Real-world treatment patterns and clinical outcomes with first-line therapy in patients with locally advanced/metastatic urothelial carcinoma by cisplatin-eligibility.

INTRODUCTION: Patients with locally advanced/metastatic urothelial carcinoma (la/mUC) have a poor prognosis. With recent therapeutic advances, data on real-world treatment patterns and overall survival (OS) in patients with la/mUC treated with first-line therapy are limited, particularly when comparing patients who are cisplatin-ineligible versus cisplatin-eligible. METHODS: This was a retrospective observational study of real-world first-line treatment patterns and OS in patients with la/mUC stratified by cisplatin-eligibility and treatment. Data were from a nationwide electronic health record-derived de-identified database. Eligible patients were adults diagnosed with la/mUC from May 2016 to April 2021 and followed until death or end of data availability in January 2022. OS stratified by first-line treatment and cisplatin eligibility was estimated using Kaplan-Meier methods and compared via multivariable Cox proportional-hazard models adjusted for clinical covariates. RESULTS: Of 4,757 patients with la/mUC, 3,632 (76.4%) received first-line treatment, with 2,029 (55.9%) cisplatin-ineligible and 1,603 (44.1%) cisplatin-eligible. Patients who were cisplatin-ineligible were older (mean age, 74.9 vs. 68.8 years) and had lower CrCl (median, 46.4 vs. 87.0 ml/min). Only 43.8% of patients receiving first-line treatment (37.6% cisplatin-ineligible vs. 51.6% cisplatin-eligible) received second-line therapy. Median OS in all patients receiving first-line treatment was 10.8 (95% CI, 10.2-11.3) months and was shorter in patients who were cisplatin-ineligible than cisplatin-eligible (8.5 [95% CI, 7.8-9.0] vs. 14.4 [13.3-16.1]; hazard ratio [HR], 0.9 [0.7-1.1]). Cisplatin-based therapy was associated with longer OS (17.6 [15.1-20.4] months) than other first-line treatments (the shortest OS was with PD-1/L1 inhibitor monotherapy; 7.7 [6.8-8.8] months), including among patients who were classified as cisplatin-ineligible. CONCLUSIONS: Outcomes for patients with newly diagnosed la/mUC are poor, particularly for patients who are cisplatin-ineligible and/or do not receive cisplatin-based therapy. Many patients with la/mUC did not receive first-line treatment and among those who did, fewer than half received second-line therapy. These data highlight the need for more effective first-line therapies for all patients with la/mUC.

Treatment with opioids in patients with locally advanced or metastatic urothelial carcinoma and matched non-cancer controls.

BACKGROUND: Locally advanced or metastatic urothelial carcinoma (la/mUC) is an aggressive disease with a poor long-term survival. While patients frequently report pain, there are limited data on the patient experience with pain and pain medication use. This study used real-world data to quantify treatment with opioids, as a proxy for pain, in patients with la/mUC compared with matched non-cancer controls. METHODS: This was a retrospective claims analysis, using the IBM® MarketScan® databases, of adults diagnosed with urothelial carcinoma and initiating ≥1 la/mUC therapy between May 2016 and June 2019. Index date was date of first systemic therapy claim for la/mUC; baseline was the 6 months pre-index; follow-up was from index until disenrollment or study end. Proportion with treatment with opioids, number of opioid prescriptions, and daily morphine-equivalent dose (MEQ; in morphine milligram equivalents/day) in patients with la/mUC and matched non-cancer controls from the same databases were assessed. RESULTS: We identified 1293 patients with la/mUC and matched 1:3 with 3862 non-cancer controls. Mean (SD) follow-up was 1.26 (0.74) years in patients with la/mUC and 1.29 (0.72) years in controls. A greater proportion of patients with la/mUC, compared with controls, used opioids during both baseline (63.6% vs. 19.4%) and follow-up (61.4% vs. 27.9%). Among those who used opioids, mean monthly prescriptions (number of medications claims/patient/month) were 0.55 both in patients with la/mUC and controls during baseline, and 0.49 and 0.39, respectively, at follow-up. Daily MEQ among those who used opioids was 53.6 and 45.7 during baseline, and 74.7 and 40.8 at follow-up, in patients with la/mUC and controls, respectively. In patients with la/mUC, mean opioid prescriptions and daily MEQ increased during later lines of therapy. CONCLUSION: In patients with la/mUC, pain requiring opioids is common at diagnosis, worsens as the patient progresses, and is consistently higher than in matched controls. Improvement in disease control with more effective therapies may reduce cancer pain in this population.

