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Supplemental Table 1 describes the adverse events with corresponding risk differences between treatment arms during induction of pivotal trial ALFA-0701.

Supplemental Table 4 and the accompanying text describe the grouped terms used for the adverse reactions described in Table 2 and the reasons for using grouped terms.

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody–drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51–0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53–0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242–6. ©2018 AACR.

Supplemental Table 2 describes the adverse events with corresponding risk differences between treatment arms during consolidation 1 of pivotal trial ALFA-0701.

Preferred Terms included in grouped terms

Supplemental Table 3 describes the adverse events with corresponding risk differences between treatment arms during consolidation 2 of pivotal trial ALFA-0701.

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

In April 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, and mast cell leukemia. This article summarizes the FDA clinical review and rationale for the approval., In April 2017, the U.S. Food and Drug Administration granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM‐AHN), or mast cell leukemia (MCL). Approval was based on results from CPKC412D2201, a single‐arm trial of midostaurin (100 mg orally twice daily) in previously treated or untreated patients. For the patients with ASM and SM‐AHN, efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by modified Valent criteria with six cycles of midostaurin. There were no CRs reported; ICR was achieved by 6 of 16 patients (38%; 95% confidence interval [CI]: 15%–65%) with ASM and by 9 of 57 patients (16%; 95% CI: 7%–28%) with SM‐AHN. Within the follow‐up period, the median duration of response was not reached for the patients with ASM (range, 12.1+ to 36.8+ months) or with SM‐AHN (range, 6.6+ to 52.1+ months). For the patients with MCL, efficacy was established on the basis of confirmed CR using modified 2013 International Working Group‐Myeloproliferative Neoplasms Research and Treatment‐European Competence Network on Mastocytosis criteria. Of 21 patients with MCL, 1 (5%) achieved a CR. Of 142 patients with SM evaluated for safety, 56% had dose modifications for toxicity, and 21% discontinued treatment due to a toxicity. Over 50% reported nausea, vomiting, or diarrhea, and ≥30% reported edema, musculoskeletal pain, fatigue, abdominal pain, or upper respiratory tract infection. New or worsening grade ≥3 lymphopenia, anemia, thrombocytopenia, or neutropenia developed in ≥20%. Although midostaurin is an active drug for treatment of advanced SM, it is not clear that the optimal dose has been identified. Implications for Practice. Midostaurin is the only U.S. Food and Drug Administration‐approved therapy for patients with systemic mastocytosis with associated hematological neoplasm and mast cell leukemia and is the only therapy approved for patients with aggressive systemic mastocytosis regardless of KIT D816V mutation status. Based on response rate and duration, midostaurin has meaningful clinical activity in these rare, life‐threatening diseases.

Meta-analysis of interventions usually relies on randomized controlled trials. However, when the dominant source of information comes from single-arm studies, or when the results from randomized controlled trials lack generalization due to strict inclusion and exclusion criteria, it is vital to synthesize both sources of evidence. One challenge of synthesizing both sources is that single-arm studies are usually less reliable than randomized controlled trials due to selection bias and confounding factors. In this paper, we propose a Bayesian hierarchical framework for the purpose of bias reduction and efficiency gain. Under this framework, three methods are proposed: bivariate generalized linear mixed effects models, hierarchical power prior model and hierarchical commensurate prior model. Design difference and potential biases are considered in all models, within which the hierarchical power prior and hierarchical commensurate prior models further offer to downweight single-arm studies flexibly. The hierarchical commensurate prior model is recommended as the primary method for evidence synthesis because of its accuracy and robustness. We illustrate our methods by applying all models to two motivating datasets and evaluate their performance through simulation studies. We finish with a discussion of the advantages and limitations of our methods, as well as directions for future research in this area.

On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR). The key secondary endpoint was overall survival, but these data were not mature at the time of clinical database cutoff. The trial demonstrated a statistically significant improvement in PFS, with an estimated HR of 0.70 for E-Ld over Ld [95% confidence interval (CI), 0.57–0.85; P = 0.0004). Estimated median PFS was 19.4 months in the E-Ld arm and 14.9 months in the Ld arm. ORR was 75.8% in the E-Ld arm compared with 65.5% in the Ld arm. Serious adverse reactions were reported in 65% of patients in the E-Ld arm compared with 57% in the Ld arm. The FDA approved elotuzumab with the following warnings and precautions: infusion reactions, infections, second primary malignancies, hepatotoxicity, and interference with the determination of complete response. Clin Cancer Res; 23(22); 6759–63. ©2017 AACR.

