Search

Background: Higher asthma burden is more likely to be experienced by Black than White patients. In clinical research, underrepresentation of minority populations is observed., Objective: To estimate response to omalizumab in Black and White patients in North America with moderate to severe asthma., Methods: Data from placebo-controlled (EXTRA) and single-armed (PROSPERO) omalizumab studies were used for this post hoc analysis. We used a Poisson regression model to examine exacerbation rates. An analysis of covariance model was used to estimate placebo-corrected change in FEV 1 and Asthma Quality of Life Questionnaire (AQLQ) by racial group., Results: This analysis included 631 White and 176 Black patients from EXTRA and 567 White and 130 Black patients from PROSPERO. In EXTRA, placebo-corrected exacerbation rate reductions (relative rate change [95% confidence interval], 22.6% [2.0-38.9%] vs 22.0% [-18.0% to 48.4%]) and FEV 1 improvements were similar for White and Black patients. There was a trend toward greater AQLQ improvements for Black versus White patients (least squares mean treatment differences: 0.0 vs 0.3, 0.6 vs 0.4, and 0.6 vs 0.2 at weeks 16, 32, and 48, respectively) throughout the study. In PROSPERO, on-study exacerbation rates (0.76 [0.65-0.88] vs 0.77 [0.56-1.10]) and AQLQ improvements (least squares mean change from baseline: 1.2 vs 1.2 and 1.3 vs 1.2 at month 6 and end of study, respectively) were similar for White versus Black patients. A trend toward greater FEV 1 improvement was observed in White versus Black patients throughout the study., Conclusions: This analysis of EXTRA and PROSPERO suggests that Black and White patients with moderate to severe asthma experience similar improvements in exacerbations, FEV 1 , and AQLQ with omalizumab., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anosmia and ageusia are symptoms commonly associated with COVID-19, but the relationship with disease severity, onset and recovery are unclear., Objective: To examine factors associated with anosmia and ageusia and the recovery from these symptoms in an ethnically diverse cohort., Methods: Individuals tested for SARS-CoV-2 between March and April 2020 were eligible for the study. Randomly selected participants answered a telephone questionnaire on COVID-19 symptoms with a focus on anosmia and ageusia. Additionally, relevant past medical history and data on the COVID-19 clinical course were obtained from electronic medical records. 486 patients were in the COVID-19 group and 103 were COVID-19-negative., Results: Patients who were younger were more likely to report anosmia and/or ageusia (odds ratio (OR) for anosmia per 1-year increase in age: 0·98, 95%CI:0-97-0·99, p  = 0·003; for ageusia: 0·98, 95%CI:0·97-0·99, p  = 0·005) as were patients with lower eosinophil counts (OR for anosmia per 0.1-K/μL increase in eosinophils: 0·02, 95%CI:0·001-0·46, p  = 0·01, for ageusia 0·10, 95%CI:0·01-0·97, p  = 0·047). Male gender was independently associated with a lower probability of ageusia (OR:0·56, 95%CI:0·38-0·82, p  = 0·003) and earlier sense of taste recovery (HR:1·44, 95%CI:1·05-1·98, p  = 0·02). Latinos showed earlier sense of taste recovery than white patients (HR:1·82, 95%CI:1·05-3·18, p  = 0·03)., Conclusion: Anosmia and ageusia were more common among younger patients and those with lower blood eosinophil counts. Ageusia was less commonly reported among men, and time to taste recovery was earlier among both men and Latinos.

Competing Interests: G.H. is on the advisory board for AstraZeneca and is a principal investigator at Genentech, Merck, and AstraZeneca. E.J. has a research grant from Cumberland Pharmaceuticals, Inc, and served on the advisory board for Sanofi/Regeneron, GSK, and Genentech/Novartis. In the previous 12 months, E.J. has served as a committee member on the National Board of Medical Education and the US Medical Licensing Examination Committee. The other authors have no funding or conflicts of interest to declare.

