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Introduction BTH1677, a 1,3-1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm (N=60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m 2 and subsequent doses 250 mg/m 2 , weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m 2 , Q3W) or Control arm (N=30; cetuximab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles; patients who responded or remained stable received maintenance therapy with BTH1677/cetuximab (BTH1677 arm) or cetuximab (Control arm). Investigator and blinded central radiology reviews were conducted. Efficacy assessments included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, time-to-progression and overall survival (OS); safety was assessed by adverse events (AEs). Potential biomarker analysis for BTH1677 response was also conducted. Results Compared to control treatment, the addition of BTH1677 numerically increased ORR by both investigator (47.8% vs 23.1%; p=0.0468) and central (36.6% vs 23.1%; p=0.2895) reviews. No other endpoints differed between arms. PK was consistent with previous studies. BTH1677 was well tolerated, with AEs expected of the backbone therapy predominating. Biomarker-positive patients displayed better ORR and OS than negative patients. Conclusions BTH1677 combined with cetuximab/carboplatin/paclitaxel was well tolerated and improved ORR as first-line treatment in patients with advanced NSCLC. Future patient selection by biomarker status may further improve efficacy ClinicalTrials.gov Identifier: NCT00874848.

Background: The Merz Hand Grading Scale (MHGS) is a 5-point scale used to grade appearance of the dorsum of the hand. The MHGS has been previously validated for assessment of photographed hands but not for live assessment., Objective: The purpose of this randomized, blinded study was to validate the MHGS for live assessment of the hands in the clinical setting., Methods: Three physician raters completed a scale qualification program that included MHGS training, ratings of standardized hand photographs, and statistical analysis for reliability. Eighty-four subjects (28 males, 30% Fitzpatrick skin Types IV-VI, mean age of 42 years), randomized to 2 live assessment sessions for independent and blinded observation of dorsa of their right hands, completed the study., Results: Overall MHGS intrarater weighted Kappa value was 0.74 (0.68-0.79 [CI 95%]). First- and second-time hand-rating agreement scores ranged from 64% to 75%. Interrater weighed Kappa values ranged from 0.59 to 0.71, representing between-rater paired results of each combination of raters., Conclusion: High-weighted Kappa values and agreements demonstrate that consistency at different time points can be achieved individually and by different raters for live assessments. The MHGS is a suitable instrument for live assessment in the clinical setting.

Non-dextran intravenous (i.v.) iron preparations seem to differentially affect proteinuria in patients with chronic kidney disease. To study effects of ferric gluconate and iron sucrose on proteinuria, we conducted a crossover trial in 12 patients with stage 3-4 chronic kidney disease. These patients were randomized to receive the same dose of either drug 1 week apart. Urine samples were obtained immediately before and at frequent intervals after the drug. The urine total protein/creatinine ratio was significantly greater after iron sucrose than ferric gluconate treatment with the effect noted within 15 min post-infusion. Furthermore, when iron sucrose was given first, a significantly greater protein/creatinine ratio was seen subsequently with ferric gluconate than with the reverse order of treatment. The urine albumin/creatinine ratio was also significantly greater with iron sucrose than with ferric gluconate. There was no significant difference, however, between the two i.v. irons in the measured urine N-acetyl-beta-D-glucosaminidase/creatinine ratio. Although our study showed that acutely, iron sucrose increased proteinuria, the long-term effects of repeated i.v. non-dextran iron on kidney function requires further study.