Acute pain pathways: protocol for a prospective cohort study.

INTRODUCTION: Opioid analgesics are often used to treat moderate-to-severe acute non-cancer pain; however, there is little high-quality evidence to guide clinician prescribing. An essential element to developing evidence-based guidelines is a better understanding of pain management and pain control among individuals experiencing acute pain for various common diagnoses. METHODS AND ANALYSIS: This multicentre prospective observational study will recruit 1550 opioid-naïve participants with acute pain seen in diverse clinical settings including primary/urgent care, emergency departments and dental clinics. Participants will be followed for 6 months with the aid of a patient-centred health data aggregating platform that consolidates data from study questionnaires, electronic health record data on healthcare services received, prescription fill data from pharmacies, and activity and sleep data from a Fitbit activity tracker. Participants will be enrolled to represent diverse races and ethnicities and pain conditions, as well as geographical diversity. Data analysis will focus on assessing patients' patterns of pain and opioid analgesic use, along with other pain treatments; associations between patient and condition characteristics and patient-centred outcomes including resolution of pain, satisfaction with care and long-term use of opioid analgesics; and descriptive analyses of patient management of leftover opioids. ETHICS AND DISSEMINATION: This study has received approval from IRBs at each site. Results will be made available to participants, funders, the research community and the public. TRIAL REGISTRATION NUMBER: NCT04509115.

Does It work in Clinical Practice? A Comparison of Colonoscopy Cleansing Effectiveness in Clinical Practice Versus Efficacy from Selected Prospective Trials.

BACKGROUND: Adequate bowel preparation is essential for a high-quality colonoscopy. Many randomized controlled trials (RCTs) have investigated bowel preparation protocols, including split-dose and low-volume regimens. However, RCTs are conducted in an ideal, controlled setting, and translation of trial results to clinical practice is challenging. In this study, we compared the quality of bowel preparations of real-world patients from clinical practice with those enrolled in several prospective trials. METHODS: Bowel preparation quality, defined by the Ottawa Bowel Preparation Scale (OBPS), from four RCTs and one prospective trial were compared with two observational diary studies. Bowel preparations were polyethylene glycol preparation (PEG) or sodium picosulfate plus magnesium citrate (P/MC) taken via traditional or split-dose timing regimen. Age, sex, average number of bowel movements per day, comorbidities, colonoscopy indication and colonoscopy completion rates were also collected. RESULTS: Patients enrolled in prospective trials had a better OBPS by one point when compared with those in observational clinical practice studies (P<0.049), after controlling for age, sex, colonoscopy indication and type of bowel preparation used. We also found that each 10-year increase in age was associated with a 0.2 point increase in OBPS (P=0.008), and men were associated with a 0.5 increase in OBPS when compared with women P=0.014). CONCLUSION: Patients from clinical practice have higher OBPS than prospective trial patients. Increased age and male sex were also associated with increased OBPS. We believe increased patient motivation and education around bowel preparation regimen plays an important role in the success of bowel preparations.

Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T.

Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.

Survival of African-American and Caucasian men after sipuleucel-T immunotherapy: outcomes from the PROCEED registry.

PURPOSE: African Americans experience greater prostate cancer risk and mortality than do Caucasians. An analysis of pooled phase III data suggested differences in overall survival (OS) between African American and Caucasian men receiving sipuleucel-T. We explored this in PROCEED (NCT01306890), an FDA-requested registry in over 1900 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T. PATIENTS AND METHODS: OS for patients who received ≥1 sipuleucel-T infusion was compared between African American and Caucasian men using an all patient set and a baseline prostate-specific antigen (PSA)-matched set (two Caucasians to every one African American with baseline PSAs within 10% of each other). Univariable and multivariable analyses were conducted. Survival data were examined using Kaplan-Meier and Cox proportional hazard methodologies. RESULTS: Median follow-up was 46.6 months. Overall survival differed between African American and Caucasian men with hazard ratios (HR) of 0.81 (95% confidence interval [CI]: 0.68-0.97, P = 0.03) in the all patient set and 0.70 (95% CI: 0.57-0.86, P < 0.001) in the PSA-matched set. Median OS was longer in African Americans than in Caucasian men for both analysis sets, e.g., 35.3 and 25.8 months, respectively, in the PSA-matched set. Similar results were observed in the all patient set. Differences were larger when treatment began at lower baseline PSA; curves were more similar among patients with higher baseline PSA. In patients with baseline PSA below the median, the HR was 0.52 (95% CI: 0.37-0.72, P < 0.001), with median OS of 54.3 versus 33.4 months. Known prognostic factors and African American race (multivariable analyses; HR: 0.60, 95% CI: 0.48-0.74, P < 0.001) were independently associated with OS. Use of post-sipuleucel-T anticancer interventions was balanced between races. CONCLUSION: In this exploratory analysis of a registry including nearly 12% African American men with mCRPC, OS was significantly different between African Americans and Caucasians, indicating further research is warranted.