Background: Comorbidities are common in asthma and may complicate treatment response., Objective: To examine response to omalizumab in patients with moderate-to-severe allergic asthma by asthma-related and allergic comorbidities., Methods: Patients aged 12 years or more from placebo-controlled 008/009 (n = 1071), EXTRA (n = 848), and INNOVATE (n = 419), and single-armed PROSPERO (n = 801) omalizumab studies were included. Poisson regression/analysis of covariance models were used to estimate adjusted exacerbation rates and forced expiratory volume in 1 second (FEV1) change from baseline after omalizumab initiation for subgroups by number of comorbidities (0, 1 [008/009]; 0, 1, ≥2 [EXTRA and INNOVATE]; 0, 1, 2, ≥3 [PROSPERO]). Self-reported comorbidities included allergic rhinoconjunctivitis, chronic rhinosinusitis, recurrent acute sinusitis, nasal polyps, atopic and contact dermatitis, urticaria, food allergy, anaphylaxis, other allergies, gastroesophageal reflux disease, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis., Results: In the EXTRA and INNOVATE studies, no consistent pattern was observed for placebo-corrected relative rate reduction in normalized asthma exacerbations among omalizumab-treated comorbidity subgroups. In PROSPERO, on-study exacerbation rates in the comorbidity subgroups were similar (0, 0.68; 1, 0.70; 2, 0.77; ≥3, 0.80). FEV1 improvements were observed throughout the study for omalizumab vs placebo for all comorbidity subgroups. There were no consistent differences in FEV1 improvements among comorbidity subgroups in 008/009, EXTRA, or INNOVATE. Similarly, no among-group differences were observed for FEV1 change from baseline at month 12 in PROSPERO (0, 0.05 L; 1, 0.08 L; 2, 0.00 L; ≥3, 0.04 L). The 95% confidence intervals overlapped substantially in all instances., Conclusion: In these analyses of placebo-controlled/single-armed studies, on-study exacerbation rates and FEV1 improvements with omalizumab treatment were similar irrespective of comorbidity burden., Trial Registration: ClinicalTrials.gov identifiers are as follows: EXTRA, NCT00314574 (https://clinicaltrials.gov/ct2/show/NCT00314574); INNOVATE, NCT00046748 (https://clinicaltrials.gov/ct2/show/NCT00046748); and PROSPERO, NCT01922037 (https://clinicaltrials.gov/ct2/show/NCT01922037)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: There is a paucity of information on coronavirus disease 2019 (COVID-19) outcomes in asthmatics., Objective: To identify risk factors associated with admission and subsequent mortality among COVID-19-infected asthmatics., Methods: Adults at our institution with a positive polymerase chain reaction for COVID-19 between March 14 and April 27, 2020, were retrospectively identified. Comorbidities, laboratory results, and mortality rates during hospitalization were recorded., Results: In total, 737 of 951 (77.5%) asthma patients with COVID-19 were seen in the emergency department (ED), and 78.8% of these ED patients (581 of 737) were admitted. Individuals with previously measured mean absolute eosinophil counts (AEC) ≥150 cells/μL were less likely to be admitted (odds ratio [OR] = 0.46, 95% confidence interval [CI]: 0.21-0.98, P = .04), whereas concomitant heart failure (CHF), chronic kidney disease (CKD), and chronic obstructive pulmonary disease (COPD) were risk factors for admission. Hospitalized patients with asthma with peak hospital-measured AEC ≥150 cells/μL (n = 104) were less likely to die compared with those whose AEC remained <150 cells/μL (n = 213) (mortality rate 9.6% vs 25.8%; OR = 0.006, 95% CI: 0.0001-0.64, P = .03). This group had also higher preadmission mean AEC (237 ± 181 vs 163 ± 147 cells/μL, P = .001, OR = 2012, 95% CI: 27.3-14,816). The mortality rate in patients with asthma alone (no associated CHF, CKD, COPD, diabetes, or hypertension) was similar to that of patients without asthma or any of these comorbidities., Conclusions: In asthmatics, pre-existing eosinophilia (AEC ≥150 cells/μL) was protective from COVID-19-associated admission, and development of eosinophilia (AEC ≥150 cells/μL) during hospitalization was associated with decreased mortality. Preadmission AEC influenced the AEC trend during hospitalization. Having a Th2-asthma phenotype might be an important predictor for reduced COVID-19 morbidity and mortality that should be further explored in prospective and mechanistic studies., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: Patients with coronavirus disease 2019 (COVID-19) can progress to a state of unregulated inflammation called cytokine storm syndrome (CSS). We describe formation and operation of a COVID-19 multidisciplinary consultation service that was allowed to individualize treatment for critically ill patients with COVID-19 during the pandemic., Methods: Institutional experts from different subspecialties formed a COVID-19 CSS task force at Montefiore Medical Center, Bronx, NY. They agreed on a set of four clinical and six laboratory parameters that can help early identify COVID-19 CSS. We describe the formation and implementation of the COVID-19 task force. The case series description of the COVID-19 CSS consultation cohort highlights consultation volume, baseline characteristics, clinical and laboratory parameters, and how biologic treatments were allocated to these patients., Results: Between April 4,2020, and May 7,2020, the COVID-19 CSS task force was formed, consisting of adult and pediatric rheumatologists and allergy and immunology physicians. The task force evaluated a total of 288 patients, of whom 197 (68%) were male, the median (interquartile range [IQR]) age was 62 (51-70) years, 122 (42%) were Hispanic, and 88 (31%) were Black or African American. The common presenting symptoms in all referred patients were dyspnea (85%) and diarrhea (80%). Thirty-one patients who received biologic therapy were younger, with a median (IQR) age of 53 (32-63) years, as opposed to 62.5 (52-70) years in the nonbiologic group (P = 0.008). A higher proportion receiving biologics was in the critical care setting (26 [84%] vs 151 [59%]; P = 0.006)., Conclusion: To the best of our knowledge, this is the first multidisciplinary collaborative effort to provide individualized patient recommendations for evaluation and treatment of patients with COVID-19 who may have CSS. This working model helped to devise an approach that may have identified patients who were most likely to benefit from biologic therapy in the absence of evidence-based guidelines., (© 2021 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Aspirin desensitization followed by daily aspirin provides therapeutic benefits to patients with aspirin-exacerbated respiratory disease (AERD). It is not well understood how eicosanoid levels change during aspirin treatment., Objective: To investigate associations between clinical outcomes of aspirin treatment and plasma eicosanoid levels in patients with AERD., Methods: Thirty-nine patients with AERD were offered aspirin treatment (650 mg twice daily) for 4 weeks. Respiratory parameters and plasma levels of multiple eicosanoids were recorded at baseline and after 4 weeks of aspirin therapy using the Asthma Control Test and Rhinoconjunctivitis Quality of Life Questionnaire. Respiratory function was evaluated using the FEV 1 and nasal inspiratory peak flow., Results: After aspirin treatment, respiratory symptoms improved in 16 patients, worsened in 12 patients, and did not change in 4 patients. Seven patients were unable to complete the desensitization protocol. Patients with symptom improvement had higher baseline plasma 15-hydroxyeicosatetraenoic acid (15-HETE) levels than did patients with symptom worsening: 7006 pg/mL (interquartile range, 6056-8688 pg/mL) versus 4800 pg/mL (interquartile range, 4238-5575 pg/mL), P = .0005. Baseline 15-HETE plasma levels positively correlated with the change in Asthma Control Test score (r = 0.61; P = .001) and in FEV 1 after 4 weeks of aspirin treatment (r = 0.49; P = .01). It inversely correlated with Rhinoconjunctivitis Quality of Life Questionnaire score (r = -0.58; P = .002). Black and Latino patients were more likely to have symptom worsening on aspirin or fail to complete the initial desensitization than white, non-Latino patients (P = .02)., Conclusions: In patients with AERD, low baseline 15-HETE plasma levels and black or Latino ethnicity are associated with worsening of respiratory symptoms during aspirin treatment., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Allergists commonly perform intradermal skin testing (IDST) after negative skin-prick testing (SPT) to comprehensively diagnose environmental allergic sensitization. However, with the availability of modern methods to detect serum-specific immunoglobulin E (ssIgE), it is unclear if ssIgE testing could substitute for IDST., Objective: To determine the efficacy of ssIgE testing and IDST when added to SPT in diagnosing environmental allergic sensitizations., Methods: SPT, IDST, and ssIgE testing to nine common environmental allergens were analyzed in 75 patients with oculonasal symptoms who presented to our allergy clinics in the Bronx, New York, between January 2014 and May 2015., Results: A total of 651 SPT and 499 ssIgE tests were independently performed and revealed 162 (25%) and 127 (25%) sensitizations, respectively. When SPT results were negative, IDST results revealed 108 of 452 additional sensitizations (24%). In contrast, when SPT results were negative, ssIgE test results only revealed 9% additional sensitizations. When both SPT and IDST results were negative, ssIgE testing only detected 3% of additional sensitizations, and ssIgE levels were typically low in these cases (median, 1.25 kU/L; range, 0.357-4.47 kU/L). When both SPT and ssIgE test results were negative, IDST results detected 15% additional sensitizations., Conclusion: IDST detected more additional environmental sensitizations compared with ssIgE testing. IDST, therefore, may be useful when the SPT and/or ssIgE testing results were negative, but the exposure history indicated relevant allergic sensitization. Serology added only a little more information if both SPT and IDST results were negative but may be useful in combination with SPT if IDST cannot be performed.