Objectives: Central abdominal uptake (CAU) on immunoscintigraphy with capromab pendetide (CP) (ProstaScint) suggests the presence of metastases from prostate cancer, but tissue confirmation is difficult and invasive. We report the outcomes data from a cohort of patients with CAU on CP images obtained for staging., Methods: The records of 341 men with prostate cancer who underwent CP imaging at two institutions from 1994 to 1999 were reviewed. The patients were divided according to the presence or absence of CAU. Metastases were confirmed in 36 patients (52%) with CAU. The median follow-up was 4.1 years. Statistical analyses compared the differences in baseline characteristics, subsequent radiotherapy, intervention with androgen ablation, and survival., Results: CAU was detected in 69 patients (20%). A total of 262 patients underwent pelvic radiotherapy after the scan, 57 (83%) with CAU and 205 (75%) without (P = 0.2). Of the 69 patients with positive CAU findings and the 272 patients with negative CAU findings, 10 (14.5%) and 14 (5.1%) had died during the follow-up period (P = 0.007). Prostate cancer-specific death occurred in 5 (7.2%) of 69 patients with CAU-positive findings versus 2 of 272 with CAU-negative findings, for a rate 10 times greater in the CAU-positive group (P = 0.02). The results were independent of either the use or timing of androgen blockade., Conclusions: The results of our study have shown that CAU on CP immunoscintigraphy is clinically important and correlates with a significantly greater risk of prostate cancer-specific death. These findings suggest that patients with CAU should be considered for earlier intervention with systemic therapy.

Background: Cystic fibrosis causes exocrine pancreatic insufficiency, leading to malabsorption. Supplemental pancreatic enzyme therapy alleviates the concomitant malnutrition experienced by cystic fibrosis patients. It is recognized that patients experience variations in clinical response to different brands of enzymes. This has prompted the US Food and Drug Administration to require that enzyme supplements be subjected to New Drug Applications., Aim: To investigate the safety and efficacy of supplemental pancreatic enzyme therapy in cystic fibrosis subjects., Methods: We compared two doses of one formulation of enteric-coated pancreatic enzymes: Ultrase MT12 (12,000 lipase units per capsule) and Ultrase MT20 (20,000 lipase units per capsule), to placebo in two separate safety and efficacy studies., Results: Mean total fat, protein and carbohydrate intake did not differ significantly between the groups. A significant difference in both fat and protein absorption occurred with the enzyme therapy groups. The Ultrase MT12 and Ultrase MT20 groups experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported., Conclusions: This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis. Excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

Purpose: Recombinant human erythropoietin (rHuEPO) is the standard of care for patients with chemotherapy-related anemia. Intravenous (IV) iron improves hemoglobin (Hb) response and decreases dosage requirements in patients with anemia of kidney disease, but its effect has not been studied in randomized trials in cancer patients., Methods: This prospective, multicenter, open-label, randomized trial enrolled 157 patients with chemotherapy-related anemia (Hb

The objective of the research was to determine the effect of the type, dose, and volume of anti-fibrinolytic agents (tranexamic acid, aprotinin) added to fibrin formulations, on adhesion development. Adhesions were induced in 228 male rats by creating apposing parietal and visceral peritoneal defects. Animals were randomized to receive no treatment or a fibrin formulation containing aprotinin or tranexamic acid. Seven days later the incidence of adhesions, and the force and energy required to detach them, were determined. Adhesions developed in 13/13 rats in the control and aprotinin groups. Treatment with fibrin (100 mg/ml tranexamic acid) resulted in adhesions in 4/14 rats (as strips, p < or = 0.0005), 4/10 rats (as spray, p < or = 0.0036), and 12/15 rats (by drip). The reduction of adhesions was dependent on the concentration of tranexamic acid with strip and spray application. Using commercial formulations, tranexamic-acid-containing fibrin (10/15, p = 0.042), but not aprotinin-containing fibrin (13/15), reduced the incidence of side-wall adhesions from 15/15 in controls. Fibrin containing either tranexamic or aprotinin reduced the incidence and severity of adhesions. This effect was greater when tranexamic acid was used and was dependent on the mode of administration, the volume, and to a degree, the concentration of tranexamic acid., (Copyright 2003 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 68B: 222-230, 2004)

