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While rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, past epidemiology studies of this malignancy used data that covered30% of the US population. Therefore, we evaluated RMS incidence using data from U.S. Cancer Statistics (USCS) and survival trends using the National Program of Cancer Registries (NPCR), which covers 100% and 94% of the U.S. population, respectively.Incidence and survival were assessed for pediatric patients diagnosed with RMS during 2003-2017 and 2001-2016, respectively. Both demographic and clinical variables were evaluated. Age-adjusted incidence rates, average annual percent change (AAPC), and 5-year relative survival (RS) were calculated, all with corresponding 95% confidence intervals (CIs). Cox regression models were used to evaluate the impact of demographic and clinical variables on survival.We identified 5656 primary RMS cases in USCS during 2003-2017. The age-adjusted incidence rate was 4.58 per 1 million (95% CI: 4.46-4.70) with an AAPC of 0.3% (95% CI: -0.7 to 1.2%). In NPCR, 5-year RS for all cases was 68.0% (95% CI: 66.6-69.3%). In multivariable analyses, non-Hispanic (NH) Black cases had worse survival compared with NH White cases (hazard ratio [HR] = 1.16, 95% CI: 1.01-1.33).The incidence and survival rates were stable in the largest and most comprehensive population-based analysis for pediatric RMS cases in the U.S. Additionally, we observed a survival disparity among NH Black cases. Findings from this study could inform interventions to address disparities, risk stratification strategies, and clinical trial design.

Multiple myeloma (MM) is a heterogeneous hematologic malignancy associated with several risk factors including genetic aberrations which impact disease response and survival. Thorough risk classification is essential to select the best clinical strategy to optimize outcomes. The SKY92 molecular signature classifies patients as standard- or high-risk for progression. The PRospective Observational Multiple Myeloma Impact Study (PROMMIS; NCT02911571) measures impact of SKY92 on risk classification and treatment plan. Newly diagnosed MM patients had bone marrow aspirates analyzed for SKY92. Physicians completed a questionnaire for each patient capturing risk classification, hypothetical treatment plan, and physician confidence in the treatment plan, before and after unblinding SKY92. One hundred forty seven MM patients were enrolled. Before unblinding SKY92, physicians regarded 74 (50%) patients as clinical standard-risk. After unblinding SKY92, 16 patients were re-assigned as high-risk by the physician, and for 15 of them treatment strategy was impacted, resulting in an escalated treatment plan. For the 73 (50%) clinical high-risk patients, SKY92 indicated 46 patients to be standard-risk; for 31 of these patients the treatment strategy was impacted consistent with a de-escalation of risk. Overall, SKY92 impacted treatment decisions in 37% of patients (

Hepatoblastoma (HB) is the most common pediatric primary malignant liver tumor, its incidence has been increasing worldwide, but recent changes in incidence and outcomes with high population coverage are not well characterized.We defined the incidence of HB diagnosed during 2003-2017 from United States Cancer Statistics (USCS) database, and survival during 2001-2016 from the National Program of Cancer Registries (NPCR). Data were stratified by sex, race/ethnicity, age, tumor stage, county population, and diagnosis year. Incidence trends were assessed by calculating average annual percent change (AAPC) using Joinpoint regression. Differences in overall 5-year survival were estimated using Cox regression analysis.2178 HB cases with an annual incidence rate of 1.76 per million persons were identified and incidence increased over time (AAPC = 2.2, 95% confidence interval [CI], 0.9-3.6). The 5-year relative survival was 76.9% (95% CI: 74.9-78.8) and the risk of death was lower for cases diagnosed after 2009 (hazard ratio [HR] = 0.77, 95% CI: 0.63-0.94), higher for ages 3-7 years and 8-19 years compared to 0-2 years (HR = 1.38, 95% CI: 1.10-1.76 and 1.83, 95% CI: 1.31-2.70, respectively), for distant compared to locoregional stage (HR = 2.77, 95% CI: 2.27-3.36), and for non-Hispanic Black compared to non-Hispanic White cases (HR = 1.39, 95% CI: 1.02-1.84).HB incidence increased, and survival improved over the study period. Disparities in survival exist by age, race or ethnicity, and stage. Further studies could identify factors affecting increases in HB cases, inform future interventions, and address disparities in outcomes.