Introduction: Asthma prevalence is reportedly higher among U.S.-born relative to foreign-born Hispanics/Latinos. Little is known about rates of asthma onset before and after relocation to the U.S. in Latinos. Asthma rates were examined by U.S. residence and country/territory of origin., Methods: In 2015-2016, age at first onset of asthma symptoms was analyzed, defined retrospectively from a cross-sectional survey in 2008-2011, in relation to birthplace and U.S. residence among 15,573 U.S.-dwelling participants (aged 18-76 years) in the Hispanic Community Health Study/Study of Latinos., Results: Cumulative incidence of asthma through age 30 years ranged from 7.9% among Mexican background individuals to 29.4% among those of Puerto Rican background. Among those born outside the U.S. mainland, the adjusted hazard for asthma was 1.52-fold higher (95% CI=1.25, 1.85) after relocation versus before relocation to the U.S. mainland, with heterogeneity in this association by Hispanic/Latino background (p-interaction<0.0001). Among foreign-born Dominicans and Mexicans, rates of asthma were greater after relocation versus before relocation (adjusted hazard ratio [AHR] for after versus before relocation, 2.42, 95% CI=1.44, 4.05 among Dominicans; AHR=2.90, 95% CI=2.02, 4.16 among Mexicans). Puerto Ricans had modestly increased asthma onset associated with U.S. mainland residence (AHR=1.52, 95% CI=1.06, 2.17). No similar increase associated with U.S. residence was observed among Central/South American immigrants (AHR=0.94, 95% CI=0.53, 1.67). Asthma rates among Cuban immigrants were lower after relocation (AHR=0.45, 95% CI=0.24, 0.82)., Conclusions: The effect of relocation to the U.S. on asthma risk among Hispanics is not uniform across Hispanic/Latino groups., (Copyright © 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The immunomodulatory effects of helminths have been well described. However, there is a relative lack of literature regarding the link between parasites and allergic diseases. A number of patients with allergic symptoms have positive serologic test results for Strongyloides stercoralis., Objective: To identify patients with allergy-type symptoms and coexisting Strongyloides infection and to analyze the effect of Strongyloides eradication therapy with ivermectin on these symptoms., Methods: The medical records of our allergy clinic sites were reviewed for Strongyloides test results between January 2011 and October 2014. Each allergy-type symptom was assessed separately with regard to improvement after ivermectin therapy., Results: Among the 1,446 patients who had Strongyloides serologic tests ordered, 127 (8.8%) had positive test results. Eighty-four patients had follow-up data regarding allergy-type symptoms after ivermectin treatment. Among these, 52 patients (61.9%) reported skin-related problems (pruritus, urticaria, angioedema, and/or rash). Forty-nine patients (58.3%) had asthma, and 73.8% had allergic rhinoconjunctivitis. Although respiratory symptoms typically did not respond to ivermectin treatment, 24 of 48 patients (50%) with skin symptoms reported a significant subjective improvement of symptoms after ivermectin treatment. Peripheral eosinophil counts significantly decreased after ivermectin treatment from 450 to 200/μL (P < .001)., Conclusion: Serologic testing for strongyloides may be indicated for patients with allergy-type symptoms and a suggestive exposure history. Patients with strongyloidiasis and primarily cutaneous symptoms experienced significant symptomatic improvement after ivermectin therapy., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Aspirin-exacerbated respiratory disease (AERD) is diagnosed through graded aspirin challenges that induce hypersensitivity reactions and eicosanoid level changes. It is not known whether diagnostically useful changes also occur after low-dose aspirin challenges that do not induce hypersensitivity reactions., Objective: To investigate the utility of low-dose oral aspirin challenges for diagnosing AERD by measuring different clinical parameters and eicosanoid changes., Methods: Sixteen patients with AERD and 13 patients with aspirin-tolerant asthma underwent oral challenges with low-dose (20 or 40 mg) aspirin and diagnostic oral graded aspirin challenges (up to 325 mg of aspirin). Forced expiratory volume in 1 second, nasal peak flow, the fraction of exhaled nitric oxide (FeNO), and eicosanoid levels in plasma and urine were analyzed., Results: In patients with AERD but not in those with aspirin-tolerant asthma, 40-mg aspirin challenges induced a significant mean (SEM) decrease from baseline in FeNO (19% [5.1%]; P = .001) without causing any hypersensitivity reaction. The FeNO decrease also occurred after higher-dose aspirin challenges (27.8% [4.9%]; P < .001). The sensitivity and specificity of 40-mg aspirin-induced FeNO changes for identifying AERD were 90% and 100% with an area under the curve of 0.98 (95% CI, 0.92-1.00). The low-dose challenge also induced a significant leukotriene E4 urine increase in patients with AERD (from 6.32 [0.08] to 6.91 [0.15] log-pg/mg creatinine; P < .001), but the sensitivity and specificity of these changes were less than for the FeNO changes., Conclusion: The low-dose aspirin-induced decrease in FeNO in patients with AERD may be useful for the diagnosis of aspirin allergy without inducing a hypersensitivity reaction., Trial Registration: clinicaltrials.gov Identifier: NCT01320072., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Chlorinated phenols are associated with atopic conditions, but it is not known whether they are associated with wheeze or asthma and whether atopy is involved in these associations., Objectives: To test the association between urine levels of 2 dichlorophenols (2,4- and 2,5-dichlorophenols) and asthma morbidity in atopic and nonatopic wheezers and between total serum immunoglobulin E (IgE) levels., Methods: Data from a sample of 2,125 participants at least 6 years old from the US National Health and Nutrition Examination Survey 2005 to 2006 were analyzed. Asthma morbidity data were available for those participants who reported wheezing in the past year ("wheezers"; n = 250). This subsample was categorized as atopic or nonatopic., Results: Atopic wheezers with higher 2,5-dichlorophenol levels were more frequently diagnosed with asthma by a physician (odds ratio [OR] 4.7 for highest vs lowest tertile, P < .001), required more prescriptions for asthma medications (OR 2.2, P = .046), and reported more exercise-induced wheezing (OR 5.8, P = .045) than atopic wheezers with low dichlorophenol levels. Atopic wheezers with higher 2,5- or 2,4-dichloropheonol levels also were more likely to miss work or school because of wheezing (OR 10.0, P < .001; OR 11.4, P < .01, respectively). In contrast, in nonatopic wheezers, there were no significant associations between dichlorophenol levels and asthma morbidity measurements. The 2 dichlorophenol metabolites were positively associated with increased serum IgE levels in the larger study sample., Conclusion: These findings indicate that in patients with atopy and a history of wheezing, asthma morbidity is associated with high urinary dichlorophenol levels. Increased urine dichlorophenol levels are associated with higher total serum IgE., (Copyright © 2014 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: AZD4877 is a potent inhibitor of the mitotic spindle kinesin, Eg5. Early-phase clinical studies in a broad range of cancers showed that AZD4877 is well tolerated. This Phase II study evaluated the efficacy, safety and pharmacokinetics (Cmax) of AZD4877 in patients with previously treated advanced urothelial cancer (ClinicalTrials.gov identifier NCT00661609)., Patients and Methods: AZD4877 25 mg was administered once-weekly for 3 weeks of each 4-week cycle until disease progression, death, unacceptable toxicity or withdrawal. The primary objective was to determine the objective response rate (RECIST). Recruitment was to be halted if ≤ 2 of the first 20 evaluable patients achieved an objective tumor response. Cmax was assessed on days 1 and 8 of cycle 1., Results: None of the first 20 patients evaluable for efficacy achieved an objective response; enrollment was therefore halted. During this initial analysis, a further 21 patients were recruited. Overall, 39 patients were evaluable for efficacy, including one with confirmed partial response (PR) and seven patients with stable disease for ≥ 8 weeks (including one unconfirmed PR). The most commonly reported treatment-related adverse events (TRAEs) were neutropenia (22 patients), fatigue (12), leukopenia (7) and constipation (6); the most commonly reported grade ≥ 3 TRAE was neutropenia (21). Four patients had serious TRAEs. On days 1 and 8, the geometric mean Cmax of AZD4877 was 138 ng/ml (CV = 75 %) and 144 ng/ml (CV = 109 %), respectively., Conclusions: AZD4877 was generally tolerable in patients with advanced urothelial cancer. Given the limited clinical efficacy, further development of AZD4877 in urothelial cancer is not planned.

