Jonathan P. Singer

Adenomatous polyposis coli gene promoter hypermethylation in non-small cell lung cancer is associated with survival

Methylation of 5′ CpG islands in promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of this study was to determine whether hypermethylation of the adenomatous polyposis coli (APC) gene promoter occurs in primary non-small cell lung cancer (NSCLC), and whether hypermethylated APC has any relationship with survival. APC promoter 1A methylation was determined in normal and corresponding tumor tissue from 91 NSCLC patients and in a control group of 10 patients without cancer, using a quantitative fluorogenic real-time PCR (Taqman®) system. APC promoter methylation was detectable in 86 (95%) of 91 tumor samples, but also in 80 (88%) of 91 normal samples of NSCLC patients, and in only two (20%) of 10 normal lung tissues of the control group. The median level of APC promoter methylation was 4.75 in tumor compared to 1.57 in normal lung tissue (P<0.001). Patients with low methylation status showed significantly longer survival than did patients with high methylation status (P=0.041). In a multivariate analysis of prognostic factors, APC methylation was a significant independent prognostic factor (P=0.044), as were pT (P=0.050) and pN (P<0.001) classifications. This investigation shows that APC gene promoter methylation occurs in the majority of primary NSCLCs. High APC promoter methylation is significantly associated with inferior survival, showing promise as a biomarker of biologically aggressive disease in NSCLC.

High Cumulative Dose Exposure to Voriconazole is Associated with Cutaneous Squamous Cell Carcinoma in Lung Transplant Recipients

BACKGROUND Lung transplant recipients (LTR) have an increased risk of cutaneous squamous cell carcinoma (SCC) due to immunosuppressive therapy. Voriconazole, which is associated with phototoxic side effects in some patients, may be an additional risk factor for SCC in this population. METHODS To test whether voriconazole is a risk factor for developing SCC in LTR, we evaluated cumulative exposure to voriconazole in 327 adults who underwent lung transplantation at one center between 1991 and 2010. Voriconazole exposure was assessed as a time-varying covariate. We used survival analysis methods to assess the risk of developing SCC over time. RESULTS Exposure to voriconazole was associated with a 2.6-fold increased risk for SCC. This phenomenon was dose-dependent: the risk for SCC increased by 5.6% with each 60-day exposure at a standard dose of 200 mg twice daily. At 5 years after transplant, voriconazole conferred an absolute risk increase for SCC of 28%. CONCLUSIONS These results suggest that caution should be taken when using voriconazole in LTR because this drug increases the already high risk for SCC in this population.

Voriconazole-Associated Cutaneous Malignancy: A Literature Review on Photocarcinogenesis in Organ Transplant Recipients

This article synthesizes the current data regarding the implication of voriconazole in the development of skin cancer in organ transplant recipients (OTRs) and offers suggestions for additional research. According to Organ Procurement and Transplantation Network data, 28 051 solid organ transplants were performed in 2012. Due to advancements in immunosuppression and management of infectious diseases, survival of OTRs has substantially increased. Voriconazole is a widely prescribed antifungal medication used for prophylaxis and for treatment of invasive fungal infections in OTRs. Case reports describing skin cancer associated with voriconazole exposure emerged shortly after US Food and Drug Administration approval of the drug, and it is now established that voriconazole is an independent risk factor for the development of cutaneous malignancy in lung transplant recipients. The mechanism of voriconazole-induced skin cancer is still unknown and may involve its primary metabolite, voriconazole N-oxide. Here we discuss the current data and potential mechanisms of voriconazole-associated photosensitivity and carcinogenesis and identify areas that require further research.

Frailty Phenotypes, Disability, and Outcomes in Adult Candidates for Lung Transplantation

RATIONALE Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation. OBJECTIVES To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates. METHODS In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively. MEASUREMENTS AND MAIN RESULTS Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB. CONCLUSIONS Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

Body Composition and Mortality after Adult Lung Transplantation in the United States

