Chuanhong Liao

Decreased percentage of CD4+FoxP3+ cells in bronchoalveolar lavage from lung transplant recipients correlates with development of bronchiolitis obliterans syndrome.

Background. Lung transplantation, in patients with end-stage lung disease, is limited by chronic rejection, which occurs with an incidence and severity exceeding most other transplanted organs. Alloimmune responses play an important role in progression to chronic rejection that manifests as bronchiolitis obliterans syndrome (BOS), but no biomarker can currently predict the progression to BOS. Studies in animal models suggest that intragraft T regulatory cells (Tregs) are important in maintaining transplantation tolerance, and FoxP3 is the protoypic Treg marker. Methods. Leukocytes in blood and bronchoalveolar lavage (BAL) fluid were compared for expression of FoxP3 by flow cytometry in 14 stable lung transplant recipients and 6 lung transplant recipients who eventually developed BOS. Results. Stable patients, compared with patients who subsequently developed BOS, consistently had a significantly increased percentage of FoxP3+ cells among CD4+ cells in BAL and greater levels of the Treg-attracting chemokine CCL22. These differences were observed in limited sequential analyses, before, at the time of acute rejection, and postacute rejection. In this pilot study, a threshold of 3.2% CD4+/FoxP3+ cells in the BAL distinguished stable recipients from those subsequently developing BOS within the first 2 years posttransplantation. Conclusion. The proportion of FoxP3+ cells among CD4+ cells in BAL may help to predict lung allograft outcome and guide therapeutic immunosuppression in lung transplant recipients.

Interobserver Variability in Grading Transbronchial Lung Biopsy Specimens After Lung Transplantation

BACKGROUND Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies. METHODS We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients. RESULTS A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection. CONCLUSIONS These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists. TRIAL REGISTRY ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.

Effectiveness of Interventions to Teach Metered-Dose and Diskus Inhaler Techniques. A Randomized Trial

RATIONALE The most effective approach to teaching respiratory inhaler technique is unknown. OBJECTIVES To evaluate the relative effects of two different educational strategies (teach-to-goal instruction vs. brief verbal instruction) in adults hospitalized with asthma or chronic obstructive pulmonary disease. METHODS We conducted a randomized clinical trial at two urban academic hospitals. Participants received teach-to-goal or brief instruction in the hospital and were followed for 90 days after discharge. Inhaler technique was assessed using standardized checklists; misuse was defined as 75% steps or less correct (≤9 of 12 steps). The primary outcome was metered-dose inhaler misuse 30 days postdischarge. Secondary outcomes included Diskus technique; acute care events at 30 and 90 days; and associations with adherence, health literacy, site, and patient risk (near-fatal event). MEASUREMENTS AND MAIN RESULTS Of 120 participants, 73% were female and 90% were African American. Before education, metered-dose inhaler misuse was similarly common in the teach-to-goal and brief intervention groups (92% vs. 84%, respectively; P = 0.2). Metered-dose inhaler misuse was not significantly less common in the teach-to-goal group than in the brief instruction group at 30 days (54% vs. 70%, respectively; P = 0.11), but it was immediately after education (11% vs. 60%, respectively; P < 0.001) and at 90 days (48% vs. 76%, respectively; P = 0.003). Similar results were found with the Diskus device. Participants did not differ across education groups with regard to rescue metered-dose inhaler use or Diskus device adherence at 30 or 90 days. Acute care events were less common among teach-to-goal participants than brief intervention participants at 30 days (17% vs. 36%, respectively; P = 0.02), but not at 90 days (34% vs. 38%, respectively; P = 0.6). Participants with low health literacy receiving teach-to-goal instruction were less likely than brief instruction participants to report acute care events within 30 days (15% vs. 70%, respectively; P = 0.008). No differences existed by site or patient risk at 30 or 90 days (P > 0.05). CONCLUSIONS In adults hospitalized with asthma or chronic obstructive pulmonary disease, in-hospital teach-to-goal instruction in inhaler technique did not reduce inhaler misuse at 30 days, but it was associated with fewer acute care events within 30 days after discharge. Inpatient treatment-to-goal education may be an important first step toward improving self-management and health outcomes for hospitalized patients with asthma or chronic obstructive pulmonary disease, especially among patients with lower levels of health literacy. Clinical trial registered with www.clinicaltrials.gov (NCT01426581).

