Ann Thorac Surg 2012;93:405-412. doi:10.1016/j.athoracsur.2011.11.012
© 2012 The Society of Thoracic Surgeons
Original Articles: General Thoracic
Human Immunodeficiency Virus Infection as a Prognostic Factor in Surgical Patients With Non-Small Cell Lung Cancer
Craig M. Hooker, MPHa,*,
Robert A. Meguid, MD, MPHb,d,*,
Alicia Hulbert, MDa,
Joshua T. Taylor, MDb,e,
James Shin, BSa,
John Wrangle, MD, MPHa,
Kristen Rodgers, BSa,
Beverly Lee, BSa,
Suvasini Laskshmanan, BSa,
Travis Brown, BSb,
Avedis Meneshian, MDb,
Marc Sussman, MDb,
Jeanne Keruly, MSc,
Richard D. Moore, MD, MHSc,
Stephen C. Yang, MDa,b,
Malcolm V. Brock, MDa,b,*
a Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland
b Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
c Department of Infectious Disease, Johns Hopkins School of Medicine, Baltimore, Maryland
d Department of Surgery, University of Washington, Seattle, Washington
e Department of Surgery, Vanderbilt University, Nashville, Tennessee
Accepted for publication November 7, 2011.
* Address correspondence to Dr Brock, 600 N Wolfe St, Blalock 240, Johns Hopkins Hospital, Baltimore, MD 21287 (Email: mabrock{at}jhmi.edu).
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Abstract
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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.
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Introduction
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Numerous epidemiologic studies have noted an elevated risk of lung cancer among human immunodeficiency virus (HIV)-infected patients [1–5]. Typically, these patients are younger, have advanced stage, and worse overall survival compared with lung cancer patients from the general population [6–8]. So advanced is their stage at presentation, that only 10% to 15% of HIV lung cancer patients undergo curative resection [7]. Owing to this paucity of patients with early disease, few data exist on surgical outcomes in these patients [9–18], with a cumulative total in the literature of fewer than 25 patients. The present general consensus based on this limited sample size has been to offer surgery with curative intent to HIV-infected non-small cell lung cancer (NSCLC) patients, regardless of their immune state, if there is localized disease and good patient performance status [9, 16].
From 1985 to 2009, 22 HIV-infected NSCLC patients underwent resection at our institution. As increasingly HIV-infected NSCLC patients present for resection, this report examines the clinical efficacy of surgery in this population.
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Material and Methods
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Study Population
The HIV infection status of 10,122 lung cancer patients treated between January 1, 1975, and December 31, 2009, was determined by cross-referencing our HIV specialty clinic and the Specialized Program of Research Excellence (SPORE) lung cancer databases. Consequently, 124 HIV-infected lung cancer patients were identified. Because the first HIV-infected lung cancer patient was diagnosed in August 1985, 2,162 patients diagnosed before 1985 were excluded. Cancer types other than NSCLC were excluded, which removed 914 patients, 10 of whom were HIV infected. Of the remaining 7,033 NSCLC patients, 4,581 (65%) received no surgical intervention, of whom 92 were HIV infected. The final study population comprises 2,452 NSCLC patients who underwent surgery for curative intent, of whom 22 were HIV infected. The Johns Hopkins Institutional Review Board approved this study.
Exposure of Interest
The HIV infection was defined as being HIV serostatus positive in the Johns Hopkins HIV specialty clinic database before pathology confirmed diagnosis of NSCLC. Persons with NSCLC who were not identified as HIV serostatus positive after cross-referencing the Johns Hopkins HIV specialty clinic and the SPORE lung cancer database were classified as HIV unspecified.