Combination of carfilzomib with dexamethasone (Kd) is approved for use in relapsed and/or refractory multiple myeloma (RRMM), with carfilzomib administered twice weekly at 56 mg/m2 (Kd56 BIW) or once weekly at 70 mg/m2 (Kd70 QW). Post hoc cross-trial comparisons were performed to compare efficacy and safety profiles of Kd70 QW vs Kd56 BIW dosing schedules using data from three trials of patients with RRMM: A.R.R.O.W., CHAMPION-1, and ENDEAVOR. To select for comparable patient populations, side-by-side efficacy and safety comparisons were performed in subgroups of patients with 2-3 prior lines of therapy who were not refractory to bortezomib. The overall response rate (ORR) was 69.9% (95% confidence interval [CI], 61.7-77.2) for Kd70 QW and 72.4% (95% CI, 65.9-78.2) for Kd56 BIW. Median progression-free survival (PFS) was 12.1 months (95% CI, 8.4-14.3) for Kd70 QW and 14.5 months (95% CI, 10.2-not evaluable) for Kd56 BIW. Frequency of grade ≥ 3 adverse events (AEs) was 67.6% for Kd70 QW and 85.3% for Kd56 BIW. Regression analyses (adjusting for prognostic factors) of all patients in the trials who received Kd70 QW vs Kd56 BIW estimated a PFS hazard ratio of 0.91 (95% CI, 0.69-1.19; P = .47) and an ORR odds ratio of 1.12 (95% CI, 0.74-1.69; P = .61). These results suggest that Kd70 QW has a comparable efficacy profile compared with Kd56 BIW and represents a convenient and well-tolerated treatment for patients with RRMM.

Patients with high-risk multiple myeloma (hrMM) relapse after autologous stem cell transplantation (ASCT) with a median progression free survival (PFS) of 8-14 months without lenalidomide maintenance and 24-39 months with lenalidomide maintenance. We hypothesized that Pembro-Rd will prolong PFS post-ASCT in patients with hrMM compared to historical controls. This Phase II study enrolled hrMM patients with primary objective to assess the efficacy of the combination of Pembro-Rd for a total of 2 cycles and then an additional 2 cycles without dexamethasone. There were 12 evaluable subjects, as enrollment was stopped after an FDA hold. With a median follow-up of 50.7 months, the median PFS was 27.7 months. The PFS rates at years 1 and 2 are 90.9% and 63.6%, respectively. The most common adverse events were neutropenia (grade 1-3), cough, diarrhea and constipation, all grade 1 or 2. The PFS rate with fixed duration therapy was comparable to that seen with continuous dose lenalidomide, potentially offering a new post-ASCT therapeutic strategy. This article is protected by copyright. All rights reserved.

Background Given the public health relevance of PSA‐based screening, various professional organizations have issued recommendations on the use of the PSA test to screen for prostate cancer in different age groups. Aim Using a large commercial claims database, we aimed to determine the most recent rates of PSA testing for privately insured men age 30 to 64 in the context of screening recommendations. Methods and Results Data from employer plans were from MarketScan commercial claims database. Annual PSA testing rate was the proportion of men with ≥1 paid test(s) per 12 months of continuous enrollment. Men with diagnosis of any prostate‐related condition were excluded. Annual percent change (APC) in PSA test use was estimated using joinpoint regression analysis. In 2011 to 2017, annual testing rate encompassing 5.02 to 5.53 million men was approximately 1.4%, age 30 to 34; 3.4% to 4.1%, age 35 to 39; 11% to 13%, age 40 to 44; 18% to 21%, age 45 to 49; 31% to 33%, age 50 to 54; 35% to 37%, age 55 to 59; and 38% to 41%, age 60 to 64. APC for 2011 to 2017 was −0.5% (P = .11), age 30 to 34; −3.0% (P = .001), age 35‐39; −3.1% (P

We conducted a population genetic analysis of the stalked kelp, Pterygophora californica, in the Santa Barbara Channel, California, USA. The results were compared with previous work on the genetic differentiation of giant kelp, Macrocystis pyrifera, in the same region. These two sympatric kelps not only share many life history and dispersal characteristics but also differ in that dislodged P. californica does not produce floating rafts with buoyant fertile sporophytes, commonly observed for M. pyrifera. We used a comparative population genetic approach with these two species to test the hypothesis that the ability to produce floating rafts increases the genetic connectivity among kelp patches in the Santa Barbara Channel. We quantified the association of habitat continuity and oceanographic distance with the genetic differentiation observed in stalked kelp, like previously conducted for giant kelp. We compared both overall (across all patches) and pairwise (between patches) genetic differentiation. We found that oceanographic transit time, habitat continuity, and geographic distance were all associated with genetic connectivity in P. californica, supporting similar previous findings for M. pyrifera. Controlling for differences in heterozygosity between kelp species using Jost's DEST , we showed that global differentiation and pairwise differentiation were similar among patches between the two kelp species, indicating that they have similar dispersal capabilities despite their differences in rafting ability. These results suggest that rafting sporophytes do not play a significant role in effective dispersal of M. pyrifera at ecologically relevant spatial and temporal scales.

Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40mg (20mg for patients aged>75years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2months (7·9months in the prior-bortezomib subgroup). Median OS was 41·7months (38·6months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477.

Twice-weekly carfilzomib (27 mg/m2 ) with lenalidomide-dexamethasone (KRd) is a standard-of-care in relapsed or refractory multiple myeloma (RRMM). This phase 1b study evaluated KRd with once-weekly carfilzomib in RRMM. Patients received carfilzomib (30-minute infusion; 56 or 70mg/m2 ) on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, 15, and 22 (day 22 omitted for cycles 9+) of 28-day cycles. Primary objective was safety/tolerability; efficacy was a secondary objective. Fifty-six RRMM patients enrolled: 22 during dose evaluation (56-mg/m2 , n = 10; 70-mg/m2 , n = 12) and 34 during dose expansion (all initiated dosing at 70 mg/m2 ). After 2 fatal adverse events (AEs) during 70-mg/m2 dose expansion, dosage reduction to 56 mg/m2 was permitted. Results are presented for carfilzomib 56-mg/m2 (n = 10) and 70-mg/m2 groups (dose evaluation/expansion; n = 46). Median carfilzomib dose was 53.2 mg/m2 (56-mg/m2 group) and 62.4 mg/m2 (70-mg/m2 group). Grade ≥3 AE rates were 70.0% (56 mg/m2 ) and 69.6% (70 mg/m2 ). Overall response rates were 90.0% (56 mg/m2 ) and 89.1% (70 mg/m2 ); ≥very good partial response rates were 50.0% (56 mg/m2 ) and 73.9% (70 mg/m2 ). Once-weekly KRd was active with acceptable toxicity in RRMM, supporting further evaluation of this regimen.

Objective The severity of anxiety, in general, has been associated with suicide ideation (SI) among youth, but research has yet to examine the specific anxiety symptoms that may contribute to SI among youth. This study examined the severity of specific anxiety symptom clusters (i.e., tense/restless, somatic/autonomic symptoms, humiliation/rejection, performing in public, separation anxiety, perfectionism, and anxious coping) and SI in youth who met diagnostic criteria for an anxiety disorder. Method Participants (N = 87) were treatment-seeking children and adolescents ages 6-17 (M = 11.1 years, SD = 3.06; 52.9% male) diagnosed with a principal anxiety disorder. Youth and their parents completed measures of youth anxiety symptom severity, depression, and SI. Results Hierarchical linear regressions revealed that when anxiety symptom clusters were entered simultaneously, only youth self-reported (and not parent-reported) somatic/autonomic symptoms of anxiety significantly predicted SI, after controlling for depression and sex. Importantly, the relationship between somatic/autonomic symptoms of anxiety and SI was stronger than that between depression and SI. Conclusions These results suggest that assessing somatic symptoms of anxiety is especially important when quantifying suicide risk among anxiety-disordered youth.

The standard of practice for forensic interviews in criminal and delinquency cases, other than those conducted as part of brief preliminary screening evaluations or in emergency situations, should include a digital recording requirement. This standard should be adopted because of the greater availability of, and familiarity with, recording technology on the part of mental health professionals, the greater use and proven effectiveness of recording in other contexts of the criminal justice system, and the improvement in court presentation and accuracy of judicial determinations involving forensic assessments that recording will provide. The experience of practitioners with recording since professional associations last studied the issue should be taken into account, as informal data suggest it has been positive. Unfortunately, the legal system is unlikely to prompt this advance without its reconsideration by the forensic mental health professions, because current constitutional jurisprudence does not require recording and effectively makes it contingent upon request by examiners. Forensic evaluators thus have a valuable opportunity to educate the legal system on the utility and importance of this key reform, and so should adopt it as a best practice.

Background Tobacco use data are important when the epidemiology and prognosis of tobacco-associated cancers are being defined. Central cancer registries in 10 National Program of Cancer Registries states pilot-tested the collection of standardized tobacco use variables. This study evaluated the capture of tobacco use data and examined smoking prevalence among cancer patients. Methods Participating registries collected data about the use of tobacco-cigarettes, other smoked tobacco, and smokeless tobacco-for cases diagnosed during 2011-2013. The percentage of cases with known tobacco variable values was calculated, and the prevalence of tobacco use was analyzed by the primary cancer site and state. Results Among 1,646,505 incident cancer cases, 51% had known cigarette use data: 18% were current users, 31% were former users, and 51% reported never using. The percentage of cases with a known status for both other smoked tobacco and smokeless tobacco was 43%, with 97% and 98% coded as never users, respectively. The percent known for cigarette use ranged from 27% to 81% by state and improved from 47% in 2011 to 59% in 2013 for all 10 states combined. The percent known for cigarette use and the prevalence of ever smoking cigarettes were highest for laryngeal cancer and tracheal, lung, and bronchus cancer. Conclusions Cancer registrars ascertained cigarette use for slightly more than half of all new cancer cases, but other tobacco-related fields were less complete. Studies to evaluate the validity of specific tobacco-related variables and the ability of cancer registries to capture this information from the medical record are needed to gauge the usefulness of collecting these variables through cancer surveillance systems. Cancer 2018;124:2381-9. © 2018 American Cancer Society.

