Endo Pharmaceuticals Research Articles

Continuous Hormone Suppression and Improved Auxology Outcomes in Children With Central Precocious Puberty Who Received a Once-Yearly Histrelin Subcutaneous Implant for 4 Consecutive Years

Continuous Hormone Suppression and Improved Auxology Outcomes in Children With Central Precocious Puberty Who Received a Once-Yearly Histrelin Subcutaneous Implant for 4 Consecutive Years Lawrence A. Silverman MD, Gad B. Kletter MD, E. Kirk Neely MD, Surya Chita PhD, Arthur Chan PhD Goryeb Children's Hospital, Atlantic Health, Morristown, NJ, USA Swedish Medical Center, Seattle, WA, USA Stanford University, Stanford, CA, USA Endo Pharmaceuticals, Inc., Chadds Ford, PA, USA

Oxymorphone Insufflation Associated with Acute Sensorineural Hearing Loss: Case Files of the University of Massachusetts Medical Toxicology Fellowship

A37-year-oldmale was found supine andminimally responsive in his mother’s basement. Emergency medical services reported miotic pupils, bradypnea, and depressed mental status that improved significantly after administration of naloxone 1 mg intramuscularly. In the emergency department, the patient had stable vital signs and normal mental status. He reported having consumed alcohol earlier, then snorting crushed Opana® (oxymorphone: Endo Pharmaceuticals Inc; Chadds Ford, PA, USA) shortly before being found unresponsive. The patient purchased the oxymorphone on the Internet and was unsure if he used the immediateor the extended-release formulation. In the emergency department, the patient felt well, except for acute subjective bilateral hearing loss described as feeling like he was “in a tunnel.” He denied any associated trauma, headaches, changes in vision, tinnitus, or ataxia. His physical examwas unremarkable except for subjective bilateral hearing loss observed by both the patient and the examiners. No formal audiologic testing was performed. What Is the Differential Diagnosis of Sensorineural Hearing Loss?

Efficacy and safety of valrubicin in non–muscle-invasive bladder cancer in older and younger patients.

309 Background: Valrubicin was approved in the United States in 1998, removed from the market in 2002 because of manufacturing issues, and reintroduced in 2009. We report the effectiveness and safety of valrubicin, stratified by patient age, from a US multicenter, observational, retrospective study. Methods: Medical records of adults with non–muscle-invasive bladder cancer (NMIBC) who used valrubicin were abstracted between March and September 2011. The median age (75 [range 42–95] years) was the stratification cutoff. Kaplan-Meier analyses were performed for event-free survival (EFS), worsening-free survival (WFS), and progression-free survival (PFS). Results: 113 patients (mean age, 73.7 years) received intravesical valrubicin (median, 6 [range, 2–18] instillations). Median EFS, WFS, and PFS were similar in patients ≤75 vs >75 years old (see Table); 1-year rates were 17.8% vs 15.4%, respectively, for EFS; 16.1% vs 14.3% for WFS; and 80.2% vs 81.4% for PFS. 11 (19%) patients aged ≤75 years vs 4 (7%) aged >75 years underwent radical cystectomy; 28 (48%) vs 28 (51%), respectively, experienced ≥1 local adverse reaction; 3 (5%) vs 4 (7%) experienced ≥1 serious adverse event; and 4 (7%) vs 1 (2%) discontinued as a result. Conclusions: In patients with NMIBC treated with intravesical valrubicin, effectiveness and safety are similar in patients aged ≤75 and >75 years. Funding: Research and abstract were supported by Endo Pharmaceuticals Inc. [Table: see text]

Effectiveness and safety of valrubicin in non–muscle-invasive bladder cancer following reintroduction: Results from a medical chart review study.