Exposure Assessment
Demographic characteristics, NSCLC subtypes, cancer staging, oncologic treatment, American Society of Anesthesiologists morbidity index classification, HIV/acquired immunodeficiency syndrome (AIDS)–related information, and associated risk factors were obtained from the Johns Hopkins SPORE lung cancer database, clinical charts, and the institution's tumor registry using standardized collection forms and quality controlled data entry procedures. Surgical procedures for curative intent were defined as lobectomy, bilobectomy, or pneumonectomy. Sublobar resections were considered curative only when the surgeon documented this intent.
Outcome Ascertainment
The primary endpoint was postoperative survival. Study entry was defined as date of surgery. Patients were followed until date of death, lost to follow-up, or administratively censored 5 years after resection. Vital status was confirmed with clinical records, death certificates, and the Social Security Death Index. The secondary endpoint was disease progression after surgery.
Individual Patient Matching
Because HIV-infected NSCLC patients are younger than patients without HIV infection [19], and other clinical characteristics related to survival can be disproportionately distributed by HIV status, such as cancer stage, histology, race, sex, NSCLC diagnosis before and after the highly active antiretroviral therapy (HAART) era, and even socioeconomic status [7, 8, 16, 19, 20], we attempted to achieve "balance" on the distribution of observed factors that might potentially bias the effect of HIV on survival [21]. Therefore, a representative subcohort was drawn from the surgical cohort. Three HIV-unspecified patients were individually matched to each HIV-infected patient by age at diagnosis, sex, race, stage, NSCLC histologic subtype, date of surgery (±5 years), and surgical procedure.
Statistical Analysis
Comparison of means and medians of continuous variables was performed using the Student's t test (two-sided) and nonparametric Mann-Whitney U test, respectively. Comparisons between proportions for binary and categorical variables were performed using the 
2 test for homogeneity or Fisher's exact test. All hypotheses tests were two-sided, and results were considered statistically significant for p values less than 0.05.
Survival was illustrated using the Kaplan-Meier method, and the association of covariates with time to death was analyzed using the Cox proportional hazards regression model. In the multivariable models, covariate adjustment for the unmatched surgical cohort was ultimately determined by differences in HIV status on observed characteristics within the entire cohort, prior belief, as well as clinical and biological plausibility. The individual matched subcohort analysis included all the covariates in the unmatched regression model, postoperative complications, and matched covariates. Results of Cox regression are reported as hazard ratios (HR) with 95% confidence interval (CI).
Covariates used for matching methods remained in the multivariable model to account for residual confounding. A test on the basis of Schoenfeld residuals confirmed the proportional hazards assumption for the matched subcohort multivariable Cox regression model (p = 0.993). Statistical analyses were performed using STATA 11.0 statistical software (StataCorp, College Station, TX).
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Results
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Our NSCLC cohort consisted of 7,033 patients, of whom 114 HIV-infected NSCLC patients were identified. Among the HIV-infected patients, 19% (22 of 114) underwent surgery for curative intent versus 35% of HIV-unspecified patients (2,430 of 6,919). Comparatively, HIV-infected patients were significantly younger, African-American, and male (Table 1). Both groups were typical of a surgical cohort, each with a similar stage of disease with stage I predominating. Lobectomy was the preferred procedure, and most patients had adenocarcinoma. Likely due to younger age, HIV-infected patients smoked fewer pack-years compared with HIV-unspecified patients, 43 versus 54 pack-years, respectively (p = 0.012). The HIV-infected patients had a longer delay from diagnosis to surgery.
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Table 1 Characteristics of Non-Small Cell Lung Cancer Patients Who Underwent Surgery According to Human Immunodeficiency Virus (HIV)-Infected and HIV-Unspecified Status (n = 2,452)
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Entire Cohort, Unmatched
The 30-day mortality among HIV-infected and HIV-unspecified patients in the entire cohort did not differ (Table 1). The postoperative median survival for HIV-infected patients was shorter at 26.4 months, versus 48.4 months for HIV-unspecified patients (p = 0.001; Fig 1). The HIV infection alone conveyed a relative hazard of mortality of more than twice that of HIV-unspecified patients (unadjusted HR, 2.24; 95% CI: 1.37 to 3.68; Table 2). After adjusting for risk factors related to overall survival among surgical patients into the multivariable Cox regression model, the relative hazard of mortality in the HIV-infected group increased and remained statistically significant (adjusted HR, 3.08; 95% CI: 1.85 to 5.13; Table 2).
