respectively). After surgery, median time to cancer progression was shorter among HIV-infected patients (20.4 months) versus HIV-unspecified patients (p=0.061). CONCLUSIONS The HIV-infected NSCLC patients have more postoperative complications, rapid progression to disease recurrence, and poorer postoperative survival. Optimizing immune status before surgery and careful patient selection based on diffusion capacity of lung for carbon monoxide may improve patient outcomes.

DREAMing: a simple and ultrasensitive method for assessing intratumor epigenetic heterogeneity directly from liquid biopsies

Many cancers comprise heterogeneous populations of cells at primary and metastatic sites throughout the body. The presence or emergence of distinct subclones with drug-resistant genetic and epigenetic phenotypes within these populations can greatly complicate therapeutic intervention. Liquid biopsies of peripheral blood from cancer patients have been suggested as an ideal means of sampling intratumor genetic and epigenetic heterogeneity for diagnostics, monitoring and therapeutic guidance. However, current molecular diagnostic and sequencing methods are not well suited to the routine assessment of epigenetic heterogeneity in difficult samples such as liquid biopsies that contain intrinsically low fractional concentrations of circulating tumor DNA (ctDNA) and rare epigenetic subclonal populations. Here we report an alternative approach, deemed DREAMing (Discrimination of Rare EpiAlleles by Melt), which uses semi-limiting dilution and precise melt curve analysis to distinguish and enumerate individual copies of epiallelic species at single-CpG-site resolution in fractions as low as 0.005%, providing facile and inexpensive ultrasensitive assessment of locus-specific epigenetic heterogeneity directly from liquid biopsies. The technique is demonstrated here for the evaluation of epigenetic heterogeneity at p14ARF and BRCA1 gene-promoter loci in liquid biopsies obtained from patients in association with non-small cell lung cancer (NSCLC) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN), respectively.

Alcohol, drug, and sexual risk behavior correlates of recent transactional sex among female black South African drug users

Introduction: Transactional sex among black South African women has become a mode of economic survival putting them at higher risk for HIV and other infectious disease. Methods: In order to inform HIV interventions, drug, and sexual risk behavior correlates of recent transactional sex among a descriptive epidemiological, cross-sectional sample of 189, black South African women in Pretoria were examined using log binomial regression. Results: Prevalence of HIV seropositivity was extremely high among non-transactional sex workers (47.1%) and transactional sex workers (54.6%), albeit not significantly different. Adjusted regression results indicated that the probability of transactional sex was greater for drug using women who tested positive for cocaine use [adjusted prevalence ratio (APR) = 1.3, 95% CI = 1.1, 1.5] and knew of anyone who died of AIDS (APR = 1.5, 95% CI = 1.1, 2.1). The probability of transactional sex was lower for female drug users who reported greater education (APR = 0.6, 95% CI = 0.4, 0.8), condom use in their first sexual encounter (APR = 0.7, 95% CI = 0.6, 1.0), or reported a recent steady sexual partnership (APR = 0.8, 95% CI = 0.7, 0.9). Conclusions: Drug use-related interventions for female transactional sex workers may need to focus on methods for the reduction of not only drug use, especially cocaine use, but also the reduction of sexual risk behaviors.

Examining Racial/Ethnic Disparities in Sexually Transmitted Diseases Among Recent Heroin-Using and Cocaine-Using Women

BACKGROUND This study examined racial differences in the prevalence of sexual risk behaviors and their associations with sexually transmitted diseases (STDs) among recent heroin-using and cocaine-using women. METHODS Participants were 214 women (59% black, 41% white) who were recruited during 2002-2010 using targeted sampling to participate in a study in Baltimore, Maryland, and reported using heroin, cocaine, or crack during the previous 6 months. Participants completed self-report questionnaires about their drug use, sexual risk behaviors, and lifetime history of one of six STDs, including gonorrhea, syphilis, chlamydia, genital herpes, genital warts, or trichomoniasis. RESULTS More black women (50%) than white women (28%) reported a lifetime STD. Although there were no racial differences in the lifetime prevalence of sexual risk behaviors assessed, there were racial differences in the sexual behaviors associated with ever having a lifetime STD. Simple logistic regressions revealed that ever having a casual sex partner or anal sex were correlates of having a lifetime STD among black women but not among white women. Multiple logistic regression analyses revealed that ever having a casual sex partner was significantly associated with having a lifetime STD among black women, and ever trading sex for money was significantly associated with having a lifetime STD among white women. CONCLUSIONS Findings are consistent with national studies and elucidate racial disparities in STDs and associated sexual behaviors among recent heroin-using and cocaine-using women. Findings underscore the need to tailor STD prevention interventions differently for black and white recent heroin-using and cocaine-using women.