296 Background: Valrubicin was approved in the United States in 1998, removed from the market in 2002 because of manufacturing issues, and reintroduced in 2009. We report secondary outcomes and concomitant medication use from a US multicenter, observational, retrospective study. Methods: Medical records of adult patients with non–muscle-invasive bladder cancer (NMIBC) who used valrubicin were abstracted (March–September 2011). Kaplan-Meier analyses were performed for disease-free survival (DFS), progression-free survival (PFS), worsening-free survival (WFS), cystectomy-free survival (CFS), and time to cystectomy. Results: 113 patients (mean age, 73.7 years) received intravesical valrubicin (median, 6 instillations [range, 2–18]). 107 patients (94.7%) received >3 instillations; 97 (85.8%) completed the full course of therapy (≥6 instillations). DFS was 51.6% (95% CI, 40.9%–61.3%) at 3 months, 30.4% (95% CI, 20.4%–41.1%) at 6 months, and median DFS was 3.5 months (95% CI, 2.5–4.0). PFS was 97.6% (95% CI, 90.9%–99.4%) at 3 months, 87.2% (95% CI, 75.4%–93.5%) at 6 months, and median PFS was 18.2 months (95% CI, 17.2–19.0). WFS was 47.4% (95% CI, 37.2%–57.0%) at 3 months and 28.1% (95% CI, 18.8%–38.2%) at 6 months. CFS was 98.0% (95% CI, 92.2%–99.5%) at 3 months and 93.7% (95% CI, 85.2%–97.4%) at 6 months. Median CFS was not reached; only 13.3% of patients underwent radical cystectomy after starting valrubicin. 56 patients (49.6%) experienced ≥1 local adverse reaction; the most common were hematuria and pollakiuria (both 17.7%), micturition urgency (15.9%), and bladder spasm (14.2%). 55 patients (48.7%) used ≥1 concomitant medication for local adverse reactions; the most commonly used were urinary antispasmodics (21.2%), fluoroquinolones (14.2%), and other urologicals (14.2%). Conclusions: In patients with NMIBC treated with intravesical valrubicin, median DFS and PFS were 3.5 and 18.2 months, respectively, and median CFS was not reached as only 13% of patients underwent radical cystectomy. Valrubicin was well tolerated, and most patients received the full course of 6 instillations. Funding: Research and abstract were supported by Endo Pharmaceuticals Inc.

Comparative Performance of Comorbidity Indices for Estimating Perioperative and 5-Year All Cause Mortality Following Radical Cystectomy for Bladder Cancer

Radical cystectomy continues to be associated with a nonnegligible risk of perioperative death and all cause mortality in the years after surgery remains relatively high. We investigated the comparative ability of various comorbidity indices to predict perioperative and 5-year all cause mortality after radical cystectomy. We evaluated 891 patients who underwent radical cystectomy between 1994 and 2005. The associations of American Society of Anesthesiologists (ASA) score, Charlson comorbidity index, Elixhauser index and ECOG (Eastern Cooperative Oncology Group) performance status with outcomes were assessed using Cox regression models. Model performance was compared with area under receiver operating curves. A total of 33 (3.7%) patients died within 90 days of radical cystectomy. On multivariate analysis locally advanced pathological tumor stage (HR 4.86, p = 0.002) as well as Elixhauser index (HR 1.48, p = 0.002), ASA score (HR 3.17, p = 0.001) and ECOG (HR 2.40, p <0.0001) were significantly associated with 90-day perioperative mortality. Median followup after radical cystectomy was 10.1 years, during which time 576 patients died. Charlson comorbidity index (HR 1.23, p <0.0001), Elixhauser index (HR 1.28, p <0.0001), ASA score (HR 1.44, p = 0.007) and ECOG (HR 1.97, p <0.0001) were independent predictors of 5-year all cause mortality. Moreover Charlson comorbidity index (AUC 0.798, p <0.0001), Elixhauser index (AUC 0.770, p = 0.03) and ECOG (AUC 0.769, p = 0.03) significantly enhanced the performance of a base model which did not include comorbidity status (AUC 0.757) to predict 5-year all cause mortality. Comorbidity status is predictive of perioperative death and 5-year all cause mortality after radical cystectomy and, therefore, should be incorporated into patient counseling and risk stratification models. Further prospective studies are warranted to overcome the retrospective limitations in determining the relative prognostic value of various comorbidity indices.

Comforter in chief in our towns

Comforter in chief in our towns

A Phase 3, Placebo Controlled Study of the Safety and Efficacy of Avanafil for the Treatment of Erectile Dysfunction After Nerve Sparing Radical Prostatectomy

We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy. This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy. Patients were randomized to 100 or 200 mg avanafil or placebo (taken 30 minutes before sexual activity) for 12 weeks. Primary end points included successful vaginal insertion (Sexual Encounter Profile [SEP] question 2), successful intercourse (SEP3) and change in score on the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire. A total of 298 patients were randomized and 84.6% completed the study. At baseline 16.1% were age 65 years or older and 71.5% had severe erectile dysfunction (mean overall IIEF-EF domain score 9.2). After 12 weeks there were significantly greater increases in SEP2 and SEP3 and change in mean IIEF-EF domain score with 100 and 200 mg avanafil vs placebo (p <0.01). Following dosing with avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p <0.01). Avanafil was generally well tolerated. No serious adverse events were reported and fewer than 2% of patients discontinued the study due to an adverse event. Avanafil in 100 and 200 mg doses was effective and well tolerated in improving erectile function after prostatectomy. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels.