This study evaluated the circumstances under which the observed progression-free survival (PFS) benefit may translate into an overall survival (OS) benefit.A simulation study, based on PFS and OS joint model decomposition, was conducted to evaluate the impact of crossover rates, survival post progression (SPP) lengths, and magnitudes of difference in median PFS on OS. Under different simulation scenarios, the degree of impact was investigated based on the probability of observing a significant OS benefit given an observed PFS benefit.Using simulation parameters defined based on historical NDA datasets, the probability of detecting an OS benefit given the observed PFS benefit depends largely on crossover rate and SPP length (ie, SPP median times). Compared to no crossover, a crossover rate of ≤ 50% decreases the probability of detecting an OS benefit by at most 15% regardless of the SPP length. A crossover rate of50% decreases the probability of detecting an OS benefit much further, and the extent of decrease is proportional to the length of SPP.Crossover rate and SPP length are important factors affecting the benefit translating from PFS to OS. This simulation study identified a threshold, of 50%, for crossover rate that is likely to confound OS effect. With a greater than 50% crossover rate, longer SPP further decreases the probability of translating a PFS benefit to OS.

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose “fractionated” schedule of 3 mg/m2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%–40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. Implications for Practice Gemtuzumab ozogamicin (GO) 3 mg/m2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age.

Aglaomorpha cornucopia (Copel.) M.C. Roos is an endemic and rare epiphytic fern from the Philippines. Ex situ germplasm storage and growth are important complementary tools for conserving this rare fern. This study was conducted to document the reproductive biology of this species. Mature sporophylls of A. cornucopia were collected in May, 2012 from Mt. Apo, the Philippines. Each sporangium bore 64 yellow, monolete spores. The average spore size was 49.3±3.7 µm. Fresh spores germinated 100% within one week of sowing (mean germination time (MGT)

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody–drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51–0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53–0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242–6. ©2018 AACR.

On November 1, 2013, the U.S. Food and Drug Administration (FDA) approved obinutuzumab (GAZYVA; Genentech, Inc.), a CD20-directed cytolytic antibody, for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). In stage 1 of the trial supporting approval, patients with previously untreated CD20-positive CLL were randomly allocated (2:2:1) to obinutuzumab + chlorambucil (GClb, n = 238), rituximab + chlorambucil (RClb, n = 233), or chlorambucil alone (Clb, n = 118). The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR). Only the comparison of GClb to Clb was relevant to this approval and is described herein. A clinically meaningful and statistically significant improvement in PFS with medians of 23.0 and 11.1 months was observed in the GClb and Clb arms, respectively (HR, 0.16; 95% CI, 0.11–0.24; P < 0.0001, log-rank test). The ORRs were 75.9% and 32.1% in the GClb and Clb arms, respectively, and the complete response rates were 27.8% and 0.9% in the GClb and Clb arms, respectively. The most common adverse reactions (≥10%) reported in the GClb arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Obinutuzumab was the first Breakthrough Therapy–designated drug to receive FDA approval. Clin Cancer Res; 20(15); 3902–7. ©2014 AACR.

On October 26, 2012, the U.S. Food and Drug Administration (FDA) granted accelerated approval to omacetaxine mepesuccinate (Synribo; Teva Pharmaceuticals USA, Inc., North Wales, PA, http://www.tevausa.com) for the treatment of adult patients with chronic phase (CP) or accelerated phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKIs). The approval was based on the FDA review of data from 111 patients with CML in CP or in AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response was achieved in 18% of patients with CP, with a median response duration of 12.5 months. Major hematologic response was achieved in 14% of patients with AP, with a median response duration of 4.7 months. The FDA safety evaluation was based on submitted data from 163 patients with CP or AP CML who had received at least one dose of omacetaxine mepesuccinate. The safety evaluation was limited by the single-arm design of the clinical trials as conducted in a small number of previously treated patients. The most common (≥20%) adverse reactions of any grade in enrolled patients included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, and infection. The FDA concluded that omacetaxine mepesuccinate has shown activity and a favorable benefit-to-risk profile for the studied population of adult patients with CML (CP or AP) with resistance and/or intolerance to two or more TKIs. Further evidence of response durability to verify clinical benefit is pending.

The U.S. Food and Drug Administration (FDA) approved eltrombopag for pediatric patients with chronic immune (idiopathic) thrombocytopenia (ITP) ages ≥6 on June 11, 2015, and ages ≥1 on August 24, 2015. Approval was based on the FDA review of two randomized trials that included 159 pediatric patients with chronic ITP who had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. This manuscript describes the basis for approval of these applications. The FDA concluded that eltrombopag has shown efficacy and a favorable benefit to risk profile for pediatric patients with chronic ITP.