Objective: To investigate the effect of 3-months' daily administration of high doses of sucralose, a non-nutritive sweetener, on glycemic control in subjects with type 2 diabetes., Design: A multicenter, double-blind, placebo-controlled, randomized study, consisting of a 6-week screening phase, a 13-week test phase, and a 4-week follow-up phase., Subjects/setting: Subjects with type 2 diabetes (age range 31 to 70 years) entered the test phase of this study; 128 subjects completed the study. The subjects were recruited from 5 medical centers across the United States and were, on average, obese., Intervention: Subjects were randomly assigned to receive either placebo (cellulose) capsules (n=69) or 667 mg encapsulated sucralose (n=67) daily for the 13-week test phase. All subjects blindly received placebo capsules during the last 4 weeks of the screening phase and for the entire 4-week follow-up phase., Main Outcome Measures: Glycated hemoglobin (HbA1c), fasting plasma glucose, and fasting serum C-peptide were measured approximately every 2 weeks to evaluate blood glucose homeostasis. Data were analyzed by analysis of variance using repeated measures., Results: There were no significant differences between the sucralose and placebo groups in HbA1c, fasting plasma glucose, or fasting serum C-peptide changes from baseline. There were no clinically meaningful differences between the groups in any safety measure., Conclusions: This study demonstrated that, similar to cellulose, sucralose consumption for 3 months at doses of 7.5 mg/kg/day, which is approximately three times the estimated maximum intake, had no effect on glucose homeostasis in individuals with type 2 diabetes. Additionally, this study showed that sucralose was as well-tolerated by the study subjects as was the placebo.

Background: Hypertension is common in chronic hemodialysis patients, yet there are limited data on the epidemiology of hypertension in these patients in the United States., Methods: We assessed the prevalence, treatment, and control of hypertension in a cohort of 2535 clinically stable, adult hemodialysis patients who participated in a multicenter study of the safety and tolerability of an intravenous iron preparation. Hypertension was defined as an average predialysis systolic blood pressure >150 mm Hg or diastolic blood pressure >85 mm Hg, or the use of antihypertensive medications., Results: Hypertension was documented in 86% (n = 2173) of patients. The prevalence of hypertension, in contrast to that observed in the general population, did not increase linearly with age and was not affected by sex or ethnicity. Hypertension was controlled adequately in only 30% (n = 659) of the hypertensive patients. In the remaining patients, hypertension was either untreated (12% [252/2173]) or treated inadequately (58% [1262/2173])., Conclusion: Control of hypertension, particularly systolic hypertension, in chronic hemodialysis patients in the United States is inadequate, despite recognition of its prevalence and the frequent use of antihypertensive drugs. Optimizing the use of medications and closer attention to nonpharmacologic interventions, such as adjustment of dry weight, a low-sodium diet, and exercise, may improve control.

Background: Secretin, a 27 amino acid polypeptide released in response to duodenal luminal acidification, stimulates secretion of water and bicarbonate from pancreatic ductal cells. To date the only secretin available for clinical use has been a biologically derived compound extracted from porcine duodenums. Although used to facilitate pancreatic duct cannulation, secretin has not been approved for this indication. In this study, a new synthetic porcine secretin with an identical amino acid composition was compared with saline solution for the facilitation of minor papilla cannulation in patients with pancreas divisum., Methods: A multicenter, prospective, randomized, placebo-controlled, double-blind, comparative trial was conducted at 4 centers with expertise in pancreaticobiliary endoscopy. Patients with pancreas divisum in whom minor papilla cannulation initially was unsuccessful were enrolled. Either saline solution (placebo) or synthetic porcine secretin was administered. If the minor papilla orifice and/or pancreatic juice flow was noted, cannulation was attempted and success or failure was documented (phase 1), as well as the time taken for successful cannulation. If cannulation was unsuccessful, no juice flow was noted, or the orifice was not seen, the alternate agent was administered (phase 2)., Results: Twenty-nine patients (7 men, 22 women; mean age 51 years, range 21-76 years) were enrolled. In phase 1, cannulation was achieved in 1 of 13 patients (7.7%) after the placebo was given and in 13 of 16 patients (81.3%) after synthetic porcine secretin was given (p < 0.0001). In phase 2, cannulation was achieved in 12 of 12 patients (100%) after synthetic porcine secretin was given and in 0 of 3 patients (0%) after the placebo was given (p = 0.0022). Overall, cannulation was successful in 25 of 28 patients (89.3%) who received synthetic porcine secretin and in 1 of 16 (6.3%) who received the placebo (p < 0.0001). Mean time to cannulation was significantly greater for the placebo than for the synthetic porcine secretin (4.75 min vs. 2.63 min; p = 0.0001). No adverse events directly attributable to synthetic porcine secretin administration were documented., Conclusions: This study confirmed the use and safety of synthetic porcine secretin in facilitating cannulation of the minor papilla in patients with pancreas divisum in whom cannulation was difficult. Use of this agent has the potential to further increase the cannulation success rate in this group of patients.