RATIONALE Obesity and underweight are contraindications to lung transplantation based on their associations with mortality in studies performed before implementation of the lung allocation score (LAS)-based organ allocation system in the United States Objectives: To determine the associations of body mass index (BMI) and plasma leptin levels with survival after lung transplantation. METHODS We used multivariable-adjusted regression models to examine associations between BMI and 1-year mortality in 9,073 adults who underwent lung transplantation in the United States between May 2005 and June 2011, and plasma leptin and mortality in 599 Lung Transplant Outcomes Group study participants. We measured body fat and skeletal muscle mass using whole-body dual X-ray absorptiometry in 142 adult lung transplant candidates. MEASUREMENTS AND MAIN RESULTS Adjusted mortality rates were similar among normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25.0-29.9), and class I obese (BMI 30-34.9) transplant recipients. Underweight (BMI < 18.5) was associated with a 35% increased rate of death (95% confidence interval, 10-66%). Class II-III obesity (BMI ≥ 35 kg/m(2)) was associated with a nearly twofold increase in mortality (hazard ratio, 1.9; 95% confidence interval, 1.3-2.8). Higher leptin levels were associated with increased mortality after transplant surgery performed without cardiopulmonary bypass (P for interaction = 0.03). A BMI greater than or equal to 30 kg/m(2) was 26% sensitive and 97% specific for total body fat-defined obesity. CONCLUSIONS A BMI of 30.0-34.9 kg/m(2) is not associated with 1-year mortality after lung transplantation in the LAS era, perhaps because of its low sensitivity for obesity. The association between leptin and mortality suggests the need to validate alternative methods to measure obesity in candidates for lung transplantation. A BMI greater than or equal to 30 kg/m(2) may no longer contraindicate lung transplantation.

Outcomes in systemic sclerosis-related lung disease after lung transplantation.

Background Lung disease is the leading cause of death in systemic sclerosis (SSc). The diagnosis of SSc-related lung disease (SSc-LD) is often a contraindication to lung transplantation (LT) due to concerns that extrapulmonary involvement will yield worse outcomes. We sought to evaluate posttransplantation outcomes in persons with SSc-LD with esophageal involvement compared with persons with nonconnective tissue disease–related interstitial lung disease (nCTD-ILD). Methods From 1998 to 2012, persons undergoing LT for SSc-LD were age and gender matched in a 2:1 fashion to controls undergoing LT for nCTD-ILD. Esophageal function was assessed by pH testing and manometry. We defined esophageal dysfunction as the presence of a DeMeester score >14 or dysmotility more severe than “mild nonspecific disorder”. The primary outcome was posttransplantation survival. Secondary outcomes included freedom from bronchiolitis obliterans syndrome (fBOS) and rates of acute rejection. Survival and fBOS were estimated with Kaplan–Meier methods. Acute rejection was compared with Student’s t test. Results Survival was similar in 23 persons with SSc-LD and 46 controls who underwent LT (P=0.47). For the SSc-LD group, 1- and 5-year survival was 83% and 76% compared with 91% and 64% in the nCTD-ILD group, respectively. There were no differences in fBOS (P=0.83). Rates of acute rejection were less in SSc-ILD (P=0.05). Esophageal dysfunction was not associated with worse outcomes (P>0.55). Conclusions Persons with SSc-LD appear to have similar survival and fBOS as persons transplanted for nCTD-ILD. The risk of acute rejection after transplantation may be reduced in persons with SSc-LD. Esophageal involvement does not appear to impact outcomes.

The impact of pretransplant mechanical ventilation on short- and long-term survival after lung transplantation.

Lung transplantation in mechanically ventilated (MV) patients has been associated with decreased posttransplant survival. Under the Lung Allocation Score (LAS) system, patients at greatest risk of death on the waiting list, particularly those requiring MV, are prioritized for lung allocation. We evaluated whether pretransplant MV is associated with poorer posttransplant survival in the LAS era. Using a national registry, we analyzed all adults undergoing lung transplantation in the United States from 2005 to 2010. Propensity scoring identified nonventilated matched referents for 419 subjects requiring MV at the time of transplantation. Survival was evaluated using Kaplan–Meier methods. Risk of death was estimated by hazard ratios employing time‐dependent covariates. We found that pretransplant MV was associated with decreased overall survival after lung transplantation. In the first 6 months posttransplant, ventilated subjects had a twofold higher risk of death compared to nonventilated subjects. However, after 6 months posttransplant, survival did not differ by MV status. We also found that pretransplant MV was not associated with decreased survival in noncystic fibrosis obstructive lung diseases. These results suggest that under the LAS, pretransplant MV is associated with poorer short‐term survival posttransplant. Notably, the increased risk of death appears to be strongest the early posttransplant period and limited to certain pretransplant diagnoses.