BACKGROUND: The dosing of drugs in patients with kidney dysfunction is often based on the estimates of kidney function. OBJECTIVE: To systematically compare the performance of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (CG) equations for dosage adjustment. METHODS: We assessed agreement (concordance, kappa statistics [κ,κω]) between CG and MDRD using a Food and Drug Administration database to evaluate the effect of renal function on the pharmacokinetics of 36 approved drugs. Across the approved drugs, we compared the correlation between these 2 equations for renal drug clearance (Clren) and area under the concentration-time curve. For 26 approved drugs that require renal dose adjustment, we also compared dosing regimens and expected exposure using these equations. Sensitivity analyses were performed by adjusting the MDRD estimates for individualized body surface area and/or range of serum creatinine assay calibration errors. RESULTS: In the pharmacokinetic database with 973 subjects (age 18-95 years, weight 35-153 kg, female 33%), we found that the CG and the MDRD classification of renal function generally agreed (64.2%, κ = 0.54, κω = 0.73). Among the subjects studied for drugs requiring renal dose adjustment, dosages in 12% were changed to a higher or lower dosing category by the MDRD compared to the CG equation. In particular, using MDRD in place of CG for dosage modification yielded higher dosing recommendations for subjects with a combination of age >80 years, weight 0.7 and ≤1.5 mg/dL; the coefficient of determination was also higher by CG than MDRD in trials that enrolled these or similar patients. CONCLUSIONS: For patients with advanced age, low weight, and modestly elevated serum creatinine, further work is needed before the MDRD equations can replace the CG equation for dose adjustment in the labeling.

Objectives To provide hearing threshold percentiles from unscreened older adults for creating new Annex B reference standards. Design Percentiles are calculated, and 95% confidence intervals for medians from two U.S. surveys are compared graphically. Results Median thresholds are lower (better) in the 1999-2006 National Health and Nutrition Examination Survey for men across all frequencies except 1 kHz. Results for women are similar; however, there is more overlap in confidence intervals across frequencies. Conclusions The prevalence of hearing impairment in older adults, age 70 years (65-74 years), is lower in 1999-2006 compared with 1959-1962, consistent with our earlier findings for younger adults.

Background: Dosing adjustments for patients with impaired kidney function are often based on estimated creatinine clearance (eCrCI) because measuring kidney (unction is not always possible for dose adjustment. However, there is no consensus on the body size descriptor that should be used in the estimation equations. Objective: To compare the use of alternative body size descriptors (ABSDs) on the performance of kidney function estimation equations compared with measured CrCI (mCrCI). Methods: We combined 2 data sources with mCrCI: a Food and Drug Administration clinical trial database that includes subjects with body mass index (BMI) less than 40 kg/m2 and published data from those 40 kg/m2 or more. The 3 parent equations (Cockcroft-Gault [CG], Modification of Diet in Renal Disease [MDRD], Chronic Kidney Disease-Epidemiology Collaboration [CKDEPI]), and 14 ABSD-modilied equations were compared with mCrCI for accuracy, bias, agreement, goodness of (it (R2). and prediction error. These equations were also compared across mCrCI and BMI strata. Results: Subjects (n = 590) were aged 19–80 years; 33.9% were female and BMI ranged from 17.2 to 95.6 kg/m2. Compared with mCrCI, the use of total weight in the CG equation yielded low accuracy (12.5%) and significant bias (–107 mL/min) in the morbidly obese group. In contrast, the use of lean body weights (BMI ≥40 kg/m2) and total ± adjusted weights (BMI 2) with the CG equation yielded higher accuracy, greater than or equal to 60.7% across all BMI strata, and was unbiased. Transforming the MDRD or CKDEPI equations with body surface area improved accuracy only at mCrCI of 30–80 mL/min and increased the overall prediction error. Conclusions: No kidney function equation was consistently accurate and unbiased across weight, mCrCI. and estimate ranges. The accuracy and over-estimation bias of the CG equation in obese subjects was improved through the selective use of total, adjusted, and lean body weight by BMI strata.