The Impact of Clinical Stage on Prostate Cancer Survival Following Radical Prostatectomy

Clinical stage has been incorporated into multiple risk stratification models for patients with newly diagnosed prostate cancer. However, the independent prognostic value of this variable remains open to debate. In this study we evaluated the association of clinical stage with death from prostate cancer in men who underwent radical prostatectomy and assessed for changes in its prognostic value over time. We reviewed the records of 14,842 consecutive patients who underwent radical prostatectomy at our institution between 1970 and 2008 without having received preoperative hormone or radiation therapy. Postoperative disease recurrence was estimated using the Kaplan-Meier method and compared using the log rank test. Multivariate Cox proportional hazard regression models were used to analyze the association of clinical stage with outcome. A total of 5,725 (38.6%) men were classified as having cT1 tumors, 8,160 (55.0%) cT2 tumors and 957 (6.4%) cT3 disease. On univariate analysis clinical stage was significantly associated with postoperative biochemical recurrence, systemic progression and death from prostate cancer (p <0.001 for each). Moreover on multivariate analysis clinical stage was significantly associated with death from cancer for patients treated before (1.45, p = 0.006) and those treated during (1.96, p <0.001) the prostate specific antigen era. Furthermore, the incorporation of clinical stage into contemporary risk stratification improved the prediction of cancer specific survival (c statistic 0.782 without and 0.802 with clinical stage). Clinical stage is significantly associated with systemic progression and death from prostate cancer. Inclusion of this variable in multivariate prediction models improves the prediction of systemic progression and cancer specific survival.

Making pharmacists’ patient care services consistent, predictable, measurable

Making pharmacists’ patient care services consistent, predictable, measurable

The Impact of Mechanical Bowel Preparation on Postoperative Complications for Patients Undergoing Cystectomy and Urinary Diversion

The benefit of routine mechanical bowel preparation for patients undergoing radical cystectomy is not well established. We compared postoperative complications in patients who did or did not undergo mechanical bowel preparation before radical cystectomy. In 2008 a single surgeon (GDS) performed open radical cystectomy with an ileal conduit or orthotopic neobladder in 105 consecutive patients with preoperative mechanical bowel preparation consisting of 4 l GoLYTELY®. In 2009 radical cystectomy with an ileal conduit or orthotopic neobladder was performed in 75 consecutive patients without mechanical bowel preparation. A comprehensive database provided clinical, pathological and outcome data. All patients had complete perioperative data available. The 2 groups were similar in age, Charlson comorbidity score, diversion type, receipt of neoadjuvant radiation or chemotherapy, blood loss, hospital stay, time to diet and pathological stage. Postoperative urinary tract infection, wound dehiscence and perioperative death rates were similar in the 2 groups. Clostridium difficile infection developed within 30 days of surgery in 11 of 105 vs 2 of 75 patients with vs without mechanical bowel preparation (p = 0.08). When adjusted for the annual hospital-wide C. difficile rate, the difference remained insignificant (p = 0.21). Clavien grade 3 or greater abdominal and gastrointestinal complications, including fascial dehiscence, abdominal abscess, small bowel obstruction, bowel leak and entero-diversion fistula, developed in 7 of 105 patients with (6.7%) vs 11 of 75 without (14.7%) mechanical bowel preparation (p = 0.08). The use of mechanical bowel preparation for patients undergoing radical cystectomy with an ileal conduit or orthotopic neobladder does not seem to impact the rates of perioperative infectious, wound and bowel complications. Larger series with multiple surgeons are necessary to confirm these findings.