Background Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. This report describes the survival of children with ALL in the United States using the most comprehensive and up-to-date cancer registry data. Methods Data from 37 state cancer registries that cover approximately 80% of the US population were used. Age-standardized survival up to 5 years was estimated for children aged 0-14 years who were diagnosed with ALL during 2 periods (2001-2003 and 2004-2009). Results In total, 17,500 children with ALL were included. The pooled age-standardized net survival estimates for all US registries combined were 95% at 1 year, 90% at 3 years, and 86% at 5 years for children diagnosed during 2001-2003, and 96%, 91%, and 88%, respectively, for those diagnosed during 2004-2009. Black children who were diagnosed during 2001-2003 had lower 5-year survival (84%) than white children (87%) and had less improvement in survival by 2004-2009. For those diagnosed during 2004-2009, the 1-year and 5-year survival estimates were 96% and 89%, respectively, for white children and 96% and 84%, respectively, for black children. During 2004-2009, survival was highest among children aged 1 to 4 years (95%) and lowest among children aged Conclusions The current results indicate that overall net survival from childhood ALL in the United States is high, but disparities by race still exist, especially beyond the first year after diagnosis. Clinical and public health strategies are needed to improve health care access, clinical trial enrollment, treatment, and survivorship care for children with ALL. Cancer 2017;123:5178-89. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Photoautotrophs vary the concentration of photosynthetic pigments in response to changing environmental conditions. In the ocean, the chlorophyll a to carbon ratio (Chl:C) has been used as a proxy for the physiological condition of phytoplankton, and there is laboratory evidence that the growth rate of juvenile giant kelp (Macrocystis pyrifera), a coastal foundation species, is positively related to Chl:C under nutrient-limited conditions. We examined the relative roles of nutrients and light in determining Chl:C dynamics and if fluctuations in Chl:C were related to changes in canopy biomass and net primary production (NPP) from sites spanning 750 km of the California coast. Seventy percent of the variability in canopy Chl:C was explained by a combination of photosynthetically active radiation and seawater nitrate concentration. In the periodically nutrient-limited waters of the Southern California Bight, changes in Chl:C positively resembled changes in available nitrate, whereas Chl:C negatively tracked changes in light for the more nutrient-replete central California coastline. Values of Chl:C were positively related to residuals from an autoregressive model of kelp biomass at the southern California sites indicating that Chl:C is a proxy for physiological state of the kelp canopy. NPP estimated through correlations with kelp biomass and lagged Chl:C compared well to established field-based estimates. These results open the possibility of assessing giant kelp physiological condition from estimates of Chl:C modeled from sea surface irradiance and nitrate concentration, which in turn can be used to estimate giant kelp primary production over large spatial and temporal scales using future remote sensing technologies.

A population pharmacokinetic (PK) model and exposure-response (E-R) analysis was developed using data collected from 5 phase 1b/2 and 2 phase 3 studies in subjects with multiple myeloma. Subjects receiving intravenous infusion on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) in each cycle at doses ranging from 15 to 20/56 mg/m2 (20 mg/m2 in cycle 1 and, if tolerated, escalated to 56 mg/m2 on day 8 of cycle 1). The population PK analysis indicated that among all the covariates tested, the only statistically significant covariate was body surface area on carfilzomib clearance; however, this covariate was unlikely to be clinically significant. Despite inclusion of different populations (relapsed or relapsed/refractory), treatments (carfilzomib monotherapy or combination therapy), infusion lengths (2 to 10 minutes or 30 minutes), and different doses, the E-R analysis of efficacy showed that after adjusting for baseline characteristics, higher area under the concentration-time curve was associated with improved overall response rate (ORR), from 15 to 20/56 mg/m2 . No positive relationships between maximum concentration and ORR were identified, indicating that ORR would not be expected to be impacted by infusion length. For safety end points, no statistically significant relationship between exposure and increasing risk of adverse events was identified. The results of an E-R analysis provided strong support for a carfilzomib dose at 20/56 mg/m2 as a 30-minute infusion for monotherapy and combination therapy. This article illustrates an example of application of E-R analysis to support labeling dose recommendation in the absence of extensive clinical data.

Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Summary Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open-label, single-institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide-refractory patients. Patients were considered lenalidomide-refractory if they had no clinical response (

Summary While proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

Renal dysfunction negatively impacts outcomes in patients with multiple myeloma (MM). Few treatment options are currently available for patients with MM and comorbid renal dysfunction, and as they are generally excluded from clinical trials, data on the use of immunomodulatory drugs in this population are scarce. In this paper, we describe a case series of five women with MM and severe renal dysfunction or dialysis dependency who were refractory to both bortezomib and either lenalidomide or thalidomide and were treated with full-dose (4 mg) pomalidomide. As part of their treatment regimen, these patients also received carfilzomib and dexamethasone with or without cyclophosphamide. All five patients achieved at least a partial response to pomalidomide-based therapy, which was relatively well tolerated. Our findings suggest that pomalidomide may represent a valuable and tolerable treatment option for MM patients with severe renal impairment. The fact that pomalidomide is extensively metabolized prior to urinary excretion may explain the improved tolerability of pomalidomide versus lenalidomide in such patients. Copyright © 2016 John Wiley & Sons, Ltd.

The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenstrom's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade ≥3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.

Ecological theory predicts that demographic connectivity structures the dynamics of local populations within metapopulation systems, but empirical support has been constrained by major limitations in data and methodology. We tested this prediction for giant kelp Macrocystis pyrifera, a key habitat-forming species in temperate coastal ecosystems worldwide, in southern California, USA. We combined a long-term (22 years), large-scale (~500 km coastline), high-resolution census of abundance with novel patch delineation methods and an innovative connectivity measure incorporating oceanographic transport and source fecundity. Connectivity strongly predicted local dynamics (well-connected patches had lower probabilities of extinction and higher probabilities of colonization, leading to greater likelihoods of occupancy) but this relationship was mediated by patch size. Moreover, the relationship between connectivity and local population dynamics varied over time, possibly due to temporal variation in oceanographic transport processes. Surprisingly, connectivity had a smaller influence on colonization relative to extinction, possibly because local ecological factors differ greatly between extinct and extant patches. Our results provide the first comprehensive evidence that southern California giant kelp populations function as a metapopulation system, challenging the view that populations of this important foundation species are governed exclusively by self-replenishment.

California's oil platforms are nearing the end of their productive lives and therefore will be decommissioned in the near future. These structures have been shown to be important habitats for both settlement and growth for reef fishes. Important information on the biological effects (i.e., loss of biomass and production) of different decommissioning options has not yet been explored in detail. An important step in the assessment of these different decommissioning options is to look at the potential loss of fish production and habitat under the different alternatives. Using the large amount of information available on fish abundances at these structures, we have created a model to estimate the standing stock of fishes and production that would be lost because of both partial (removal from surface to 85 ft) and complete removal (the 2 decommissioning options being considered). Complete removal of a platform will likely eliminate most of its fish biomass; however, this study has shown that for rockfishes, which settle predominantly below 85 feet (26 m) and move deeper as they age, partial removal through topping would leave more than 90% of the fish biomass at the deeper platforms. Modeling of larval dispersal suggests that platforms provide an important opportunity for recruitment of fish larvae and that many larvae produced near the platforms would settle elsewhere in the region. The results presented here indicate that, even if topped, the potential contribution of platform habitat to biological resources (e.g., fish production) in this region is significant.

Aim Coastal marine environments experience a wide range of biotic and abiotic forces that can limit and punctuate the geographical range and abundance of species through time. Determining the relative strengths and nonlinear effects of these processes is vital to understanding the biogeographical structures of species. There has been an ongoing discussion concerning the relative importance of these processes in controlling the dynamics of giant kelp, Macrocystis pyrifera, an important structure-forming species on shallow reefs in the eastern Pacific. We used novel spatial time-series that span nearly three decades to determine the dominant drivers of giant kelp canopy biomass and the temporal and spatial scales over which they operate across the dominant range of the giant kelp in North America. Location Near-shore areas from Ano Nuevo, California, to the USA/Mexico border. Methods We employed empirical orthogonal functions to elucidate the primary drivers of giant kelp canopy biomass across space and time and then fit generalized additive and linear models to determine the nonlinear effect and relative importance of each of these potential drivers along the c. 1500-km study region over a 25-year period. Results Wave disturbance, nitrate availability and the state of the North Pacific Gyre Oscillation were the most important environmental predictors of giant kelp canopy biomass, explaining 24.5%, 12.7% and 6.1% of the variance, respectively. Environmental drivers of canopy biomass exhibited profound spatial differences in relative effect sizes. Nonlinear effect shapes of each potential biomass driver were determined, which explained these spatial differences. Main conclusions These large-scale analyses help to reconcile the local-scale conclusions of canopy biomass dynamics across the California coastline and show that these dynamics differ predictably in space and time in accordance with local and regional differences in environmental drivers. By characterizing the nonlinear effects of these drivers, we identified spatio-temporal patterns of processes that cannot be detected by remote sensing.