Purpose: Siltuximab is a chimeric, anti-interleukin-6 monoclonal antibody with potential therapeutic benefit in castration-resistant prostate cancer (CRPC) patients. We assessed the safety and tolerability of siltuximab in combination with docetaxel, the pharmacokinetics of docetaxel alone and with siltuximab, and the efficacy and pharmacodynamics of siltuximab plus docetaxel., Patients and Methods: In an open-label, dose-escalation, multicenter, phase 1 study, patients with metastatic, progressive CRPC received docetaxel 75 mg/m(2) q3w plus siltuximab 6 mg/kg q2w (n=12), 9 mg/kg q3w (n=12), or 12 mg/kg q3w (n=15). Dose-limiting toxicity (DLT), PSA, and radiologic response according to WHO criteria were evaluated., Results: DLT was reported in 1 of 11 patients receiving 6 mg/kg, 1 of 12 receiving 9 mg/kg, and in 1 of 14 receiving 12 mg/kg. Common Grade ≥ 3 adverse events were neutropenia (73 %), leukopenia (60 %), lymphopenia (30 %), dyspnea (19 %), and fatigue (14 %). Toxicities were not dose dependent. Siltuximab did not affect docetaxel pharmacokinetics. The pharmacokinetic profile for siltuximab in combination was similar to single-agent siltuximab pharmacokinetics. Twenty-three (62 %; 95 % CI 45 %, 78 %) of 37 combination-treated patients achieved a confirmed ≥ 50 % PSA decline. Of 17 patients with measurable disease at baseline, 2 confirmed and 2 unconfirmed radiologic partial responses ranging 190 to 193 days were achieved with 9- and 12-mg/kg siltuximab. C-reactive protein concentrations were suppressed throughout treatment in all patients., Conclusion: These results suggest that siltuximab in combination with docetaxel is safe and shows preliminary efficacy in patients with CRPC, although alternative siltuximab schedules may be better tolerated for future studies.

Hydroxyzine is commonly used to treat pruritic skin lesions. Although rare, hydroxyzine can sometimes be linked to worsening dermatitis in patients who have sensitivities to phenothiazines and/or ethylenediamines. Herein we describe a patient who developed papulovesicular eruptions following the use of topical neomycin. Our patient's contact dermatitis initially improved after the use of oral steroids. However, the patient's skin condition was exacerbated by the continued use of hydroxyzine to treat her pruritus. Patch testing was positive at 48 hours for neomycin sulfate, ethylenediamine dihydrochloride, and p-phenylenediamine. Given the suspected cross-reactivity between hydroxyzine and ethylenediamine, hydroxyzine was discontinued and the patient's cutaneous symptoms improved. In summary, physicians must be aware that oral hydroxyzine can worsen contact dermatitis in ethylenediamine-sensitive patients.

Background: Epidemiologic studies support the hypothesis that reduced microbial exposure in westernized societies promotes atopy. Dichlorophenols are widely used as pesticides and for chlorination of water. They have a strong bactericidal effect that could affect microflora in the environment. However, it is unknown whether their use is associated with a higher prevalence of allergies., Objective: To test the association between exposure to environmental pesticides represented by dichlorophenols and allergic sensitization measured by allergen-specific serum IgE levels in a US nationally representative sample of 2,211 persons 6 years and older in the National Health and Nutrition Examination Survey 2005-2006., Methods: Exposure to dichlorophenols was defined as high if their levels in urine were present at the 75th percentile and above. Association of the high exposure to dichlorophenols with sensitization to food and environmental allergens was assessed in logistic regression models after adjustment for sample weights and potential confounders., Results: Sensitizations to 1 or more food allergens were more common in those with exposure to 2 dichlorophenol metabolites. After multivariable adjustment, urine dichlorophenol levels at the 75th percentile and above were associated with the presence of sensitization to foods (odds ratio, 1.8; 95% confidence interval, 1.2-2.5; P = .003). No significant association was found between dichlorophenol exposure and sensitization to aeroallergens alone., Conclusion: High urine levels of dichlorophenols are associated with the presence of sensitization to foods in a US population. Excessive use of dichlorophenols may contribute to the increasing incidence of food allergies in westernized societies., (Copyright © 2012 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer., Patients and Methods: Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m(2) with or without paclitaxel 80 mg/m(2) per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks., Results: We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases)., Conclusion: Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

Purpose: Temsirolimus is an effective treatment for renal cell carcinoma. It is associated with increases in serum cholesterol, triglyceride, and glucose. We investigated whether changes of these biomarkers could predict its efficacy., Experimental Design: We examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to IFN or temsirolimus in the Global Advanced Renal Cell Carcinoma Trial. Using time-dependent proportional hazards models, we quantified the association between changes in these biomarkers from baseline with overall survival (OS) and progression-free survival (PFS). We also assess the extent to which changes of these biomarkers predict the effects of temsirolimus on survival., Results: Temsirolimus was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P = 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with IFN and improved survival rate (OS: HR = 0.76, P = 0.02; PFS: HR = 0.70, P = 0.001). Cholesterol increase during study was associated with longer survival (OS: HR = 0.77 per mmol/L, P < 0.0001; PFS: HR = 0.81 per mmol/L; P < 0.0001). Temsirolimus effect on cholesterol predicted its effect on survival with no additional survival advantage observed after adjusting for cholesterol change during study (OS: HR = 1.14, P = 0.37; PFS: HR = 0.88, P = 0.35). Temsirolimus effect on triglycerides or glucose did not predict its effect on survival, with survival advantage in favor of temsirolimus still observed after adjusting for these factors (P = 0.003 and P = 0.002)., Conclusion: Cholesterol increase is a potential predictor for temsirolimus efficacy. Longer survival in patients treated with temsirolimus was observed in those with larger increases in cholesterol. Prospectively designed biomarker studies of temsirolimus or other mTOR inhibitors are recommended.