Clinical and Histologic Predictors of Renal Function Decline After Laparoscopic Partial Nephrectomy

BACKGROUND AND PURPOSE Clinical and surgical factors predict renal function decline after laparoscopic partial nephrectomy (LPN). Additional histopathologic predictors may be found in the specimens nonneoplastic tissue but were not studied. This study investigated the significance of histologic findings in addition to other known predictors of renal function after LPN. PATIENTS AND METHODS Data of 150 patients who underwent LPN was analyzed. Renal function changes (median follow-up 15 months) were correlated with perioperative and histopathologic parameters. Three histopathologic features were evaluated and graded in the nonneoplastic parenchyma: Glomerulosclerosis, arteriosclerosis (AS), and interstitial fibrosis/tubular atrophy. Estimated GFR (eGFR) and percent decline on postoperative day 1 (POD1) and at the last follow-up were measured. RESULTS Median eGFR percent decline at POD1 and last follow-up was -17 and -10, respectively (P<0.001). New-onset ≥stage III chronic kidney disease developed in only 7% of the patients. Three factors independently predicted POD1 eGFR decline: Artery and vein clamping vs artery only clamping (P=0.002), male sex (P=0.015), and larger tumor (P=0.02). Long-term loss of renal function was associated with POD1 eGFR decline (P=0.002) and the percentage of AS (P=0.01). The study limitations include a retrospective analysis leading to variability in the follow-up length and a small size cohort. CONCLUSIONS LPN is associated with a favorable renal function outcome in most patients. Pathologic findings in the nonneoplastic tissue, in addition to clinical parameters, can be used to predict which patients are more likely to experience renal function impairment.

Association of soluble HLA-G with acute rejection episodes and early development of bronchiolitis obliterans in lung transplantation

Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of bronchiolitis obliterans syndrome (BOS). Soluble HLA-G, a mediator of adaptive immunity that modulates regulatory T cells and certain classes of effector T cells, may be a useful marker of survival free of BOS. We conducted a retrospective, single-center, pilot review of 38 lung transplant recipients who underwent collection of serum and bronchoalveolar lavage fluid 3, 6 and 12 months after transplantation, and compared soluble HLA-G concentrations in each to the presence of type A rejection and lymphocytic bronchiolitis in the first 12 months and to the presence of BOS at 24 months after transplantation. Lung soluble HLA-G concentrations were directly related to the presence of type A rejection but not to lymphocytic bronchiolitis. Our data demonstrate that soluble HLA-G concentrations in bronchoalveolar lavage but not in serum correlates with the number of acute rejection episodes in the first 12 months after lung transplantation, and thus may be a reactive marker of rejection.

Quality of Life after Post-Prostatectomy Intensity Modulated Radiation Therapy: Pelvic Nodal Irradiation Is Not Associated with Worse Bladder, Bowel, or Sexual Outcomes

Background Limited data exist regarding toxicity and quality of life (QOL) after post-prostatectomy intensity modulated radiation therapy (IMRT) and whether pelvic nodal RT influences these outcomes. Methods 118 men were treated with curative-intent RT after radical prostatectomy. 69 men (58%) received pelvic nodal RT. QOL data and physician-assigned toxicity were prospectively collected. Changes in QOL from baseline were assessed with Wilcoxon signed-rank tests and risk factors associated with each domain were identified with generalized estimating equation (GEE) models. Late freedom from (FF) toxicity was estimated by the Kaplan-Meier method and comparisons were tested using the log-rank test. Results Urinary irritation/obstruction, bowel, and sexual domain scores declined at 2 months (all P ≤ 0.01) but were no different than baseline at subsequent visits through 4 years of follow-up. At 4 years, FF grade 2+ GI toxicity was 90% and FF grade 2+ GU toxicity was 89%. On GEE analysis, pelvic nodal RT was associated with decreased bowel function (P = 0.09) and sexual function (P = 0.01). On multivariate analysis, however, there was no significant association with either decreased bowel (P = 0.31) or sexual (P = 0.84) function. There was also no association with either FF grade 2+ GI toxicity (P = 0.24) or grade 2+ GU toxicity (P = 0.51). Conclusions Receipt of pelvic nodal RT was not associated with inferior QOL or toxicity compared to prostate bed alone RT. For the entire cohort, RT was associated with only temporary declines in patient-reported urinary, bowel, or sexual QOL.