Background: Several novel therapeutics are being developed for AML with demonstrable effects on response rates (e.g. complete remission [CR], CR with incomplete hematologic recovery [CRi], CR with incomplete platelet recovery [CRp], overall response rate [ORR = CR+CRi/CRp]), and EFS. Improvement in EFS recently served as the basis of approval of gemtuzumab ozogamicin (GO) for the treatment of newly-diagnosed CD33-positive AML in adults (Jen et al. Clin Cancer Res 2018). The relationship between response rate, EFS, and OS in newly-diagnosed AML has not been conclusively established. Therefore, we conducted trial-level and patient-level meta-analyses of newly-diagnosed AML trials submitted to the FDA. Methods: We searched for trials submitted with Biologics License or New Drug Applications for treatment of newly-diagnosed AML between 2007 and 2017. Criteria for inclusion were randomized, active-controlled, multicenter trials of intensive AML induction and consolidation chemotherapy. The estimated odd ratios (OR - ratio of odds of response in treatment to odds of response in controls) of CR and ORR and hazard ratios (HR - ratio of hazard of treatment versus control) for EFS and OS were calculated for each study. EFS was defined as time from randomization to treatment failure (defined as date of randomization for patients who failed to achieve CR following induction), disease relapse following CR, or death. Associations between treatment effects at the trial-level were evaluated using weighted least square (WLS) regression analyses on the log-scale (weighted by sample size of each randomized comparison). Coefficient of determination (R2) and 95% confidence interval (CI) were calculated to measure the strength of associations. Individual patient data for OS were plotted against EFS to explore their relationship. An exploratory patient-level responder analysis was performed to compare OS between responders and non-responders, regardless of treatment assignment in the pooled dataset. We estimated HRs of OS from Cox proportional hazards models. OS estimates by response were obtained based on the Kaplan-Meier method. Results: We identified 8 trials with a total of 4482 patients and 3 experimental agents (GO, n=5; [daunorubicin and cytarabine] liposome injection, n=2; midostaurin, n=1) for treatment of newly-diagnosed AML. Two trials tested therapy in defined patient populations (FLT3 mutant = 1 and secondary AML = 1). The association between OS HR and CR OR at the trial-level was moderate (R2 = 0.67, 95% CI: 0.16 - 0.94; Figure 1), whereas the association between OS HR and ORR OR was weak (R2 = 0.43, 95% CI: 0.03 - 0.98). For the OS vs. EFS HR analysis, a weaker than expected association was observed (data to be presented at the meeting). Individual patient level data scatter plots suggested that one possible reason for the lack of a strong association between EFS and OS was that early failures and relapses did not always result in worse OS (Figure 2). In the patient-level responder analysis, patients who achieved a CR response had better OS compared with CRi+CRp response and no response (Figure 3). Conclusions: On a trial level, the meta-analysis of randomized, active-controlled trials in newly-diagnosed AML suggests a moderate association between OS and CR rate, but not ORR. A strong association between EFS and OS is not established and may be confounded by improvements in salvage therapy, supportive care, hematopoietic stem cell transplantation, and/or differing censoring across trials. A patient-level responder analysis showed that CR responders have better OS compared with CRi+CRp responders and nonresponders. While our results are limited by the number of trials, they suggest that CR remains the response endpoint associated with greatest long-term benefit and that EFS, while clinically meaningful, is not a surrogate for OS. Disclosures No relevant conflicts of interest to declare.

Objectives: (1) To present hearing threshold data from a recent nationally representative survey in the United States (National Health and Nutrition Examination Survey, 1999–2004) in a distributional format that might be appropriate to replace Annex B in international (ISO-1999) and national (ANSI S3.44) standards and (2) to compare these recent data with older survey data (National Health Examination Survey I, 1959–1962) on which the current Annex B is based. Design: Better-ear threshold distributions (selected percentiles and their confidence intervals) were estimated using linear interpolation. The 95% confidence intervals for the medians for the two surveys were compared graphically for each of the four age groups and for both men and women. In addition, we calculated odds ratios comparing the prevalences of better-ear hearing impairment (thresholds > 25 dB HL) between the two surveys, for 500, 1000, 2000, and 4000 Hz, and for their four-frequency average. Results: Across age and sex groups, median thresholds were lower (better) in the 1999–2004 survey at 500, 3000, 4000, and 6000 Hz (8000 Hz was not tested in the 1959–1962 survey). For both men and women, the prevalence of hearing impairment was significantly lower in 1999–2004 at 500, 2000, and 4000 Hz, but not at 1000 Hz. Conclusions: For men and women of a specific age, high-frequency hearing thresholds were lower (better) in 1999–2004 than in 1959–1962. The prevalences of hearing impairment were also lower in the recent survey. Differences seen at 500 Hz may be attributable at least in part to changes in standards for ambient noise in audiometry. The National Health and Nutrition Examination Survey 1999–2004 distributions are offered as a possible replacement for Annex B in ISO-1999 and ANSI S3.44.