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Fig 1. Kaplan-Meier curves of all-cause survival after surgery comparing human immunodeficiency virus (HIV)-unspecified non-small cell lung cancer (NSCLC) patients (n = 2,430 [solid line]) to HIV-infected NSCLC patients (n = 22 [dashed line]).
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Table 2 Crude and Multivariable Cox Regression Models of Long-Term Survival for Non-Small Cell Lung Cancer Patients After Surgery (n = 2,452)
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Matched Subcohort
Characteristics of the individual-matched subcohort analysis according to HIV infection status are presented in Table 3. Balance was achieved on all matched characteristics in the subcohort. Fifty-three percent of HIV-unspecified patients were married compared with 18% of HIV-infected patients (p = 0.004). In the HIV-unspecified group, the median household income was slightly higher ($32,458 versus $28,945, p = 0.14). Both groups reside mainly within Baltimore City. It is noteworthy that 4 patients with stage IV disease underwent curative resection, specifically, 3 HIV-unspecified patients with solitary brain lesions and 1 HIV-infected patient with contralateral pulmonary lesions.
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Table 3 Study Characteristics of a Matched Subcohort of Non-Small Cell Lung Cancer Surgical Patients According to Human Immunodeficiency Virus (HIV)-Infected and HIV-Unspecified Status (n = 88)
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The median duration from diagnosis to surgery was longer for HIV-infected patients (72 versus 40 days; p = 0.02; Table 4). The HIV-infected patients also experienced longer hospital stays (9 versus 5 days; p = 0.03), a likely consequence of more postoperative complications. Nearly half of HIV-infected patients experienced two or more complications (46% versus 9%, p < 0.001). There were no statistical differences between mean percent predicted forced vital capacity, or mean percent predicted forced expiratory volume in 1 second. Although mean percent predicted diffusion lung capacity for carbon monoxide (DLCO) differed by HIV status, data were available on only 55% of HIV-infected patients (12 of 22) and 65% of HIV-unspecified patients (43 of 66).
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Table 4 Treatment Characteristics of a Matched Subcohort of Non-Small Cell Lung Cancer Surgical Patients According to Human Immunodeficiency Virus (HIV)-Infected and HIV-Unspecified Status (n = 88)
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The proportion of adjuvant therapy received was comparable in both groups (Table 4). Seventy-six percent of patients with stage II or greater had progressive disease. Patients with stage I compared with stage II or greater experienced similar postoperative complication rates (data not shown). Thirty-day mortality did not differ between the two groups (Table 4). The proportion of lung cancer-related deaths was identical in both groups (Table 4).
Individual-matched modeling estimated the adjusted hazard ratios between HIV infection status and postoperative mortality (Table 5). Matched on age, sex, race, histology, stage, surgical procedure, and surgical date, the crude relative hazard of mortality in the HIV-infected patients increased by 81% compared with HIV-unspecified patients (crude HR, 1.81; 95% CI: 1.02 to 3.25; p = 0.047). In the adjusted model, HIV-infected patients were associated with a significantly higher hazard of mortality relative to HIV-unspecified patients (adjusted HR, 2.31; 95% CI: 1.11 to 4.81; p = 0.026). Having two or more complications was associated with an adjusted relative hazard of mortality almost four times greater than fewer complications (adjusted HR, 3.85; 95% CI: 1.39 to 10.68; p = 0.009). The cancer-specific survival of the 22 HIV-infected surgical patients differed significantly by CD4 cell count (Fig 2). Survival was significantly shorter among patients with CD4 cell counts below 200 cells/mm3 (median survival, 8.3 versus 40.0 months; p = 0.031). Of the 6 patients with CD4 count less than 200 cells/mm3, 5 died. Four patients died of lung cancer, and 1 patient of AIDS-related causes. Four of the 6 patients with CD4 counts less than 200 also had cancer progression after surgery. Additionally, median time after surgery to cancer progression was shorter among HIV-infected patients compared with HIV-unspecified patients (20.4 months versus not yet reaching 50th percentile, p = 0.061; Fig 3).