LBA25_PR - Arades Trial: A First-in-Man, Open-Label, Phase I/II Safety, Pharmacokinetic, and Proof-of-Concept Study of ODM-201 in Patients (PTS) with Progressive Metastatic Castration-Resistant Prostate Cancer (MCRPC)

ABSTRACT Background CRPC is characterized by persistent, high level androgen receptor (AR) expression and resistance to conventional antiandrogens such as bicalutamide. ODM-201 is a novel, new generation, AR antagonist that does not, unlike other antiandrogens, enter brain in nonclinical models, and that lacks the partial agonist activity seen with bicalutamide in the setting of AR overexpression. Unlike bicalutamide, ODM-201 inhibits AR function by blocking nuclear translocation, and has no agonist activity when AR is overexpressed. Methods A first-in-man, multi-center Phase I/II dose-escalation trial in progressive mCRPC pts with and without prior chemotherapy was started in March 2011 to assess safety, pharmacokinetics, and anti-tumor effects. ODM-201 was administered orally, twice daily with food. In the study, three to six pts were to be enrolled per dose-escalation cohort on the preplanned doses of 100, 200, 300, 500, 700 and 900 mg twice daily. Once the safety of an administered dose was established, next dose level was administered, and pts with previous dose level were allowed to continue treatment until progression or intolerable adverse event (AE). Results The dose-escalation part of the study is still ongoing at 700 mg × 2 dose level. In 21 treated pts, ODM-201 has been well-tolerated to date, with no significant treatment emerged AEs. The most common AEs were asthenia, nausea and diarrhea. A PSA response (defined as ≥ 50% PSA decrease) was obtained in 13 (87%) of 15 patients currently evaluable at 12-weeks. All 6 docetaxel-pretreated pts had a PSA decrease at 12-weeks. All evaluable pts so far achieved a partial response or remained stable according to RECIST criteria at 12-weeks. The pharmacokinetics is linear in dose range 100 - 300 mg × 2 and the steady state is reached at day 8. Conclusions ODM-201, a uniquely designed AR antagonist, showed good tolerability and high anti-cancer activity in pts with mCRPC, including docetaxel-pretreated pts, in this Phase I/II trial. Expansion of Phase II trial has started in June 2012. ARADES trial is sponsored by Orion Corporation Orion Pharma and Endo Pharmaceuticals. NCT01317641. Disclosure C. Massard: The author is investigator in Orion Corporation sponsored clinical trial NCT01317641. N. James: The author is investigator in Orion Corporation sponsored clinical trial NCT01317641. S. Culine: The author is investigator in Orion Corporation sponsored clinical trial NCT01317641. R. Jones: The author is investigator in Orion Corporation sponsored clinical trial NCT01317641. A. Vuorela: The author is employee in Orion Corporation NCT01317641. M. Mustonen: The author is employee in Orion Corporation NCT01317641. K. Fizazi: The author is principal investigator in Orion Corporation sponsored clinical trial NCT01317641. The author is member of ODM-201 Advisory Board of Orion Corporation Orion Pharma and Endo Pharmaceuticals.

FDA approves final ER/LA opioid analgesic REMS

FDA approves final ER/LA opioid analgesic REMS

Frequency and Impact of Persistent Nausea in Persons with Migraine: Results from the American Migraine Prevalence and Prevention (AMPP) Study (P04.234)

Objective: Assess the rates and impact of persistent frequent nausea (PFN) in a longitudinal population-based sample of persons with migraine. Background Cross-sectional studies show that in persons with migraine, headache-related nausea is associated with greater pain severity, diminished health related quality of life, functional ability, and delayed use of medication. However, little is known about the frequency and impact of persistent nausea. Design/Methods: In the AMPP study, a longitudinal population-based study, ICHD-2 symptom criteria were used to identify persons with migraine. Eligible persons met an ICHD-2 case definition of migraine and provided data in 2008 and 2009. Depression (PHQ), anxiety (PHQ), headache-related impact (HIT-6) and disability (MIDAS), and ratings of nausea occuring Never, Rarely, Results: Among of 3,526 eligible participants 8% remained nausea free (Never or Rarely), 11.9% reported infrequent nausea ( Conclusions: Frequent persistent nausea is common (45.2% of migraineurs) and associated with female gender, age, depression and headache impact. Nausea is an important target in a sizeable subgroup of people with migraine. Supported by: The American Migraine Prevalence and Prevention Study is funded through a research grant to the National Headache Foundation from Ortho-McNeil Neurologics, Inc., Titusville, NJ. Additional analyses and abstract preparation were supported by a grant from NuPathe Inc., Conshohocken, PA to the National Headache Foundation. Disclosure: Dr. Lipton has received personal compensation for activities with Advanced Bionics, Allergan, Inc., AstraZeneca Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb Company, Cierra, Endo, GlaxoSmithKline, Inc., Minster, Merck & Co., Inc., Neuralieve, Novartis, and OrthoMcNeil Pharmaceuticals. Dr. Lipton holds stock and/or stock options in Minster Pharma. Dr. Lipton9s institution has received research support from Allergan, Inc., OrthoMcNeil Pharmaceuticals, Minster, Endo, GlaxoSmithKline, Inc., Merck & Co., Inc., Neuralieve, and ProEthics. Dr. Buse has received personal compensation for activities with Allergan, Inc., MAP Pharmaceuticals, Nupathe, and Merck & Co., Inc. Dr. Buse has received research support from Allergan, Inc., Endo Pharmaceuticals Inc., MAP Pharmaceuticals, Nupathe, and Merck & Co., Inc. Dr. Fanning has nothing to disclose. Dr. Reed has received research support from GlaxoSmithKline, AstraZeneca, Ortho-McNeil Neurologics, Ortho-McNeil Janssen, Talecris, Merz, Ascend, and Merck.