Bladder dose-volume parameters are associated with urinary incontinence after postoperative intensity modulated radiation therapy for prostate cancer

PURPOSE Urinary incontinence is a potential side effect of prostatectomy and intensity modulated radiation therapy (IMRT) for prostate cancer. There are limited data on dosimetric parameters that may predict for poor continence recovery in men who receive postoperative IMRT. METHODS AND MATERIALS Eighty-seven men with nonmetastatic prostate cancer who underwent prostatectomy followed by adjuvant (13%) or salvage (87%) IMRT were identified. The Expanded Prostate Cancer Index composite questionnaire was prospectively collected at baseline, 6 weeks, and 6, 12, 18, 24, 36, and 48 months post-IMRT. Relevant critical structures were contoured and dose-volume metrics collected. The primary endpoint was urinary continence global score. Longitudinal analysis using a generalized estimating equation model was performed. RESULTS There was no statistically significant change in Expanded Prostate Cancer Index composite urinary continence global scores over time as compared with baseline (all P > .05). In univariate analysis, bladder volume receiving 70 Gy (V70 Gy) and penile bulb V70 Gy were associated with urinary continence (odds ratio, 0.82; P < .05). In a multivariable model that included body mass index, distance between vesicourethral junction and genitourinary diaphragm, time from surgery, use of antihypertensive medications, age, diabetes, and bladder V70 Gy, only bladder V70 Gy (odds ratio, 0.82; P = .03) was associated with outcome. After 2 years, there was a significant difference in global score for those with V70 Gy < 42.27 versus ≥42.27 mL (all P < .05 at 2 and 3 years post-IMRT). CONCLUSION There was no significant change in patient-reported urinary continence scores after postprostatectomy IMRT. Bladder V70 Gy was independently associated with a decrease in urinary continence scores. Further evaluation is necessary to optimize quality of life in these men.

PD57-09 NATIONAL SURGICAL QUALITY IMPROVEMENT PROGRAM SURGICAL RISK CALCULATOR POORLY PREDICTS COMPLICATIONS IN PATIENTS UNDERGOING RADICAL CYSTECTOMY WITH URINARY DIVERSION: THE CASE FOR A PROCEDURE-SPECIFIC RISK CALCULATOR

and diagnosis of bladder cancer controlling for age, smoking history and race. RESULTS: We identified 42,774 patients with BPH. The median follow-up was 87 months. There were 11,864 (27.7%) African Americans (AA), 11,863 (27.7%) Caucasians, and 6,340 (14.8%) Hispanics in this population. 5,698 (13.3%) patients were prescribed Finasteride. Bladder cancer was diagnosed in 84 of 5,698 (1.5%) patients who were prescribed Finasteride compared with 863 of 37,076 (2.3%), who were not prescribed Finasteride (p<0.001). Multivariate logistic regression analysis showed that Finasteride use was protective of bladder cancer (OR: 0.57, CI: 0.45-0.71, p<0.001). When we stratified the data based on race, Finasteride use was protective of bladder cancer in Caucasians (2.1% vs. 3.8%, p1⁄40.001) and Hispanics (0.8% vs. 1.6%, p1⁄40.042), but not in AA (1.7% vs. 1.7%, p1⁄40.854). CONCLUSIONS: Our study confirms previous findings from the PLCO study that men who are on Finasteride have lower incidence of bladder cancer but only in Caucasians and Hispanics. Future research and randomized controlled studies may be needed to confirm these findings.