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Table 5 Crude and Multivariable Cox Regression Models of Long-Term Survival for Non-Small Cell Lung Cancer Patients After Surgery in a Matched Subcohort (n = 88)
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Fig 2. Kaplan-Meier curves of cancer-specific survival after surgery for human immunodeficiency virus–infected non-small cell lung cancer patients (n = 22) by CD4 cell counts: less than 200 cells/mm3 (n = 6 [dashed line]) versus 200 cells/mm3 or higher (n = 16 [solid line]).
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Fig 3. Cumulative probability of cancer progression after surgery comparing matched human immunodeficiency virus (HIV)-unspecified non-small cell lung cancer (NSCLC) patients (n = 63 [solid line]) to HIV-infected NSCLC patients (n = 21 [dashed line]). *Stage IV patients excluded (4). (NYR = not yet reached 50th percentile.)
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Comment
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Compared with HIV-unspecified NSCLC patients, HIV-infected NSCLC patients displayed grim postoperative survival. Overall survival and progression-free survival are equally dismal among HIV-infected patients. Even after adjustment for important clinical prognostic indicators, HIV-infected patients exhibited greater mortality. Furthermore, immunosuppression at surgery correlates with rapid decline in survival. This finding runs contrary to prior recommendations advocating surgery for HIV-infected patients regardless of immune status [16].
Given the strong relationship between stage and survival, it was expected that stage would account for the majority of variance in the model and attenuate the effect of HIV-infected status [7, 22]. Instead, after matching and conditioning on stage, the effect of HIV infection increased, indicating that even with similar NSCLC stage, HIV-infected patients have significantly poorer survival postoperatively. To account for stage migration over the study's 20 years, the surgical year was included in our regression models and matched study design. Nonetheless, the impact of HIV on survival in either the entire analytic cohort or in the matched subcohort estimates remained elevated.
Compared with HIV-unspecified patients, HIV-infected patients underwent surgery a month later after diagnosis. We speculate that this difference is indicative of potential barriers to medical care access commonly associated with HIV-infected populations, including low income, lack of medical insurance, HIV related comorbidities, drug abuse, and even transient residence [23]. Nevertheless, any delay in surgery had no detrimental effect on survival in HIV patients on multivariable analysis.
We show differences in survival between HIV patients by CD4 cell count, corroborating Thurer and colleagues [11] who found in 4 HIV-positive NSCLC surgical patients, long-term survival in the sole patient with CD4 lymphocytes greater than 200 cells/mm3. This value is not completely arbitrary as constitutional symptoms begin in HIV patients with CD4 counts less than 300 cells/mm3, serious opportunistic infections occur at CD4 counts less than 100 cells/mm3 [11], and from 1992 to 2006, the Centers for Disease Control defined AIDS as CD4 cell counts less than 200 cells/mm3 [24]. In this study, the CD4 cell count was measured as a fixed variable at the closest time before surgery. The CD4 count can vary markedly within an individual person, especially when patients are noncompliant with antiretroviral regimens [25]. Multiple measures of CD4 cell counts or of the nadir CD4 cell counts could reveal persistently low values that may better characterize immunosuppression.
In our study, HIV-infected patients were significantly more likely to develop two or more postoperative complications than HIV-unspecified patients were. Increased postoperative complications, in general, and postoperative pulmonary complications, in particular, were associated with decreased pulmonary functional status [26, 27]. Although DLCO might be a relevant factor, we hesitate to make definitive conclusions owing to few study patients with DLCO data. The HIV-infected patients also showed increased progression to recurrence. This maybe important as it suggests a potential biologic mechanism of NSCLC progression involving immunosuppression [28].