Purpose: To describe the Food and Drug Administration review and marketing approval considerations for bortezomib (Velcade) for the treatment of patients with mantle cell lymphoma. Experimental Design: Food and Drug Administration reviewed a multicenter study of bortezomib in 155 patients with progressive mantle cell lymphoma after at least one prior therapy. Results: Seventy-seven percent were stage IV, and 75% had one or more extranodal sites of disease. Prior therapy included an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. Median age was 65 years. All received bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, and 11 of each 3-week cycle. The primary end point was response. Response and progression were determined by independent review of serial computed tomography scans using International Lymphoma Workshop Response Criteria. The overall response rate was 31%, including complete response (CR) plus CR unconfirmed (CRu) plus partial response; median response duration was 9.3 months. The CR plus CRu response rate was 8% with a median duration of 15.4 months. Adverse events were similar to those observed previously for bortezomib. The most commonly reported treatment-emergent adverse events were asthenia (72%), peripheral neuropathies (55%), constipation (50%), diarrhea (47%), nausea (44%), and anorexia (39%). The most common adverse event leading to discontinuation was neuropathy. Conclusions: Bortezomib received regular approval for the treatment of patients with mantle cell lymphoma in relapse after prior therapy.

This study evaluated the toxic effects of substituted anilines on Pseudokirchneriella subcapitata with the use of a closed algal toxicity testing technique with no headspace. Two response endpoints (i.e., dissolved oxygen production [DO] and algal growth rate) were used to evaluate the toxicity of anilines. Both DO and growth rate endpoints revealed similar sensitivity to the effects of anilines. However, trichloroanilines showed stronger inhibitory effects on microalgal photosynthetic reactions than that on algal growth. For various aquatic organisms, the relative sensitivity relationship for anilines is Daphnia magna > luminescent bacteria (Microtox) > or = Pocelia reticulata > or = Pseudokirchneriella subcapitata > or = fathead minnow > Tetrahymena pyriformis. The susceptibility of P. subcapitata to anilines is similar to fish, but P. subcapitata is apparently less sensitive than the water flea. The lack of correlation between the toxicity revealed by different aquatic organisms (microalgae, D. magna, luminescent bacteria, and P. reticulata) suggests that anilines might have different metabolic routes in these organisms. Both hydrogen bonding donor capacity (the lowest unoccupied molecular orbital energy, Elumo) and hydrophobicity (1-octanol:water partition coefficient, Kow) were found to provide satisfactory descriptions for the toxicity of polar narcotics (substituted anilines and chlorophenols). Quantitative structure-activity relationships (QSARs) based on Elumo, log Kow, or both values were established with r2 values varying from 0.75 to 0.92. The predictive power for the QSAR models were found to be satisfactory through leave-one-out cross-validation. Such relationships could provide useful information for the estimation of toxicity for other polar narcotic compounds.

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome–negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager. The basis for the approval was a single-arm trial with 185 evaluable adults with R/R ALL. The complete remission (CR) rate was 32% [95% confidence interval (CI), 26%–40%], and the median duration of response was 6.7 months. A minimal residual disease response was achieved by 31% (95% CI, 25%–39%) of all patients. Cytokine release syndrome and neurologic events were serious toxicities that occurred. Other common (>20%) adverse reactions were pyrexia, headache, edema, febrile neutropenia, nausea, tremor, and rash. Neutropenia, thrombocytopenia, and elevated transaminases were the most common (>10%) laboratory abnormalities related to blinatumomab. A randomized trial is required in order to confirm clinical benefit. Clin Cancer Res; 21(18); 4035–9. ©2015 AACR.

Objective The objective of the study was to examine the relationship of maternal age with stillbirth risk throughout gestation. Study design A total of 5,458,735 singleton gestations without reported congenital anomalies from the 2001 to 2002 National Center for Health Statistics perinatal mortality and natality files were analyzed. Hazard rates (risk) of stillbirth (fetal death 20 weeks or longer) were calculated for each week of gestation. Results The risk of stillbirth at 37 to 41 weeks for women 35 to 39 years old was 1 in 382 ongoing pregnancies and for women 40 years old or older, 1 in 267 ongoing pregnancies. Compared with women younger than 35 years old, the relative risk of stillbirth was 1.32 (95% confidence interval 1.22, 1.43) for women 35 to 39 years old and 1.88 (95% confidence interval 1.64, 2.16) for women 40 years old or older at 37 to 41 weeks. This effect of maternal age persisted despite accounting for medical disease, parity, and race/ethnicity. Conclusion Women who are of advanced maternal age are at higher risk of stillbirth throughout gestation; the peak risk period is 37 to 41 weeks.