Rates of Stressful Life Events in Chronic and Episodic Migraine: Results of the American Migraine Prevalence and Prevention (AMPP) Study (P04.240)

Objective: To assess the occurrence of stressful life events (SLEs) in a population-based sample of adults with chronic and episodic migraine. Background SLEs have been associated with many medical conditions, including the onset of chronic daily headache. Design/Methods: The American Migraine Prevalence and Prevention (AMPP) study is a longitudinal, US population-based study with annual questionnaires mailed to 24,000 severe headache sufferers identified in 2004 and followed between 2005-2009. Respondents to the 2007 survey who met ICHD-2 criteria for migraine were divided into CM (≥15 HA days/month) or EM ( Results: In 2007, 14,069 responded, of which 557 had CM and 7,748 had EM. 5,858 migraineurs reported ≥1 SLE. In the CM group, 100(18.2%) reported no SLEs, 145(26.3%) reported 1, 153(27.8%) reported 2, and 153(27.8%) reported ≥3. Similarly, 1,639(21.4%) respondents with EM reported no SLEs, 2,098(27.5%) reported 1, 1,987(26%) reported 2, and 1,920(25.1%) reported ≥3. The unadjusted cumulative odds ratio indicated that the odds of experiencing SLEs were approximately 19% greater for persons with CM than EM. Adjusting for age, gender, race and BMI increased the trend (22% greater for CM than EM). Conclusions: It is unknown why SLEs are more common among persons with CM and the directionality of occurrence. Future work will examine the temporal sequencing of SLEs related to new-onset CM. Supported by: AMPP study funded through research grant to the National Headache Foundation from Ortho-McNeil Neurologics, Titusville, NJ. Additional analyses and abstract preparation supported by a grant from Allergan, Irvine, CA, to the National Headache Foundation. Disclosure: Dr. Manack has received personal compensation for activities with Allergan, Inc. Dr. Serrano has received personal compensation for activities as an employee of a pharmaceutical company. Dr. Turkel has received personal compensation for activities with Allergan, Inc. as an employee. Dr. Turkel holds stock and/or stock options in Allergan, Inc. Dr. Lipton has received personal compensation for activities with Advanced Bionics, Allergan, Inc., AstraZeneca Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb Company, Cierra, Endo, GlaxoSmithKline, Inc., Minster, Merck & Co., Inc., Neuralieve, Novartis, and OrthoMcNeil Pharmaceuticals. Dr. Lipton holds stock and/or stock options in Minster Pharma. Dr. Lipton9s institution has received research support from Allergan, Inc., OrthoMcNeil Pharmaceuticals, Minster, Endo, GlaxoSmithKline, Inc., Merck & Co., Inc., Neuralieve, and ProEthics. Dr. Buse has received personal compensation for activities with Allergan, Inc., MAP Pharmaceuticals, Nupathe, and Merck & Co., Inc. Dr. Buse has received research support from Allergan, Inc., Endo Pharmaceuticals Inc., MAP Pharmaceuticals, Nupathe, and Merck & Co., Inc.