Background: This multicenter phase II trial evaluated the efficacy and safety of trabectedin in metastatic castration-resistant prostate cancer (CRPC)., Patients and Methods: Two schedules were evaluated in three cohorts: weekly as 3-h i.v. infusion at 0.58 mg/m(2) for 3 out of 4 weeks (Cohort A, n = 33), and every 3 weeks (q3wk) as 24-h infusion at 1.5 mg/m(2) (Cohort B1, n = 5) and 1.2 mg/m(2) (Cohort B2, n = 20). The primary end point was prostate-specific antigen (PSA) response; secondary end points included safety, tolerability and time to progression (TTP)., Results: Trabectedin resulted in PSA declines ≥ 50% in 12.5% (Cohort A) and 10.5% (Cohort B2) of patients. Among men pretreated with taxane-based chemotherapy, PSA response was 13.6% (Cohort A) and 15.4% (Cohort B2). PSA responses lasted 4.1-8.6 months, and median TTP was 1.5 months (Cohort A) and 1.9 months (Cohort B2). The dose of 1.5 mg/m(2) (approved for soft tissue sarcoma) given as 24-h infusion q3wk was not tolerable in these patients. At 1.2 mg/m(2) q3wk and 0.58 mg/m(2) weekly, the most common adverse events were nausea, fatigue and transient neutropenia and transaminase increase., Conclusions: Two different trabectedin schedules showed modest activity in metastatic CRPC. Further studies may require identification of predictive factors of response in prostate cancer.

Purpose: This open-label phase II trial assessed mitoxantrone/prednisone (M/P) with and without siltuximab (CNTO 328), an anti-interleukin-6 chimeric monoclonal antibody, for patients with metastatic castration-resistant prostate cancer who received prior docetaxel-based chemotherapy., Methods: Part 1 assessed the safety of biweekly siltuximab 6 mg/kg plus M 12 mg/m(2) every 3 weeks and P. Part 2 assessed efficacy and safety of siltuximab plus M/P versus M/P alone. The primary end-point was progression-free survival (PFS). Progression was defined as progressive disease per Response Evaluation Criteria in Solid Tumours (RECIST), or ≥ 3 new skeletal lesions with clinical deterioration or without deterioration confirmed by repeated bone scan. Rising prostate-specific antigen was not considered progression., Results: Siltuximab plus M/P was well tolerated in Part 1 (n=9). In Part 2, 48 and 49 patients received siltuximab plus M/P or M/P alone, respectively. Enrolment was prematurely terminated by the Independent Data Monitoring Committee since an apparent imbalance in patient baseline characteristics (favoring the M/P only arm) made it unlikely that the study could achieve its primary efficacy end-point. Median PFS was 97 days with siltuximab combination and 228 days with M/P alone (hazard ratio, 1.72; P=0.043). Use of a novel non-validated PFS definition may have contributed to this result. Abnormal laboratory assessments were more frequent with the combination. Infection and febrile neutropenia rates were similar between groups. Greater C-reactive protein suppression was achieved during siltuximab combination treatment compared with M/P alone (P=0.0003)., Conclusion: While siltuximab plus M/P appeared well tolerated, improvement in outcomes was not demonstrated., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Mugwort pollen is known to cross-react with a variety of spices and vegetables that are typically part of elimination diets used in the treatment of chronic urticaria (CU)., Objective: We sought to investigate the association between CU and allergic sensitization to mugwort pollen., Methods: We conducted 2 case-control studies comparing aeroallergen skin prick test results between patients with and without CU and with or without allergic rhinitis (total n = 202)., Results: CU patients with coexisting allergic rhinitis were more than twice as likely to be sensitized to mugwort as subjects not suffering from CU (67 vs. 30%; p = 0.004). Ragweed, cat, rat and mite sensitization were also significantly associated with CU. Overall, patients with CU had more positive aeroallergen skin tests than patients without CU (p < 0.005)., Conclusion: Mugwort sensitization was associated with CU, possibly contributing to beneficial effect of elimination diets., (Copyright © 2012 S. Karger AG, Basel.)

Background: Asthma exacerbation patterns are cyclic in nature and often correlate with air particle concentrations., Objective: To examine the relationship between asthma-related emergency department (ED) visits and outdoor air quality for pediatric and adult patients in a high asthma prevalence area, the New York City borough of the Bronx., Methods: Numbers of daily asthma-related adult and pediatric ED visits during one complete year (1999) were obtained from the seven major Bronx hospitals. Daily values of nitrogen oxides (NO(x)), ozone (O(3)), sulfur dioxide (SO(2)), and pollen counts were acquired., Results: Asthma-related ED visit numbers were highest in December-January and lowest in July. There were three distinct peaks of increased asthma ED visits: winter (December-January), spring (late April-May), and fall (October). The spring peak was the most striking and coincided with high tree pollen counts (tree pollen: r = 0.90, p = .03). We observed a positive correlation between asthma ED visits in the winter and SO(2) and NO(x) levels. Winter peaks of SO(2) and NO(x) in early December appeared to precede the winter asthma peak., Conclusions: The spring asthma peak is closely associated with increased tree pollen counts, and the asthma increase at this time is likely due to allergic reactions to pollen. No significant associations could be established with the fall peak. The winter peak correlates with elevated SO(2) and NO(x) levels.

Objectives: To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC., Methods: Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase)., Results: The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia., Conclusions: Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis., Patients and Methods: Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method., Results: Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P < .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients., Conclusion: Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.

Background and Objectives: For patients with advanced cancers, it is important that treatment improves the quality as well as the quantity of survival. This quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) analysis provides a combined measure of both the overall survival interval and the quality of survival for patients with advanced renal cell carcinoma (RCC) receiving temsirolimus, interferon (IFN)-alpha or the combination of these agents, using data from a phase III clinical trial., Methods: Overall survival was partitioned into three distinct health states: time with serious toxicity (TOX), time after progression (REL) and time without symptoms of progression or toxicity (TWiST). Health states were quality weighted by patient-reported EQ-5D measures collected while receiving treatment., Results: All 626 patients from the trial were included in computation of health-state durations. EQ-5D questionnaires were obtained from 260 patients upon progression and from 230 after a grade 3 or 4 adverse event, and from 278 patients in the TWiST state. Patients receiving temsirolimus had 38% longer TWiST than those receiving IFNalpha (6.5 vs 4.7 months, respectively; p = 0.0005). Patients receiving temsirolimus had 25% longer quality-adjusted survival in terms of Q-TWiST than those receiving IFNalpha (7.0 vs 5.6 months, respectively; p = 0.0015). Differences between the combination (temsirolimus + IFNalpha) and IFNalpha groups were not statistically significant. Threshold utility analysis indicated that temsirolimus was the preferred alternative for all possible utility weights for REL and TOX health states., Conclusion: Temsirolimus resulted in significantly longer Q-TWiST (quality-adjusted survival) in patients with advanced RCC than IFNalpha therapy.

Purpose: Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC)., Experimental Design: Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks., Results: Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved > or =40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate., Conclusions: This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC.