Safe Delivery of Endoscopic Brachytherapy in a Patient with a Dual Chamber Pacemaker.

In patients with advanced esophageal cancer, management of dysphagia is a challenge with significant implications on patient quality of life. Brachytherapy has been shown to be an effective and safe treatment option for symptoms related to dysphagia. The effect of endoscopic brachytherapy on patients with a cardiac implantable electronic device has not previously been described in literature. We present an 89-year-old female with a dual chamber permanent pacemaker who elected to undergo palliative brachytherapy delivered via endoscopy for treatment of dysphagia secondary to locally advanced esophageal adenocarcinoma.

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

Cell size sensing in animal cells coordinates anabolic growth rates and cell cycle progression to maintain cell size uniformity.

Cell size uniformity in healthy tissues suggests that control mechanisms might coordinate cell growth and division. We derived a method to assay whether cellular growth rates depend on cell size, by monitoring how variance in size changes as cells grow. Our data revealed that, twice during the cell cycle, growth rates are selectively increased in small cells and reduced in large cells, ensuring cell size uniformity. This regulation was also observed directly by monitoring nuclear growth in live cells. We also detected cell-size-dependent adjustments of G1 length, which further reduce variability. Combining our assays with chemical/genetic perturbations confirmed that cells employ two strategies, adjusting both cell cycle length and growth rate, to maintain the appropriate size. Additionally, although Rb signaling is not required for these regulatory behaviors, perturbing Cdk4 activity still influences cell size, suggesting that the Cdk4 pathway may play a role in designating the cell's target size.

Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association with Overall Survival.

Purpose: Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood.Patients and Methods: Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T-induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T-treated patient and healthy volunteer samples.Results: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferation from baseline to week 6 was observed (N = 14) post-sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (P < 0.0001; N = 22). At 26 weeks post-sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52; P = 0.013) or PA2024 (Pearson R, 0.67; P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P = 0.0005; N = 22), with PA2024 responses correlating with PAP responses at week 26 (R = 0.90; P = 1.53E-08).Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. Clin Cancer Res; 24(19); 4662-71. ©2018 AACR.

Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length.

Animal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.

Objective assessment of colonoscope manipulation skills in colonoscopy training.

OBJECTIVE: Manipulation of the colonoscope is a technical challenge for novice clinicians which is best learned in a simulated environment. It involves the coordination of scope tip steering with scope insertion, using a rotated image as reference. The purpose of this work is to develop and validate a system which objectively assesses colonoscopy technical skills proficiency in an arbitrary training environment, allowing novices to assess their technical proficiency prior to real patient encounters. METHODS: We implemented a motion tracking setup to objectively analyze and assess the way operators perform colonoscopies, including an analysis of wrist and elbow joint motions. Subsequently, we conducted a validation study to verify whether our motion analysis could discriminate novice colonoscopists from experts. Participants navigated a wooden bench-top model using a standard colonoscope while their motions were tracked. RESULTS: The developed motion tracking setup allowed colonoscopists of varying levels of proficiency to have their colonoscope manipulation assessed, and was able to be operated by a trained non-technical operator. Novice operators had significantly greater median times (101.5 vs. 31.5 s) and number of hand movements (62.0 vs. 21.5) than experts. Experts, however, spent a significantly greater proportion of time in extreme ranges of wrist and elbow joint motion than novices. CONCLUSION: We have developed and implemented a hand and joint motion analysis system that is able to discriminate novices from experts based on objective measures of motion. These metrics could, thus, serve as proxies for technical proficiency during training.

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial.

Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis.Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time ≤12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time.Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase-specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P = 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08-0.67; P = 0.007). Sipuleucel-T with ADT was generally well tolerated.Conclusions: Sipuleucel-T→ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation. Clin Cancer Res; 23(10); 2451-9. ©2016 AACR.

Depression and cholesteatoma: Preliminary findings from a nationwide population-based retrospective cohort study.