Supply shortage, rare tablet mix-up

Supply shortage, rare tablet mix-up

Mersana Therapeutics Raises Profile with Antibody-Drug Conjugate Collaboration with Endo

Mersana Therapeutics has formed a collaboration with Endo Pharmaceuticals to develop next-generation antibody-drug conjugates (ADCs) against a single, undisclosed cancer target. Mersana will combine its Fleximer® conjugation technology with anticancer antibodies discovered by Endo to produce Fleximer-ADC candidates for development, manufacturing and commercialisation by Endo. With this deal, Mersana has emerged as a competitor of Seattle Genetics and ImmunoGen in the development of ADCs.

Availability of a 5% lidocaine patch used prophylactically for venipuncture- or injection-related pain in children

Venipuncture- or injection-related pain is still major problem during anesthetic induction in children. This study was designed to determine the availability of a 5% lidocaine patch used prophylactically for venipuncture- or injection-related pain during the induction of anesthesia. In a randomized, double-blind study, 72 pediatric patients were allocated to one of two groups: pretreatment with a 5% lidocaine patch (Lidoderm(®), Endo Pharmaceuticals, Chadds Ford, PA, USA) (group A) or pretreatment with a placebo patch (group B). Pain severity was evaluated on the Faces, Legs, Activity, Cry, and Consolability Scale (FLACC) during venipuncture, and a 4-point scale during the injection of rocuronium. The FLACC score during venipuncture was significantly lower for group A than group B (p<0.001). There was no significant difference in the grades of the 4-point scale observed during the injection of rocuronium between groups A and B. No significant adverse effect was noted for the groups. Although pretreatment with a 5% lidocaine patch was found to be a safe, effective, and simple method of preventing venipuncture pain in children, this method did not reduce drug injection pain during the induction of anesthesia.

Intravesical (IVe) valrubicin for treatment of carcinoma in situ (CIS) of the bladder: Use in clinical practice.

317 Background: IVe valrubicin is indicated for bacillus Calmette-Guérin (BCG)-refractory CIS when cystectomy is not an option. An ongoing retrospective clinical-practice chart review is being conducted to examine use of valrubicin since its reintroduction (Oct 2009). Methods: Records were analyzed for adults with non-muscle invasive bladder cancer (NMIBC) treated with valrubicin. Results: In this ongoing study, 62 patients received valrubicin (date range; 10/7/2009-6/10/2011). Most were male (52, 84%) and white (49, 79%); median age was 79 y (range, 49–89). 49 patients (79%) had a history of CIS + papillary tumors, 8 had CIS (13%), 4 had papillary (7%), 1 had NMIBC unspecified (1%). 57 patients (92%) received prior IVe therapy (median [range], 2 [0–11] courses); 13 patients (21%) received 1 course, 16 (26%) 2 courses, and 28 (45%) ≥3 courses. Immunotherapy (eg, BCG, unspecified) was the most common prior treatment (54 patients, 87%; median [range], 2 [0–7] courses); 17 patients (27%) received 1 course, 15 (24%) 2 courses, and 22 (35%) ≥3 courses. Prior IVe chemotherapy was less common (21 patients, 34%). 47 patients (76%) had ≥1 transurethral resection of the bladder tumor (median [range], 2 [0–9] for n=62 patients). Fewer had undergone ≥1 fulguration procedures (27, 44%). Most valrubicin courses (49/67, 73%) used the recommended 6 instillations (median [range], 6 [2–7]). Retention time (median [range], 120 [0–180] min) was recorded for 89/381 instillations (23%). Adverse events (AEs) were observed for 31 patients (50%); most AEs (102/106, 96%) were mild or moderate. 3 patients (5%) had serious AEs (treatment-relationship unknown). Median followup for all patients was 5.2 mo (range, 0–13.9). 13 patients (21%) underwent cystectomy at a median of 5.3 mo (range, 1-13) from the last valrubicin dose. 2 patients died, at 1.1 (metastatic disease) and 11.9 mo after finishing valrubicin. Conclusions: Patients treated with valrubicin in clinical practice often had concomitant papillary tumors and were heavily pretreated. One in 8 patients had no record of previous immunotherapy. Drug administration adhered closely to labeled instructions and was well tolerated. Funding: Endo Pharmaceuticals.