Purpose: To investigate the efficacy and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 in patients with metastatic renal cell carcinoma (mRCC) refractory to prior therapies that included, but were not limited to, sorafenib., Patients and Methods: In this multicenter, open-label, phase II study, patients with sorafenib-refractory mRCC received a starting dose of axitinib 5 mg orally twice daily. A one-arm, single-stage design was used to estimate the primary end point of objective response rate (ORR), defined by RECIST (Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival (PFS), overall survival (OS), and patient-reported outcomes., Results: Of 62 patients recruited, 100% had received prior sorafenib, and 74.2% had received two or more prior systemic treatments. The axitinib dose was titrated to greater than 5 mg twice daily in 53.2% of patients, and 35.5% of patients had the dose modified to less than 5 mg twice daily. In 62 patients evaluable for response, the ORR was 22.6%, and the median duration of response was 17.5 months. Median PFS and OS times were 7.4 months (95% CI, 6.7 to 11.0 months) and 13.6 months (95% CI, 8.4 to 18.8 months), respectively. All-causality grade 3 to 4 adverse events included hand-foot syndrome (16.1%), fatigue (16.1%), hypertension (16.1%), dyspnea (14.5%), diarrhea (14.5%), dehydration (8.1%), and hypotension (6.5%)., Conclusion: Axitinib has antitumor activity in patients with mRCC refractory to prior VEGF-targeted therapy, including sorafenib. Toxicities were mild to moderate and were manageable. A randomized, phase III trial to compare axitinib with sorafenib in patients who have mRCC refractory to one prior first-line therapy regimen is underway.

Background: Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to determine if baseline levels of the tumor molecular markers PTEN and HIF1 alpha correlated with efficacy in patients treated with temsirolimus (Torisel) versus interferon-alpha (IFN)., Methods: Patients in the IFN group received 3 million U (MU) subcutaneously 3x weekly, escalating to 18 MU. Patients in the temsirolimus group received 25 mg intravenously weekly. PTEN and HIF1 alpha baseline levels were measured in archived tumor specimens by immunohistochemistry., Results: There was no correlation between baseline PTEN and HIF1 alpha levels and treatment effect with respect to overall survival (OS), progression-free survival, or objective response rate (ORR) in patients with advanced renal cell carcinoma with poor-risk prognostic factors., Conclusions: The baseline status of the molecular markers PTEN and HIF1 alpha did not correlate with efficacy in renal cell carcinoma patients treated with temsirolimus versus IFN. Patients demonstrated OS and progression-free survival benefit when treated with temsirolimus regardless of PTEN and HIF1 alpha status. Thus, baseline PTEN and HIF-1 levels may not predict response to temsirolimus. Alternatively, the lack of correlation may be due to the variability in tumor specimens that occurred because of the global nature of the clinical trial. Other markers in the phosphoinositide 3-kinase (PI3K)/Akt pathway may be of utility as predictors of response to temsirolimus in patients with advanced renal cell carcinoma.

Background: Despite the existence of numerous dermatology-specific quality-of-life questionnaires, there exists a need for a well-validated instrument to evaluate and monitor patients with chronic urticaria., Objective: To develop and validate a novel chronic urticaria-specific questionnaire, the Urticaria Severity Score (USS)., Methods: The USS was developed with 12 questions and 7 response options per question included in the final questionnaire. The USS was pilot tested on 28 patients with symptomatic chronic urticaria, and a modified version was tested in 80 patients. In this latter group, the USS was compared with the previously validated Dermatology Life Quality Index (DLQI). Patients completed both questionnaires at baseline and at follow-up (median, 2 weeks). Spearman rank correlation tests were used to compare the USS with the DLQI. At a subsequent visit, 9 additional patients completed the USS to evaluate test-retest reliability., Results: There was a positive correlation between the USS and DLQI at baseline (r = 0.64) and follow-up (r = 0.69). The test-retest reliability correlation for the USS was adequate (r = 0.96) (P = .001). The USS was more sensitive in detecting symptom improvement than the DLQI. The mean (SD) "raw score" change from baseline to follow-up for the USS was 9.95 (12.80), whereas the mean (SD) change from baseline to follow-up for the DLQI was 2.25 (4.87)., Conclusions: The USS is a valid and reliable instrument for monitoring urticaria severity. The USS is more sensitive than the DLQI for quantifying urticaria severity and may be moreapplicable in the evaluation of urticaria-specific treatment efficacy.

Background: Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor that has demonstrated superior efficacy over interferon (IFN)-alpha in a phase III trial in first-line, metastatic renal cell carcinoma (RCC). Herein, we report the results of a phase I dose-finding study of sunitinib in combination with IFN-alpha as first-line treatment in patients with metastatic RCC., Patients and Methods: Treatment-naive patients with clear-cell metastatic RCC received sunitinib at a starting dose of 50 mg or 37.5 mg orally once daily in 6-week cycles (schedule 4/2) plus IFN-alpha at a starting dose of 3 MU subcutaneously 3 times a week, with weekly intrapatient dose escalation to a maximum of 9 MU as tolerated. Patients who did not tolerate either drug received lower doses of either or had dose interruptions., Results: Twenty-five patients were enrolled; their median age was 64 years (range, 45-77 years). All patients experienced grade 3/4 treatment-emergent adverse events; the most common were neutropenia, fatigue, and thrombocytopenia. After a median of 4 cycles (range, 1-9 cycles), 3 patients (12%) had a partial response, and 20 (80%) had stable disease., Conclusion: Although reduced starting doses were tolerated (37.5 mg for sunitinib and 3 MU for IFN-alpha), even these lower doses might not be well tolerated for long-term treatment of patients with metastatic RCC. Based on historical data, sunitinib on schedule 4/2 appears to be more effective as single-agent therapy. Further study of sunitinib plus IFN-alpha on this schedule is not being pursued in RCC.

Purpose: To determine the impact of adjuvant androgen deprivation therapy (ADT) for patients who have node-positive prostate cancer in the prostate-specific antigen (PSA) era., Patients and Methods: We used linked Surveillance, Epidemiology and End Results-Medicare data to construct a cohort of men who underwent radical prostatectomy (RP) between 1991 and 1999 and who had positive regional lymph nodes. We classified men as receiving adjuvant ADT if they received ADT within 120 days of RP, and we compared them to the men who had not received adjuvant ADT. We used propensity scores to balance potential confounders of receiving adjuvant ADT (ie, tumor characteristics, extent of nodal disease, demographics, receipt of radiation therapy) and Cox proportional hazard methods to measure the impact of adjuvant ADT on overall survival (OS), stratified by propensity score quintile. We conducted a sensitivity analysis that used 90, 150, 180, and 365 days as the definition for adjuvant ADT., Results: A total of 731 men were identified, 209 of whom received ADT within 120 days of RP. There was no statistically significant difference in OS between the adjuvant ADT and non-ADT group (HR, 0.97; 95% CI, 0.71 to 1.27). There was no statistically significant survival difference with 90, 150, 180, and 365 days as the adjuvant ADT definition., Conclusion: Deferring immediate ADT in men with positive lymph nodes after RP may not significantly compromise survival. Because observational studies should be considered hypothesis-generating studies, these results should be validated in a prospective fashion in a similar patient population.