Observations from the Santa Barbara Channel, California, were used to evaluate relationships among optical properties and phytoplankton community structure. Phytoplankton community structure was determined by statistically analyzing 10 diagnostic phytoplankton pigment concentrations using empirical orthogonal function (EOF) analysis. The first four EOF modes explained 82% of phytoplankton community structure variability and were interpreted as a mixed community mode composed mostly of nanoplankton, a mode dominated by microplankton (diatoms and dinoflagellates), a mode describing alternating diatom and dinoflagellate dominance, and a mode reflecting picoplankton presence. Variations in colored dissolved organic matter (CDOM) and phytoplankton absorption spectra were related to changes of the mixed microplankton modal amplitudes. Characteristics of the CDOM spectrum were further dependent on whether diatoms or dinoflagellates were dominant. The particle backscattering coefficient was significantly correlated with EOF modes describing the mixed microplankton and the picoplankton communities. The influence of phytoplankton community structure was also seen in the performance of standard ocean color algorithms using the in situ data set. The present results demonstrate that many optical characteristics vary significantly with changes in phytoplankton community structure and suggest that improvements in remote-sensing algorithms will require model coefficients to vary accordingly. Further, changes in phytoplankton community composition affect both dissolved and particle absorption and scattering properties, not simply the phytoplankton-specific properties, creating challenges for the development of algorithms aimed at assessing phytoplankton community structure from satellite observations.

Exchange and retention of coastal waters modulate dispersal of marine larvae, affecting marine ecosystem dynamics. A hypothesis was put forward in the 1980s describing the coastal upwelling front as a “tattered curtain” that retains larvae. This front was envisioned to be broken up by squirts and eddies, hitting the coast under upwelling relaxation events. Here we revise this hypothesis by using an idealized ocean model of an eastern boundary upwelling current, and an idealized particle/larvae model appropriate for shelf-spawning benthic species. Modeled larval settlement patterns were controlled by retention in the core of the upwelling jet, bounded by regions of high-velocity shear on the flanks of the jet. Squirts, filaments, poleward-moving eddies, and meanders modulated settlement patterns locally, while dense packets moved equatorward within the upwelling jet. Correlation between settlement (i.e., particles 20–40 d old

The ubiquitin–proteasome pathway regulates bone formation through osteoblast differentiation. We analyzed variation alkaline phosphatase (ALP) during carfilzomib treatment. Data from 38 patients enrolled in the PX-171-003 and 29 patients in PX-171-004 studies, for patients with relapsed ⁄ refractory myeloma, were analyzed. All patients received 20 mg ⁄ m 2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Sixty-seven patients from ALP data were evaluable. In PX-171-003, the ORR (>PR) was 18% and the clinical benefit response (CBR; >MR) was 26%, while in PX-171-004, the ORR was 35.5% overall and 57% in bortezomib-naive patients. ALP increment from baseline was statistically different in patients who achieved ‡VGPR compared with all others on Days 1 (P = 0.0049) and 8 (P = 0.006) of Cycle 2. In patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline. An ALP increase over the same period of time was seen in 26%, 13% and 11% of patients achieving PR, MR, and SD, respectively. This retrospective analysis of patients with relapsed or refractory myeloma treated with single-agent carfilzomib indicates that early elevation in ALP is associated with subsequent myeloma response.

Ocean currents are expected to be the predominant environmental factor influencing the dispersal of planktonic larvae or spores; yet, their characterization as predictors of marine connectivity has been hindered by a lack of understanding of how best to use oceanographic data. We used a high-resolution oceanographic model output and Lagrangian particle simulations to derive oceanographic distances (hereafter called transport times) between sites studied for Macrocystis pyrifera genetic differentiation. We build upon the classical isolation-by-distance regression model by asking how much additional variability in genetic differentiation is explained when adding transport time as predictor. We explored the extent to which gene flow is dependent upon seasonal changes in ocean circulation. Because oceanographic transport between two sites is inherently asymmetric, we also compare the explanatory power of models using the minimum or the mean transport times. Finally, we compare the direction of connectivity as estimated by the oceanographic model and genetic assignment tests. We show that the minimum transport time had higher explanatory power than the mean transport time, revealing the importance of considering asymmetry in ocean currents when modelling gene flow. Genetic assignment tests were much less effective in determining asymmetry in gene flow. Summer-derived transport times, in particular for the month of June, which had the strongest current speed, greatest asymmetry and highest spore production, resulted in the best-fit model explaining twice the variability in genetic differentiation relative to models that use geographic distance or habitat continuity. The best overall model also included habitat continuity and explained 65% of the variation in genetic differentiation among sites.