A Thematic Analysis of Quality of Life in Lung Transplant: The Existing Evidence and Implications for Future Directions

Health‐related quality of life (HRQL) has been assessed in various lung transplantation (LT) investigations but never analyzed systematically across multiple studies. We addressed this knowledge gap through a systematic literature review. We searched the PubMed, CINAHL and PsychInfo databases for publications from January 1, 1983 to December 31, 2011. We performed a thematic analysis of published studies of HRQL in LT. Using a comparative, consensus‐based approach, we identified themes that consistently emerged from the data, classifying each study according to primary and secondary thematic categories as well as by study design. Of 749 publications initially identified, 73 remained after exclusions. Seven core themes emerged: (1) Determinants of HRQL; (2) Psychosocial factors in HRQL; (3) Pre‐ and posttransplant HRQL comparisons; (4) Long‐term longitudinal HRQL studies; (5) HRQL effects of therapies and interventions; (6) HRQL instrument validation and methodology; (7) HRQL prediction of clinical outcomes. Overall, LT significantly and substantially improves HRQL, predominantly in domains related to physical health and functioning. The existing literature demonstrates substantial heterogeneity in methodology and approach; relatively few studies assessed HRQL longitudinally within the same persons. Opportunity for future study lies in validating existing and potential novel HRQL instruments and further elucidating the determinants of HRQL through longitudinal multidimensional investigation.

Respiratory and Skeletal Muscle Strength in Chronic Obstructive Pulmonary Disease: IMPACT ON EXERCISE CAPACITY AND LOWER EXTREMITY FUNCTION

PURPOSE We sought to quantify the impact of respiratory muscle and lower extremity strength on exercise capacity and lower extremity function (LEF) in patients with chronic obstructive pulmonary disease (COPD). METHODS In 828 persons with COPD, we assessed the impact of reduced respiratory (maximum inspiratory pressure, MIP) and lower extremity muscle strength (quadriceps strength, QS) on exercise capacity (6-minute walk test, 6MWT), and LEF (short physical performance battery). Multiple regression analyses taking into account key covariates, including lung function and smoking, tested the associations between muscle strength and exercise and functional capacity. RESULTS For each 0.5 SD decrement in QS, men walked 18.3 m less during 6MWT (95% confidence interval [CI], -24.1 to -12.4); women 25.1 m less (95% CI, -31.1 to -12.4). For each 0.5 SD decrement in MIP, men walked 9.4 m less during 6MWT (95% CI, -15.2 to -3.6); women 8.7 m less (95% CI, -14.1 to -3.4). For each 0.5 SD decrease in QS, men had a 1.32 higher odds (95% CI, 1.11-1.15) of poor LEF; women had a 1.87 higher odds (95% CI, 1.54-2.27). Lower MIP (per 0.5 SD) was associated with increased odds of poor LEF in women (odds ratio = 1.18; 95% CI, 1.00-1.39), but not in men (odds ratio = 1.10; 95% CI, 0.93-1.31). CONCLUSIONS In COPD, reduced respiratory and lower extremity muscle strength are associated with decreased exercise and functional capacity. Muscle weakness is likely an important component of impairment and disability in patients with COPD.

Relationship of obesity with respiratory symptoms and decreased functional capacity in adults without established COPD

BACKGROUND Obesity contributes to respiratory symptoms and exercise limitation, but the relationships between obesity, airflow obstruction (AO), respiratory symptoms and functional limitation are complex. AIMS To determine the relationship of obesity with airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD). METHODS We analysed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilisation attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, six-minute walk test (SMWT), and the Short Performance Physical Battery (SPPB). Multiple regression analyses were used to test the associations of obesity (body mass index >30 kg/m2) and smoking with AO (forced expiratory volume in 1s/forced vital capacity ratio <0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO. RESULTS Of 371 subjects (aged 40-65 years), 69 (19%) had AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI 1.04 to 1.49) while obesity was negatively associated with AO (OR 0.54; 95% CI 0.30 to 0.98). Obesity was associated with increased odds of reporting dyspnoea on exertion (OR 3.6; 95% CI 2.0 to 6.4), productive cough (OR 2.5; 95% CI 1.1 to 6.0), and with decrements in SMWT distance (67 ± 9 m; 95% CI 50 to 84 m) and SPPB score (OR 1.9; 95% CI 1.1 to 3.5). None of these outcomes was associated with AO. CONCLUSIONS Although AO and obesity are both common among adults without an established COPD diagnosis, obesity (but not AO) is linked to a higher risk of reporting dyspnoea on exertion, productive cough, and poorer functional capacity.