The obvious limitation of this study is the lack of precision inherent in a small sample size, precluding strong recommendations. The observed estimates of effect could simply be due to random variability. Second, it was uncommon to test for HIV antibodies during the initial work-up of the general NSCLC patient at our institution. It is plausible, albeit unlikely, that at NSCLC diagnosis, some patients with subclinical HIV infection could have been misclassified. Lastly, the treatment assignment of HIV infection status is a complex construct of many factors related to health and survival. The mechanism through which decreased survival is associated with HIV infection is not fully understood within the context of this study. Notwithstanding, this study utilized a powerful design and analytic methods to improve statistical efficiency and balance on HIV infection status. Unmeasured covariates that could account for the observed effect would have to be strongly associated with HIV infection and survival.
Despite HIV-infected patients having comparable 30-day mortality rates to HIV-unspecified patients, surgery is associated with more postoperative complications, rapid progression to recurrence, and poorer survival rates. Shortened progression-free survival and overall survival seem particularly evident in patients with chronically suppressed immune status, namely, patients with CD4 counts less than 200 cells/mm3. Careful HIV-infected patient selection based on DLCO may improve postoperative complication rates, and optimizing immune status preoperatively may ameliorate cancer survival rates, but the lack of statistical power precludes definitive recommendations. Future investigations should consider pooled analytic designs as well as prospective measures of HIV immunosuppression and DLCO.
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Acknowledgments
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We sincerely thank Kathryn Bender and Josephine Allen for their assistance in manuscript preparation. Sponsors include the National Institutes of Health grants P50 CA058184, P30-A142855, and 5K23CA117820-03.
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Footnotes
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* Craig M. Hooker and Dr Robert Meguid are co-first authors.
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References
|
|---|
- Chaturvedi AK, Pfeiffer RM, Chang L, Goedert JJ, Biggar RJ, Engels EA. Elevated risk of lung cancer among people with AIDS AIDS 2007;21:207-213.[Medline]
- Engels EA, Brock MV, Chen J, Hooker CM, Gillison M, Moore RD. Elevated incidence of lung cancer among HIV infected individuals J Clin Oncol 2006;24:1383-1388.[Abstract/Free Full Text]
- Dal Maso L, Polesel J, Serraino D, Franceschi S. Lung cancer in persons with AIDS in Italy, 1985-1998 AIDS 2003;17:2117-2119.[Medline]
- Shiels MS, Cole SR, Mehta SH, Kirk GD. Lung cancer incidence and mortality among HIV infected and HIV uninfected injection drug users J Acquir Immune Defic Syndr 2010;55:510-515.[Medline]
- Kirk GD, Merlo C, O'Driscoll P, et al. HIV infection is associated with an increased risk for lung cancer, independent of smoking Clin Infect Dis 2007;45:103-110.[Abstract/Free Full Text]
- Powles T, Thirwell C, Newsom-Davis T, et al. Does HIV adversely influence the outcome in advanced non-small-cell lung cancer in the era of HAART? Br J Cancer 2003;89:457-459.[Medline]
- Brock MV, Hooker CM, Engels EA, et al. Delayed diagnosis and elevated mortality in an urban population with HIV and lung cancer: implications for patient care J Acquir Immune Defic Syndr 2006;43:47-55.[Medline]