Background: Iron dextran administration is associated with a high incidence of adverse reactions including anaphylaxis and death. Although dextran, rather than iron, is believed to be the cause of these reactions, it is not known whether iron dextran-sensitive patients can be safely administered another form of parenteral iron, sodium ferric gluconate in sucrose (SFGC)., Methods: In a 69 center, prospective, double-blind, controlled trial of safety and tolerability of SFGC, the rate of reactions to SFGC and placebo in 144 iron dextran-sensitive patients was compared with 2194 patients who were previously tolerant to iron dextran preparations. Serum tryptase levels, a marker of mast cell degranulation, also were measured., Results: Among 143 iron dextran-sensitive patients exposed to SFGC, three (2.1%) were intolerant. All three had suspected allergic events to SFGC, including one patient with a serious reaction (0.7%). One dextran-sensitive patient (0.7%) had a suspected allergic reaction after placebo. In contrast, among 2194 iron dextran-tolerant patients, reactions to SFGC were significantly less common, with SFGC intolerance seen in seven patients (0.3%; P = 0.020), including five (0.2%) who had suspected allergic events (P = 0.010), but none who had serious events (0.0%; P = 0.061). Two iron dextran-tolerant patients (0.09%) had allergic-like reactions following placebo injections. Two of the three suspected allergic events in the iron dextran-sensitive group were confirmed as mast cell dependent by a 100% increase in serum tryptase, while there were no confirmed allergic events in the iron dextran-tolerant group. Long-term exposure to SFGC in iron dextran-sensitive patients resulted in intolerance in only one additional patient and no serious adverse events., Conclusions: Patients with a history of iron dextran sensitivity had approximately sevenfold higher rates of reaction to both placebo and SFGC compared to iron dextran tolerant patients. However, logistic regression analysis, performed to account for the higher reaction rate to placebo, suggests that this increased reactivity was not drug-specific nor immunologically mediated, but represented host idiosyncrasy. These results support the conclusions that reactions to SFGC can be attributed to pseudoallergy, and that SFGC is not a true allergen.

Background: Parenteral iron is often required by hemodialysis patients to maintain adequate iron stores. Until recently, the only available form of intravenous iron was iron dextran, which is associated with significant adverse reactions, including anaphylaxis and death. Sodium ferric gluconate complex (SFGC) was recently approved for use in the U.S. under FDA's priority drug review. This Phase IV study was designed to evaluate the safety of a single dose of intravenous SFGC as compared to placebo and a historical iron dextran control., Methods: This multicenter, crossover, randomized, double blind, placebo-controlled prospective comparative study was performed in hemodialysis patients requiring at least 125 mg of elemental iron. The historical control was obtained from a meta-analysis of four publications examining outcomes in patients exposed to iron dextran. SFGC naïve patients were administered SFGC without a test dose, undiluted, at a rate of 125 mg over 10 minutes, and compared to placebo comprising bacteriostatic saline., Results: A total of 2534 patients were enrolled. The incidence of drug intolerance (an adverse event precluding re-exposure) was significantly less [0.44%, confidence interval (CI) 0.21 to 0.71%] after SFGC as compared to the iron dextran control (2.47%, CI 1.87 to 3.07%, P < 0.0001), but higher than after placebo (0.1%, P = 0.02). There was no difference found between SFGC and placebo in serious adverse events. A single life-threatening event occurred after SFGC (0.04%, CI 0.00 to 0.22%), which was significantly less than following iron dextran (0.61%, CI 0.36 to 0.86%), P = 0.0001., Conclusion: SFGC is well tolerated when given by intravenous push without a test dose. SFGC has a significantly lower incidence of drug intolerance and life-threatening events as compared to previous studies using iron dextran. The routine use of iron dextran in hemodialysis patients should be discontinued.