Purpose Exploratory subgroup analyses from the phase 3 global advanced renal cell carcinoma (ARCC) trial were conducted to assess the influence of tumor histology on outcome of patients treated with temsirolimus (Torisel) or interferon-alpha (IFN). Patients and methods Patients with ARCC including clear cell and other types such as papillary and chromophobe histologies received either IFN (3 million units [MU] subcutaneously three times weekly, escalating to 18 MU) or temsirolimus (25 mg intravenously weekly). Results Approximately 80% of patients had clear cell and 20% of patients had other histologies, the majority of which were papillary. Patients with clear cell and other RCC histologies, treated with temsirolimus, demonstrated comparable median overall and progression-free survival. In contrast, patients with other RCC histologies, treated with IFN, demonstrated shorter median overall and progression-free survival than patients with clear cell RCC. Hazard ratios for death for treatment with temsirolimus versus IFN were less than 1 for patients regardless of tumor histology. For patients treated with temsirolimus, 59% with clear cell and 68% with other RCC histologies experienced tumor reductions. For patients treated with IFN, 35% with clear cell and 14% with other RCC histologies had tumor reductions. However, temsirolimus did not appear to improve the objective response rate compared to IFN. Temsirolimus resulted in a superior clinical benefit rate compared with IFN, regardless of tumor histology. Conclusion Temsirolimus appears to be efficacious in patients with clear cell and non-clear cell histologies and can, therefore, be used for the treatment of all types of RCC.

Gaucher disease (GD), the most common lysosomal storage disorder, demonstrates an autosomal recessive pattern of inheritance. The genetic defect in GD leads to decreased production of the lysosomal enzyme glucosylceramide hydrolase, thereby resulting in the deposition of glucosylceramide sphingolipids within multiple organ systems. Although the precise mechanisms remain unclear, GD is usually associated with chronic antigenic stimulation and hyperimmunoglobulinaemia. We report a novel case of type I GD coexisting with relatively low serum immunoglobulins, impaired antibody production, and recurrent bacterial infections in a 62-year-old male. The patient had been diagnosed with GD 30 years previously and had subsequently started enzyme replacement therapy. Since being diagnosed with GD, the patient had suffered from repeated episodes of acute bronchitis and a recent severe bout of community-acquired pneumonia that required a lengthy hospitalization. On our initial evaluation, the patient had laboratory testing that demonstrated: decreased serum IgG, IgG2, and IgA levels; reduced absolute CD3(+)/CD4(+), CD3(+)/CD8(+), and lymphocyte counts; low IgG titres to pneumococcal polysaccharide vaccine; and decreased anti-tetanus antibodies. Lymphocyte function analysis demonstrated a normal response to phytohaemagglutinin, and decreased responses to concanavalin A and pokeweed mitogen. Repeat testing after 6 months revealed normal serum immunoglobulin levels and mitogenic responses. Although the explanation for our observed transient hypogammaglobulinaemia remains unclear, this patient's clinical constellation (i.e. repeated infections, hypogammaglobulinaemia and lymphopenia, decreased post-vaccination titres, and impaired responses to some mitogens) shares overlapping features with common variable immunodeficiency (CVID).

Purpose: A tool that quantifies the risk of treatment-related toxicity based on individual patient characteristics can augment the informed consent process and safety monitoring in the setting of phase II cancer treatment trials of molecularly targeted agents (MTAs)., Methods: A regression model was constructed to predict the risk of a serious adverse event (SAE) with an MTA and presented as a nomogram. Estimation of risk can be performed by integrating risk estimates from the nomogram and from a reference or average patient. Internal validation was performed using bootstrapping techniques., Results: A total of 578 patients were treated with one of 14 MTAs given alone or in combination on one of 27 clinical trials performed by the Princess Margaret Hospital Drug Development Program between 2001 and 2006. Approximately 50% and 24% of patients experienced an SAE and an attributable SAE (SAEatt) during cycle 1, respectively. Albumin, lactate dehydrogenase (LDH), number of target lesions, prior radiotherapy, Charlson score, age, and performance status were included in the optimal model as predictors of a cycle 1 SAE, whereas the number of prior chemotherapy regimens, baseline creatinine, LDH, prior radiotherapy, Charlson score, body-surface area, and performance status were included as predictors of an SAEatt. Moderate-good internal validity was demonstrated, with area under the curve estimates ranging from 56.7% to 86.1% for all SAEs and 63.0% to 89.7% for SAEatts., Conclusion: A regression model was constructed that predicts the SAE and SAEatt risk for an individual patient during cycle 1 of phase II trial treatment with moderate to good internal validity. External validation is still required.

Based on the pre-clinical spectrum of activity in taxane-resistant cell lines, we evaluated KOS-862 (epothilone D; 12,13-desoxyepothilone B) as second-line chemotherapy in androgen-independent prostate cancer.Thirty-eight men with metastatic androgen-independent prostate cancer and evidence of progression following docetaxel-based chemotherapy were treated with KOS-862, 100 mg/m(2) (maximum of 240 mg) i.v. weekly for 3 weeks, repeated every 4 weeks. The primary objective for this study was to determine the antitumor activity, measured by PSA decline by more then 50% confirmed 4 weeks later. Two patients (5.3%, 90% CI 1-16%) met criteria for confirmed PSA decline. While both of these patients had previously been treated with docetaxel, neither had confirmed docetaxel-refractory disease. None of the 24 patients with measurable disease had a confirmed partial response. Seventy-three percent of patients had an adverse event leading to dose delay, reduction, or treatment discontinuation. Neurological toxicity and fatigue predominated. Seventeen patients (44.7%) had treatment related grade 3 neurological adverse events including peripheral sensory neuropathy (n = 4, 10.5%), ataxia (n = 3, 7.9%), peripheral motor neuropathy (n = 1, 2.6%), involuntary muscle contractions (n = 1, 2.6%) and neuropathic pain (n = 1, 2.6%). One subject (2.6%) had a grade 4 treatment peripheral motor neuropathy. Further study of this dose and schedule of KOS-862 in this patient population cannot be recommended due to both lack of activity and excessive toxicity.