- Bower M, Powles T, Nelson M, et al. HIV related lung cancer in the era of highly active antiretroviral therapy AIDS 2003;17:371-375.[Medline]
- Spano JP, Massiani MA, Bentata M, et al. Lung cancer in patients with HIV Infection and review of the literature Med Oncol 2004;21:109-115.[Medline]
- Vyzula R, Remick SC. Lung cancer in patients with HIV infection Lung Cancer 1996;15:325-339.[Medline]
- Thurer RJ, Jacobs JP, Holland 2nd FW, Cintron JR. Surgical treatment of lung cancer in patients with human immunodeficiency virus Ann Thorac Surg 1995;60:599-602.[Abstract/Free Full Text]
- Mouroux J, Riquet M, Padovani B, Debesse B, Richelme H. Surgical management of thoracic manifestations in human immunodeficiency virus-positive patients: indications and results Br J Surg 1995;82:39-43.[Medline]
- Sridhar KS, Flores MR, Raub Jr WA, Saldana M. Lung cancer in patients with human immunodeficiency virus infection compared with historic control subjects Chest 1992;102:1704-1708.[Medline]
- Massera F, Rocco G, Rossi G, et al. Pulmonary resection for lung cancer in HIV positive patients with low (<200 lymphocytes/mm(3)) CD4(+) count Lung Cancer 2000;29:147-149.[Medline]
- Lavole A, Wislez M, Antoine M, Mayaud C, Milleron B, Cadranel J. Lung cancer, a new challenge in the HIV infected population Lung Cancer 2006;51:1-11.[Medline]
- Cadranel J, Garfield D, Lavole A, Wislez M, Milleron B, Mayaud C. Lung cancer in HIV infected patients: facts, questions and challenges Thorax 2006;61:1000-1008.[Abstract/Free Full Text]
- Bazot M, Cadranel J, Khalil A, et al. Computed tomographic diagnosis of bronchogenic carcinoma in HIV infected patients Lung Cancer 2000;28:203-209.[Medline]
- Aviram G, Fishman JE, Schwartz DS. Metachronous primary carcinomas of the lung in an HIV infected patient AIDS Patient Care STDS 2001;15:297-300.[Medline]
- Shiels MS, Pfeiffer RM, Engels EA. Age at cancer diagnosis among persons with AIDS in the United States Ann Intern Med 2010;153:452-460.[Medline]
- Ou SH, Zell JA, Ziogas A, Anton-Culver H. Low socioeconomic status is a poor prognostic factor for survival in stage I nonsmall cell lung cancer and is independent of surgical treatment, race, and marital status Cancer 2008;112:2011-2020.[Medline]
- Stuart EA. Matching methods for causal inference: a review and a look forward Stat Sci 2010;25:1-21.[Medline]
- Meguid RA, Hooker CM, Harris J, et al. Long-term survival outcomes by smoking status in surgical and nonsurgical patients with non-small cell lung cancer: comparing never smokers and current smokers Chest 2010;138:500-509.[Medline]
- Krawczyk CS, Funkhouser E, Kilby JM, Kaslow RA, Bey AK, Vermund SH. Factors associated with delayed initiation of HIV medical care among infected persons attending a southern HIV/AIDS clinic South Med J 2006;99:472-481.[Medline]
- 1993 Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults MMWR Recomm Rep 1992;41:1-19.[Medline]
- Malta M, Strathdee SA, Magnanini MM, Bastos FI. Adherence to antiretroviral therapy for human immunodeficiency virus/acquired immune deficiency syndrome among drug users: a systematic review Addiction 2008;103:1242-1257.[Medline]
- Ferguson MK, Vigneswaran WT. Diffusing capacity predicts morbidity after lung resection in patients without obstructive lung disease Ann Thorac Surg 2008;85:1158-1164.[Abstract/Free Full Text]
- Cerfolio RJ, Bryant AS. Different diffusing capacity of the lung for carbon monoxide as predictors of respiratory morbidity Ann Thorac Surg 2009;88:405-410.[Abstract/Free Full Text]
- Wistuba II, Behrens C, Milchgrub S, et al. Comparison of molecular changes in lung cancers in HIV positive and HIV indeterminate subjects JAMA 1998;279:1554-1559.[Medline]
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Abstract
Introduction