BACKGROUND Micronutrient deficiencies are common among older adults. We hypothesized that low serum micronutrient concentrations were predictive of frailty among older disabled women living in the community. METHODS We studied 766 women, aged 65 and older, from the Women's Health and Aging Study I, a population-based study of moderately to severely disabled community-dwelling women in Baltimore, Maryland. Serum vitamins A, D, E, B(6), and B(12), carotenoids, folate, zinc, and selenium were measured at baseline. Frailty status was determined at baseline and during annual visits for 3 years of follow-up. RESULTS At baseline, 250 women were frail and 516 women were not frail. Of 463 nonfrail women who had at least one follow-up visit, 205 (31.9%) became frail, with an overall incidence rate of 19.1 per 100 person-years. Compared with women in the upper three quartiles, women in the lowest quartile of serum carotenoids (hazard ratio [HR] 1.39; 95% confidence interval [CI], 1.01-1.92), alpha-tocopherol (HR 1.39; 95% CI, 1.02-1.92), and 25-hydroxyvitamin D (HR 1.34; 95% CI, 0.94-1.90) had an increased risk of becoming frail. The number of nutritional deficiencies (HR 1.10; 95% CI, 1.01-1.20) was associated with an increased risk of becoming frail, after adjusting for age, smoking status, and chronic pulmonary disease. Adjusting for potential confounders, we found that women in the lowest quartile of serum carotenoids had a higher risk of becoming frail (HR 1.54; 95% CI, 1.11-2.13). CONCLUSIONS Low serum micronutrient concentrations are an independent risk factor for frailty among disabled older women, and the risk of frailty increases with the number of micronutrient deficiencies.

People live in different oral sensory worlds. This variation affects health and quality of life. The need to make valid comparisons across individuals/groups to reveal this variation highlighted invalid use of conventional labeled scales (e.g., visual analogue, category scales). Valid comparisons can be made with magnitude matching and the general Labeled Magnitude Scale (gLMS) employing multiple standards (real and remembered), thus permitting associations between oral sensation, preferences, intake (e.g., fats, vegetables), and health outcomes (e.g., cancer, phantoms, burning mouth syndrome). These measurement insights broadly apply to sensory/hedonic assessment of differences across groups in many different fields. As an illustration, we assess differences across groups experiencing different types of pain.

Background.—Military hospitals currently use gestational age-specific growth curves based on data collected in Denver, Colo, from 1948 to 1961. A number of population and environmental factors and medical practice changes may make these curves nonrepresentative. Objective.—Determine if presently used growth curves represent norms for infants born in military hospitals and create new curves for use in military hospitals. Methods.—Data were collected from medical records of tertiary- and primary-care military hospitals. We created growth curves created for birth weight, length, and head circumference and compared these curves at gestational ages 23–42 weeks to previously published norms and to 1998 national vital statistics. Racial and ethnic differences between groups were compared. A retrospective analysis of blood-glucose measurements for healthy term infants was performed to identify potential safety issues. Results.—Significant increases in growth parameters were noted for infants born in military hospitals. Specific racial and ethnic groups within the military also had an increase when compared with these groups in the United States as a whole. Less than 1% of infants classified as large for gestational age (LGA) according by old standards but average for gestational age (AGA) according to new curves experienced hypoglycemia. Conclusion.—Published growth curves may not represent infants born in military hospitals. Term infants born in military hospitals as a group and in racial and ethnic subgroups are larger than term infants born in US civilian hospitals. Prospective use of curves will help to validate their long-term applicability in military and civilian nurseries.

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection. Clin Cancer Res; 21(5); 950–4. ©2015 AACR.

OBJECTIVE:To estimate the trend of maternal racial and ethnic differences in mortality for early-term (37 0/7 to 38 6/7 weeks of gestation) compared with full-term births (39 0/7 to 41 6/7 weeks of gestation).METHODS:We analyzed 46,329,018 singleton live births using the National Center for Health S

Objective We sought to determine factors associated with racial disparities in stillbirth risk. Study Design Stillbirth hazard was analyzed using 5,138,122 singleton gestations from the National Center of Health Statistics perinatal mortality and birth files, 2001–2002. Results Black women have a 2.2-fold increased risk of stillbirth compared with white women. The black/white disparity in stillbirth hazard at 20–23 weeks is 2.75, decreasing to 1.57 at 39–40 weeks. Higher education reduced the hazard for whites more than for blacks and Hispanics. Medical, pregnancy, and labor complications accounted for 30% of the hazard in blacks and 20% in whites and Hispanics. Congenital anomalies and small for gestational age contributed more to preterm stillbirth risk among whites than blacks. Pregnancy and labor conditions contributed more to preterm stillbirth risk among blacks than whites. Conclusion The excess stillbirth risk for blacks was greatest at preterm gestations, and factors contributing to stillbirth risk vary by race and gestational age.