OBJECTIVE: To estimate the risk of developing depressive disorder (DD) following diagnosis with cholesteatoma. METHODS: In the study, we analyzed data from the Longitudinal Health Insurance Database of Taiwan. A total of 599 patients newly diagnosed with cholesteatoma between 1997 and 2007 were included with a comparison cohort of 2995 matched non-cholesteatoma enrollees. Each patient was followed for 3 years to identify the subsequent development of DD. Cox proportional hazard regression analysis was performed to compute adjusted 3-year hazard ratios. RESULTS: The incidence of DD per thousand person-years was approximately twice as high among patients with cholesteatoma (11.32) as among those without cholesteatoma (5.85). After adjusting for potential confounders, patients with cholesteatoma were 1.99 times (95% CI=1.18-3.34, P=0.010) more likely to suffer from DD within 3 years compared to those without cholesteatoma. CONCLUSIONS: This is the first study to demonstrate a link between cholesteatoma and subsequent DD within a three-year followup. We suggest that clinicians keep this critical but neglected issue in mind and carefully investigate the possibility of subsequent psychological problems among cholesteatoma patients.

A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients. EXPERIMENTAL DESIGN: mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety. RESULTS: Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints. CONCLUSIONS: These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-T's clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging.

Purposeful normalization when caring for husbands recovering from prostate cancer.

Despite a growing awareness that prostate cancer is a "couple's disease," the coping strategies, subjective distress, and emotional needs of partners are not adequately addressed. To better understand wives' experiences and processes they enact, we recruited 28 low-income Latinas caring for husbands recovering from prostatectomies to participate in interviews at three time points. Their narratives destabilize a common focus on physical side effects and an implicit bias toward men's reactions. We critically examine an overarching process of normalization, with underlying themes working both toward and against normality. We identified dissonance between detailed accounts of major lifestyle changes and professed normalization. We detail the women's purposeful methods to counteract negative impacts on their lives while seeking support externally. A better understanding of women's strategies and coping is critical to design interventions and education to both capitalize on partners' role in recovery while also addressing hidden causes of increased subjective distress.

Elevated serum interleukin-6 (IL-6) in solid-organ transplant recipients is positively associated with tissue destruction and IL-6 gene expression in the periodontium.

BACKGROUND: The number of transplanted solid organs and life expectancy after transplantation are steadily rising worldwide. Inflammation is widely recognized as playing a pivotal role in transplant rejection, and several studies have shown that serum interleukin-6 (IL-6) levels can identify individuals who are at greater risk for rejection. Given the known association between IL-6 and chronic periodontitis, the aim of our study was to assess the periodontal status of solid-organ transplant subjects compared to systemically healthy controls, to quantify the IL-6 levels in the serum and periodontal tissues, and to explore their association. METHODS: Forty-seven heart and kidney transplant and 18 systemically healthy age-matched individuals were recruited. Subjects received a complete periodontal examination, and blood and periodontal tissue samples were collected for quantification of IL-6 protein and mRNA levels, respectively. RESULTS: Transplant subjects had significantly higher serum IL-6 levels and slightly but statistically significantly increased mean probing depths than healthy controls. Multivariable linear regression analysis adjusting for gender, diabetes, smoking, and immunosuppressant dose showed that the mean probing depth, number of missing teeth, and mean percentage of sites with > or =4 mm attachment loss were independent predictors for elevated serum IL-6 levels. Transplant subjects with chronic periodontitis had higher mean serum IL-6 levels than those without chronic periodontitis, and there was a positive correlation between periodontal IL-6 gene expression levels and serum IL-6 protein levels. CONCLUSIONS: Periodontal tissue destruction and local IL-6 synthesis are associated with elevated serum IL-6 levels in transplant recipients. This may have serious implications in solid-organ transplant deterioration and chronic rejection.

Vasculitis of the lacrimal sac wall in Wegener granulomatosis.

A 35-year-old woman with a 4-year history of generalized Wegener granulomatosis (WG) had clinically controlled disease. She was evaluated for a 6-month history of right lacrimal sac mass. On examination, a right chronic dacryocystitis and mucocele were observed. A right external dacryocystorhinostomy was performed. The surgical biopsy specimen from the lacrimal sac showed leukocytoclastic vasculitis with more aggressive damage to the small vessels in the deeper mucosa and focal microhemorrhages. The patient was free of symptoms 1 year after surgery. We believe this is the first report of generalized WG presenting features of an active vasculitis of the lacrimal sac wall on surgical biopsy specimen. We conclude that the lacrimal drainage system can be affected directly by focal WG vasculitis, suggesting that nasolacrimal duct obstruction is not always due to contiguous paranasal disease.