Use of Fluorescence In Situ Hybridization to Predict Response to Bacillus Calmette-Guérin Therapy for Bladder Cancer: Results of a Prospective Trial

No reliable methods currently exist to predict patient response to intravesical immunotherapy with bacillus Calmette-Guérin given after transurethral resection for high risk nonmuscle invasive bladder cancer. We initiated a prospective clinical trial to determine whether fluorescence in situ hybridization results during bacillus Calmette-Guérin immunotherapy can predict therapy failure. Candidates for standard of care bacillus Calmette-Guérin were offered participation in a clinical trial. Fluorescence in situ hybridization was performed before bacillus Calmette-Guérin, and at 6 weeks, 3 months and 6 months during bacillus Calmette-Guérin therapy with maintenance. Cox proportional hazards regression was used to assess the relationship between fluorescence in situ hybridization results and tumor recurrence or progression. The Kaplan-Meier product limit method was used to estimate recurrence-free and progression-free survival. A total of 126 patients participated in the study. At a median followup of 24 months 31% of patients had recurrent tumors and 14% experienced disease progression. Patients who had positive fluorescence in situ hybridization results during bacillus Calmette-Guérin therapy were 3 to 5 times more likely than those who had negative fluorescence in situ hybridization results to experience recurrent tumors and 5 to 13 times more likely to have disease progression (p <0.01). The timing of positive fluorescence in situ hybridization results also affected outcomes. For example, patients with a negative fluorescence in situ hybridization result at baseline, 6 weeks and 3 months demonstrated an 8.3% recurrence rate compared to 48.1% for those with a positive result at all 3 points. Fluorescence in situ hybridization results can identify patients at risk for tumor recurrence and progression during bacillus Calmette-Guérin immunotherapy. This information may be used to counsel patients about alternative treatment strategies.

What Predicts Adrenal Insufficiency in Patients with Thalassemia Major?

Abstract 5299 Background:Thalassemia is one of the most common genetic blood disorders worldwide. With recent improvements in medical therapy, patients with transfusion-dependent thalassemia, i.e., thalassemia major, are living longer. As a result, there is a greater need to address endocrine complications related to chronic iron overload. Adrenal insufficiency (AI), in particular, is important to identify because therapies are available and can be life-saving. Objectives:The objectives of this study are to determine the prevalence of AI in our population of subjects with thalassemia major; to identify risk factors that predict AI in these individuals; and to localize the origin of the AI within the hypothalamic-pituitary-adrenal (HPA) axis. Methods:This is a prospective study of individuals with thalassemia major with an enrollment goal of 30 subjects. All subjects enrolled were initially tested for AI using a glucagon stimulation test. Those found to have AI (stimulated cortisol <18 mcg/dL) subsequently underwent an ovine corticotrophin-releasing hormone (oCRH) stimulation test for confirmatory purposes and to define the physiological basis for the AI. Results:Eleven subjects (8 - 29 years old, 6 female) have been enrolled to date. In our population of patients with TM, the prevalence of AI was 55%. There was no correlation between age, number of years transfused, or ferritin levels and AI. All male patients failed the glucagon stimulation test, whereas 5 of 6 females passed the glucagon stimulation test, p = 0.0024. There was no correlation between 8 AM ACTH levels and 8 AM cortisol levels. There was a significant correlation (p = 0.025) between 8 AM cortisol level and peak cortisol level following glucagon stimulation testing. Of the six subjects with AI, two subjects subsequently failed the oCRH stimulation test (peak cortisol < 21.9 mcg/dL). In these two subjects, peak oCRH ACTH levels were elevated, 144 and 164 pg/mL, respectively, suggesting primary adrenal insufficiency. Conclusions:We conclude that 8 AM cortisol level is a good predictor of adrenal insufficiency in our population, and can potentially be used as a simple screening test for AI with a strong negative predictive value. There appears to be a male predominance of AI in our population. This may indicate a protective role of female sex in this population. Two subjects had classic primary AI with robust ACTH levels in the face of inadequate cortisol production following oCRH testing. Four subjects (all males) who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol response to oCRH, indicating a possible hypothalamic origin to their AI. This dysfunction is likely independent of iron overload and warrants further investigation. Alternatively, these subjects may have impaired sympathetic nervous system function leading to hypoglycemic unawareness. Both outcomes are novel to the field and of medical significance. Disclosures:Geffner:Daiichi- Sankyo: Steering Committee for Clinical Trial; Eli Lilly, Inc.: Research Contract; Endo Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Data Safety Monitoring Board and Research Contract; Novo Nordisk: Research Funding; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.