Learning Objectives After completing this course, the reader should be able to: Describe the clinical trial that led to the approval of lapatinib in combination with capecitabine for the treatment of previously treated patients with HER-2–overexpressing metastatic breast cancer.Determine appropriate patients to receive lapatinib plus capecitabine treatment.Assess and manage the toxicities of lapatinib plus capecitabine treatment. CME This article is available for continuing medical education credit at CME.TheOncologist.com On March 13, 2007, the U.S. Food and Drug Administration approved lapatinib (Tykerb® tablets; GlaxoSmithKline, Philadelphia), an oral, small molecule, dual tyrosine kinase inhibitor of ErbB-2 and ErbB-1, for use in combination with capecitabine for the treatment of patients with human epidermal growth factor receptor (HER)-2–overexpressing metastatic breast cancer who had received prior therapy including an anthracycline, a taxane, and trastuzumab. One multicenter, open-label, randomized trial was submitted. Eligible patients had stage IIIb or IV breast cancer, ErbB-2 overexpression (immunohistochemistry 3+ or 2+ with fluorescence in situ hybridization confirmation), measurable disease, a 0 or 1 Eastern Cooperative Oncology Group performance status score, a cardiac ejection fraction within the institutional normal range, and adequate laboratory function. Patients received either lapatinib (1,250 mg once daily on days 1–21) plus capecitabine (1,000 mg/m2 every 12 hours on days 1–14) every 21 days or capecitabine alone (1,250 mg/m2 every 12 hours on days 1–14) every 21 days. The primary endpoint was time to progression (TTP) determined by a blinded independent review panel. After TTP results of a prespecified interim analysis were made available, study enrollment was discontinued (399 patients enrolled). The median TTP was 27.1 versus 18.6 weeks (hazard ratio, 0.57; p = .00013) favoring the lapatinib plus capecitabine arm. Response rates were 23.7% (lapatinib plus capecitabine) versus 13.9% (capecitabine alone). Survival data were not mature. Although the toxicities observed in the lapatinib and capecitabine combination arm were generally similar to those in the capecitabine alone arm, a higher incidence of diarrhea and rash was noted with the combination. Grade 3 or 4 adverse reactions that occurred with a frequency of >5% in patients on the combination arm were diarrhea (13%) and palmar–plantar erythrodysesthesia (12%). There was a 2% incidence of reversible decreased left ventricular function in the combination arm.

Hypoparathyroidism is one of the few remaining hormonal insufficiency states for which replacement therapy is unavailable. Previous short-term controlled trials have shown PTH to be a safe and effective treatment of hypoparathyroidism. In this randomized, parallel group, open-label trial, we compared synthetic human PTH-(1-34) (PTH) with conventional therapy, calcitriol and calcium, over a 3-yr period. Twenty-seven patients with confirmed hypoparathyroidism, aged 18-70 yr, were randomized to either twice daily sc PTH or oral calcitriol and calcium. The primary end points were calcium levels in serum and urine. Secondary end points were creatinine clearance, markers of bone turnover, and bone mineral density. Throughout the 3-yr study period, serum calcium levels were similar in both treatment groups within or just below the normal range. Mean urinary calcium excretion was within the normal range from 1-3 yr in PTH-treated patients, but remained above normal in the calcitriol group. Bone mineral content and bone mineral density showed no significant between-group differences over the 3-yr study period. We conclude that treatment with twice daily sc PTH provides a safe and effective alternative to calcitriol therapy and is able to maintain normal serum calcium levels without hypercalciuria for at least 3 yr in patients with hypoparathyroidism.

Using data from 145,007 adults in the Disability Supplement to the National Health Interview Survey, we investigated the effect of balance difficulties on frequent depression after controlling for age, gender, race, and other baseline health status information. There were two major complications: (i) 80% of subjects were missing data on depression and the missing-data mechanism was likely related to depression, and (ii) the data arose from a complex sample survey. To adjust for (i) we investigated three classes of models: missingness in depression, missingness in depression and balance, and missingness in depression with an auxiliary variable. To adjust for (ii) we developed the first linearization variance formula for nonignorable missing-data models. Our sensitivity analysis was based on fitting a range of ignorable missing-data models along with nonignorable missing-data models that added one or two parameters. All nonignorable missing-data models that we considered fit the data substantially better than their ignorable missing-data counterparts. Under an ignorable missing-data mechanism, the odds ratio for the association between balance and depression was 2.0 with a 95% CI of (1.8, 2.2). Under 29 of the 30 selected nonignorable missing-data models, the odds ratios ranged from 2.7 with 95% CI of (2.3, 3.1) to 4.2 with 95% CI of (3.9, 4.6). Under one nonignorable missing-data model, the odds ratio was 7.4 with 95% CI of (6.3, 8.6). This is the first analysis to find a strong association between balance difficulties and frequent depression.