Objective: To evaluate the safety and efficacy of an oxidized, regenerated, cellulose adhesion barrier (Interceed TC7) in the reduction of pelvic adhesions., Study Design: Clinical studies published or completed by December 31, 1994, evaluating the barrier used at laparotomy were considered for a metaanalysis., Results: Of 10 studies (n = 560) identified, data from 7 (n = 389) met the inclusion criteria for determining the reduction in the incidence of adhesions and 5 (n = 311) for determining the reduction in adhesion extent (raw surface area after adhesiolysis). There was a 24.2 +/- 3.3% difference in the incidence of adhesions (P < .001) between barrier-treated and untreated sites. Adhesion-free outcomes were 1.5-2.5 times more likely at barrier-treated sites than at sites with good surgical technique alone (odds ratio = 2.89; 95% confidence interval = 2.15-3.90). Barrier treatment resulted in a greater reduction (1.1 +/- 0.4 cm2) in adhesion extent (raw surface area) than good surgical technique alone (P < .001). Four adverse events were recorded; they were typical of those seen after surgery. No event was considered to be definitely related to the use of the barrier., Conclusion: The barrier significantly reduced the incidence and extent of adhesions as compared with no treatment, confirming the conclusion from individual studies that it is safe and effective in pelvic laparotomy surgery.

Objective: To document rates of adhesion development after abdomino-pelvic surgery, stratified by adhesion type, access method, and use of crystalloid solution instillates., Design: Reports from a MEDLINE search (1/1/1966-12/18/1996) detailing rates of adhesion development and meeting the inclusion criteria were subjected to meta-analysis., Setting: Meta-analysis., Patient(s): Patients undergoing abdomino-pelvic surgery., Intervention(s): Intraperitoneal crystalloid solution instillates., Main Outcome Measure(s): Percentage adhesion-free outcome in patients ("patients") or surgical sites ("sites")., Result(s): Adhesion-free outcome (sites) was lowest for reformed (26.3% laparotomy; 14.3% laparoscopy), higher for de novo 1b (direct trauma) (45.2% laparotomy, 37.2% laparoscopy), and highest for de novo 1a (indirect trauma) adhesions (82.4% laparoscopy). Crystalloid solution instillates reduced adhesion-free outcome at sites (45.2% versus 20% de novo 1b adhesions in laparotomy) and in patients (43.5% versus 19.9% reformed, laparotomy; 71.7% versus 25% de novo 1b, laparoscopy)., Conclusion(s): Adhesion-free outcome was lowest for reformed, higher for de novo 1b, and highest for de novo 1a adhesions. Surprisingly, it was lower in laparoscopy than in laparotomy for de novo 1b and reformed adhesions. Crystalloid instillates did not increase adhesion-free outcome. Although limited by the retrospective and heterogeneous nature of the data, these conclusions nonetheless provide a basis on which to formulate future hypotheses.

Urinary pyridinoline and deoxypyridinoline crosslinks (crosslink) are excreted when bone is resorbed. The aims of this study in healthy infants were to determine whether crosslinks a) could predict growth velocity, b) are variable due to circadian rhythm, and c) differ in infants who were either breast-fed or formula-fed. In 78 healthy infants (48 male; 30 female) urine samples were collected and anthropometric measurements were taken at 2, 3, 4, 5, 6, 8, 10 and 12 months of age. In addition, a total of 25 samples were collected during the day (0700-2000) in 5 of the infants to determine circadian rhythm of crosslink excretion. Crosslink excretion decreased (p < 0.001) with age between 2 and 12 months. Pyridinoline excretion showed a significant, but weak correlation (r > or = 0.21; p < 0.05) with linear growth velocity and weight velocity in the subsequent month until 6 months of age, and no correlation thereafter. Infants studied for circadian rhythm showed a 63% greater (p < 0.05) rate of pyridinoline excretion after a nap as compared to the 13-hour mean value. In a subset of infants whose energy intake was exclusively from breast milk (BF, n = 23) or formula (FF, n = 10), crosslink excretion was greater in BF infants at 3 months of age (p < 0.05). The correlations between crosslink excretion and growth parameters indicate that crosslinks may be useful as a marker of growth in infant populations. However sources of variation in crosslink excretion, such as circadian rhythm and diet may limit their utility to predict growth in an individual infant. These factors should be considered in future studies examining markers of bone turnover in infants.