Background: Estramustine phosphate is a mustard-oestradiol conjugate, and has hormonal and non-hormonal effects. In phase II trials of patients with cancer, response to microtubule inhibitors increases when these drugs are combined with estramustine. We aimed to assess whether combining estramustine with chemotherapy increases survival in patients with castration-refractory prostate cancer., Methods: We systematically searched for randomised clinical trials that compared chemotherapy regimens with and without estramustine in patients with histologically-proven prostate cancer and were published between 1966 and 2004. Data from these studies were verified centrally and updated individual patient data were analysed. The primary endpoint was overall survival. Secondary endpoints were prostate-specific antigen (PSA) response, time to PSA progression, and toxicity. A Cox regression model that was stratified by trial and adjusted for covariates at baseline was used., Findings: The initial search identified seven eligible trials that included 742 patients, from which data from five trials including 605 patients had been collected. Individual patient data from two trials (137 patients) were no longer available. The 605 patients had been accrued between Jan 1, 1993 and Dec 1, 2003 and randomly assigned to chemotherapy plus estramustine or to chemotherapy without estramustine. Chemotherapy (with or without estramustine) consisted of docetaxel, paclitaxel, ixabepilone, and vinblastine. Median follow-up was 2.8 years (range 0.0-3.4), and 510 deaths had occurred by the end of follow-up. Cox regression analysis stratified by trial showed that concentrations of serum haemoglobin (p<0.0001), use of chemotherapy plus estramustine (p=0.008), performance status (p=0.002), and serum PSA concentrations (p=0.04) were associated independently with overall survival. Overall survival was significantly better in patients assigned chemotherapy plus estramustine (adjusted hazard ratio [HR] 0.77 [95% CI 0.63-0.93], p=0.008). Estimated absolute increase in overall survival when estramustine was added to chemotherapy was 9.5% (SE 4.0) at 1 year after randomisation. We did not note a significant association between treatment effect on overall survival and age, concentration of serum haemoglobin, performance status, or serum PSA concentration. Patients who received chemotherapy plus estramustine had a better PSA response than those who received chemotherapy without estramustine (RR 0.53 [0.38-0.72], p<0.0001). Time to PSA progression was significantly longer in patients assigned chemotherapy plus estramustine than in those assigned chemotherapy without estramustine (HR 0.74 [0.58-0.94], p=0.01). Patients assigned chemotherapy and estramustine had more grade 3 or grade 4 thromboembolic events compared with those assigned chemotherapy without estramustine (12 of 271 vs 1 of 275)., Interpretation: In patients with castration-refractory prostate cancer, addition of estramustine to chemotherapy increases time to PSA progression and overall survival compared with chemotherapy without estramustine. However, this benefit should be balanced with the risk of increased thromboembolic events in patients who receive estramustine and chemotherapy in combination compared with chemotherapy without estramustine.

We introduce a new study design in which patients are evaluated early in their treatment for disease progression. Our design is appropriate when lack of progression, both early and late, is the criterion for treatment success. An initial cohort of n(1) patients is followed until the last one has been evaluated. If enough of these patients are progression free (PF) at an early time point, t(1) after arrival, a second cohort is recruited until n(2) total patients are evaluable for PF survival at the final time t(2). Otherwise, the trial is terminated for futility both early in time and with a minimal number of patients. Patients in the initial cohort who are PF at t(1) continue on study and are again evaluated at t(2). The design permits early stopping for rapid progression of disease, an indication of futility both for cytotoxic and newer non-cytotoxic targeted therapies. The design tests the composite hypothesis of a probability p(1) of being PF at t(1) and p(2) of being PF at t(2) given PF at t(1). Power and type I error are maintained at design point levels over a wide range of parameters p(1) and p(2). No distributional assumptions are needed other than the binomial, so the design provides rigorous power analysis for this type of study. Tables of optimal designs are supplied for a broad range of requirements., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

Background: Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability. Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, may benefit patients with this disease., Methods: In this multicenter, phase 3 trial, we randomly assigned 626 patients with previously untreated, poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly, 3 million U of interferon alfa (with an increase to 18 million U) subcutaneously three times weekly, or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly. The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group., Results: Patients who received temsirolimus alone had longer overall survival (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.58 to 0.92; P=0.008) and progression-free survival (P<0.001) than did patients who received interferon alone. Overall survival in the combination-therapy group did not differ significantly from that in the interferon group (hazard ratio, 0.96; 95% CI, 0.76 to 1.20; P=0.70). Median overall survival times in the interferon group, the temsirolimus group, and the combination-therapy group were 7.3, 10.9, and 8.4 months, respectively. Rash, peripheral edema, hyperglycemia, and hyperlipidemia were more common in the temsirolimus group, whereas asthenia was more common in the interferon group. There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group (P=0.02)., Conclusions: As compared with interferon alfa, temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis. The addition of temsirolimus to interferon did not improve survival. (ClinicalTrials.gov number, NCT00065468 [ClinicalTrials.gov].)., (Copyright 2007 Massachusetts Medical Society.)

Background: Association of common variable immunodeficiency (CVID) with Takayasu arteritis has rarely been reported., Objective: To describe a case of Takayasu arteritis in a 53-year-old Hispanic woman with CVID undergoing long-term (3-year) intravenous immunoglobulin (IVIG) treatment., Methods: The patient's serum immunoglobulin levels and antibody titers to measles, mumps, and rubella were measured. She also underwent angiography of the large vessels., Results: Low to undetectable serum IgA, IgM, and IgG levels and low antibody titers to mumps, measles, and rubella were consistent with the diagnosis of CVID. The angiogram showed narrowing of the proximal left subclavian artery (2-3 mm in diameter)., Conclusions: This patient developed Takayasu arteritis while receiving IVIG for CVID. She clinically improved after her IVIG dose was increased. To our knowledge, this is the second reported case of Takayasu arteritis associated with CVID.

Context: Prostate-specific antigen screening has led to an increase in the diagnosis and treatment of localized prostate cancer. However, the role of active treatment of low- and intermediate-risk disease in elderly men is controversial., Objective: To estimate the association between treatment (with radiation therapy or radical prostatectomy) compared with observation and overall survival in men with low- and intermediate-risk prostate cancer., Design and Setting: Observational US cohort from Surveillance, Epidemiology, and End Results Medicare data., Patients: At total of 44,630 men aged 65 to 80 years who were diagnosed between 1991 and 1999 with organ-confined, well- or moderately differentiated prostate cancer and who had survived more than a year past diagnosis. Patients were followed up until death or study end (December 31, 2002). Patients were classified as having received treatment (n=32,022) if they had claims for radical prostatectomy or radiation therapy during the first 6 months after diagnosis. They were classified as having received observation (n=12,608) if they did not have claims for radical prostatectomy, radiation, or hormonal therapy. Patients who received only hormonal therapy were excluded., Main Outcome Measure: Overall survival., Results: At the end of the 12-year study period, 4663 men (37%) in the observational group and 7639 men (23.8%) in the treatment group had died. The treatment group had longer 5- and 10-year survival than the observation group. After using propensity scores to adjust for potential confounders (tumor characteristics, demographics, and comorbidities), there was a statistically significant survival advantage associated with treatment (hazard ratio, 0.69; 95% confidence interval, 0.66-0.72). A benefit associated with treatment was seen in all subgroups examined, including older men (aged 75-80 years at diagnosis), black men, and men with low-risk disease., Conclusions: This study suggests a survival advantage is associated with active treatment for low- and intermediate-risk prostate cancer in elderly men aged 65 to 80 years. Because observational data cannot completely adjust for potential selection bias and confounding, these results must be validated in randomized controlled trials of alternative management strategies in elderly men with localized prostate cancer.