Background Bed sharing with parents has been described as both beneficial to infant well-being and as a potentially lethal situation. Objective To examine trends in bed sharing between infants and caregivers, and the factors that influence this behavior. Design Annual nationally representative telephone surveys conducted between 1993 and 2000. Setting The 48 contiguous United States. Participants Nighttime caregivers of infants born within 7 months prior to interview between 1993 and 2000. Approximately 1000 interviews were conducted each year for a total sample of 8453 nighttime caregivers. Main Outcome Measures Where and with whom the infant usually slept at night in the preceding 2 weeks. Results Forty-five percent of infants spent at least some time at night on an adult bed in the last 2 weeks. Between 1993 and 2000, the proportion of infants usually sharing an adult bed at night increased from 5.5% to 12.8%. More than 90% of infants who "usually" slept on an adult bed shared it with their parents. In a multivariate analysis, factors associated with increased probability of routine bed sharing included: maternal age less than 18 years (odds ratio [OR] = 2.26; 95% confidence interval [CI], 1.22-4.21), maternal race or ethnicity reported as black (OR = 4.04; 95% CI, 3.04-5.36) or as Asian or "other" (OR = 2.72; 95% CI, 1.74-4.22), household income less than $20 000 (OR = 1.49; 95% CI, 1.15 = 1.92), living in the Southern states compared with living in the Midwest (OR, 1.59; 95% CI = 1.23, 2.06), and infant age less than 8 weeks (OR = 1.60; 95% CI, 1.10-2.33). Living in the Mid-Atlantic compared with the Midwest (OR = 0.63; 95% CI, 0.44-0.90), and being born with low birthweight and preterm (OR = 0.32; 95% CI, 0.14-0.74) were associated with decreased probability of routine bed sharing. Conclusions Bed sharing as a routine practice is growing in the United States. Given that this practice seems to be widespread and strongly influenced by cultural factors, more studies of the consequences of bed sharing are needed to inform health care providers and parents on the risks and benefits.

ContextThe success and simplicity of the 1994 national "Back to Sleep" campaign to reduce sudden infant death syndrome provides an opportunity to study which elements determine whether a behavior will change in the desired direction in response to a public health intervention.ObjectiveTo examine sociodemographic characteristics, motivation, and message exposure to ascertain which factors influenced a caregiver's choice of infant sleep position after implementation of the campaign.DesignAnnual nationally representative telephone surveys conducted between 1994 and 1998.SettingThe 48 contiguous United States.ParticipantsNighttime caregivers of infants born within the 7 months prior to interview between 1994 and 1998. Approximately 1000 interviews were conducted each year.Main Outcome MeasuresThe position the infant was usually placed in for sleep, sleep position recommendations received from specific sources, and reasons reported for position choice.ResultsBetween 1994 and 1998, prone placement declined from 44% to 17% among white infants and from 53% to 32% among black infants. Supine placement increased from 27% to 58% among white infants and from 17% to 31% among black infants. During this period, reports of supine recommendations from at least 1 source doubled from 38% to 79%. From 1995 to 1998, 86% of caregivers who placed the infant prone reported receiving only nonprone recommendations. Infant comfort was given as a reason for prone placement by 82% of these caregivers. In multivariate analysis, physician recommendation of "supine not prone" had the strongest influence and was associated with decreased prone placement (odds ratio [OR], 0.25 [95% confidence interval {CI}, 0.16-0.39]) and increased supine placement (OR, 3.37 [95% CI, 2.38-4.76]). Recommendations from all 4 sources (the physician, neonatal nurse, reading materials, and radio/television) further increased the probability of supine placement (OR, 6.01 [95% CI, 4.57-7.90]). Other factors independently associated with increased prone and decreased supine placement included maternal black race, parity of more than 1, and living in a southern or mid-Atlantic state.ConclusionsAccording to our study, as of 1998, approximately one fifth of infants were still placed prone, and only half were placed supine. Recommendations of supine placement during infancy by physicians at well-baby checks and by neonatal nursery staff and print and broadcast media have increased the proportion of infants placed supine. Caregiver beliefs regarding perceived advantages of prone sleeping should be addressed to attain further reduction in prone placement.