Variability in the optical particle backscattering coefficient (b(bp)) is investigated in oceanic waters from two sites, namely the BOUee pour l'acquiSition d'une Serie Optique a Long termE site in the northwestern Mediterranean Sea and the Plumes and Blooms stations in the Santa Barbara Channel off Southern California. Data from these two sites span two orders of magnitude in b(bp) and likely cover typical open ocean values. A significant relationship is found between b(bp) at wavelengths of 442 and 555 nm and chlorophyll concentration. However the large spread in this relationship makes chlorophyll a poor predictor of b(bp). The relationship between b(bp) and the particulate beam attenuation coefficient at 660 nm is tighter for both sites, indicating covariability of the particle size ranges that determine both coefficients. A detailed study of the seasonal changes of the b(bp) vs. chlorophyll relationship reveals that this bio-optical relationship might be best described as a succession of distinct regimes with rapid transitions from one to another. The backscattering ratio ((b) over tilde (bp); the ratio of b(bp) to total particulate scattering, b(p)) ranges from about 0.2% to 1.5%, which is similar to previously reported values. The relationship between (b) over tilde (bp) and chlorophyll was not significant, while values of the backscattering ratio varied spectrally.

The understanding of biogeochemical cycles has benefited from technological advances facilitating new kinds of measurements and observations. Satellite-borne ocean-color sensors that assess the physiological status of phytoplankton have led to improved estimates of oceanic productivity, as have micrometeorological approaches measuring terrestrial photosynthesis and respiration. The advent of satellites fitted with synthetic aperture radar (a specialized sensor used to determine inundation extent and vegetation types in wetlands) has revealed large fluxes of carbon dioxide and methane from these areas. Advances in the measurement of chemical constituents and turbulence have allowed the detection of high-resolution coupling between physical and biogeochemical processes. Genomics and proteomics – the study of genes and of an organism's complement of proteins, respectively – have revolutionized our understanding of the types of cells present in the environment and their ability to transform elements by allowing direct assessment of gene and protein sequences.

Marine species frequently show weak and ⁄or complex genetic structuring that is commonly dismissed as ‘chaotic’ genetic patchiness and ecologically uninformative. Here, using three datasets that individually feature weak chaotic patchiness, we demonstrate that combining inferences across species and incorporating environmental data can greatly improve the predictive value of marine population genetics studies on small spatial scales. Significant correlations in genetic patterns of microsatellite markers among three species, kelp bass Paralabrax clathratus, Kellet’s whelk Kelletia kelletii and California spiny lobster Panulirus interruptus, in the Southern California Bight suggest that slight differences in diversity and pairwise differentiation across sampling sites are not simply noise or chaotic patchiness, but are ecologically meaningful. To test whether interspecies correlations potentially result from shared environmental drivers of genetic patterns, we assembled data on kelp bed size, sea surface temperature and estimates of site-to-site migration probability derived from a high resolution multi-year ocean circulation model. These data served as predictor variables in linear models of genetic diversity and linear mixed models of genetic differentiation that were assessed with information–theoretic model selection. Kelp was the most informative predictor of genetics for all three species, but ocean circulation also played a minor role for kelp bass. The shared patterns suggest a single spatial marine management strategy may effectively protect genetic diversity of multiple species. This study demonstrates the power of environmental and ecological data to shed light on weak genetic patterns and highlights the need for future focus on a mechanistic understanding of the links between oceanography, ecology and genetic structure.

In many companies, numbers equal authority. Quantitative data is often viewed as more definitive than qualitative data, while its shortcomings are overlooked. Many of us have worked to marry quantitative with qualitative methods inside organizations to present a fuller view of the people for whom we develop. One area of research that increasingly needs to blend quantitative and qualitative methods is user segmentations. Our software technology product team has been using a segmentation based on quantitative data since 2005. One outcome of this effort has been the development of an algorithm-based “typing” tool intended to be used as a standard tool in recruiting for all segmentation-focused research. We learned that the algorithm was an indecipherable black box, its inner workings opaque even to those who owned it internally. This case study looks at how qualitative research came up against the impenetrable authority of a quantitative segmentation and its associated typing tool, and subsequently contributed to the redesign of future segmentation methodologies and the integration of qualitative research as a key component of segmentation creation.

Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1-21) and dexamethasone 40 mg/d (days 1-4, 9-12, and 17-20 of cycles 1-4; days 1-4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, approximately 60% were male, median age was 64 years, and 61.7% had Durie-Salmon stage III disease. Median time on study was 15.4 weeks (range: 0.1-49.1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common gradeor =3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM.

Despite growing attention to the role of social context in determining political participation, the effect of the structure of social networks remains little examined. This article introduces a model of interdependent decision making within social networks, in which individuals have heterogeneous motivations to participate, and networks are defined via a qualitative typology mirroring common empirical contexts. The analysis finds that some metrics for networks' influence—size, the prevalence of weak ties, the presence of elites—have a more complex interaction with network structure and individual motivations than has been previously acknowledged. For example, in some contexts additional network ties decrease participation. This presents the potential for selection bias in empirical studies. The model offers a fuller characterization of the role of network structure and predicts expected levels of participation across network types and distributions of motivations as a function of network size, weak and strong ties, and elite influence.

Oceanic sources of nutrients to the kelp forests of the Santa Barbara Channel were diagnosed using time series from three moorings in 12- to 17-m water depth. An in situ nitrate autoanalyzer on the moorings provided the first high-resolution time series of nitrate + nitrite (dissolved inorganic nitrogen, DIN) concentrations for this environment. Measurements between February 2001 and May 2003 show that the major mechanisms that supply DIN to the inner shelf of the Santa Barbara Channel are upwelling, diurnal internal motions, and storm runoff. These supply mechanisms vary in importance seasonally. Upwelling dominates increases of inner-shelf DIN concentration between March and May and accounts for more than half of the annual advective DIN transport to shelf reefs. In summer, baroclinic motions akin to internal waves are an important source of DIN because they occur when surface nutrient concentrations are depleted and other supply mechanisms are inactive. Brief episodes of upwelling become important in late autumn and early winter. DIN inputs from storm runoff, detected as salinity dilution at the moorings and estimated from measurements of stream discharge and nutrient concentration, are significant during winter runoff events.

The collapse of many of the world's fisheries has induced a reevaluation of existing fisheries management strategies. This has fueled interest in the establishment of networks of no-take marine reserves as an additional form of protection. Proponents of marine reserves have suggested that reserves can provide a number of advantages over other, more traditional, methods. However, concerns have also persisted that marine reserves will reduce overall catch. In a theoretical context, this concern has been only partially addressed by previous work suggesting that reserves can produce equivalent yields to those from traditional management, since this possibility is widely interpreted as a limiting case. However, an ''equivalence-at-best'' scenario is based on a highly simplified model construct that ignores all spatial pattern and size structure characterizing real populations. By contrast, when coupled effects of (1) spatial pattern in adult densities and larval dispersal, (2) population size structure, and (3) aspects of life history are considered in their most basic forms, model results suggest that reserve networks may have the potential to enhance fishery yields under a surprisingly large number of circumstances. Such enhancement is predicted to be greatest, and at times substantial, in species exhibiting postdispersal density depen- dence and that have relatively long-lived and sedentary adults, life history traits common to many harvested fishes and invertebrates. A goal of this study is to spark further theoretical attention and experimental testing on this unanticipated front.

Apparent quantum yields and rates of dimethylsulfide (DMS) photolysis were determined from Sargasso Sea seawater with the goal of assessing the extent to which photoreactions affect the unusually elevated upper ocean concentrations of DMS during the summer, the so-called DMS summer paradox. Apparent quantum yields determined with monochromatic radiation decrease exponentially with increasing wavelength and indicate that DMS photolysis is driven by ultraviolet (UV) radiation. The relative spectral partitioning differs between samples collected from the surface mixed layer (15 m) and from the chlorophyll a maximum (80 m), presumably because of differences in chromophoric dissolved organic matter (CDOM) quality (e.g., apparent degree of bleaching). Quantum yields are also temperature dependent, and an approximate doubling of photolysis rates occurs for a 208C increase in temperature. The significance of DMS photolysis to upper ocean sulfur budgets is explored using a multiyear (1992‐ 1994) DMS time series, concurrent irradiance determinations and temperature profiles, and estimates of CDOM absorption. Depth-integrated, mixed-layer DMS photolysis rates peak in the summer (15‐25 mmol m 22

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.

Background Pediatric cancer survivors are at increased risk of developing low bone mineral density (BMD) due to cancer treatment. This study assessed the yield of screening for low BMD in pediatric-aged cancer survivors as per the Children's Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines, which recommend screening survivors who received steroids, methotrexate, or hematopoietic cell transplant (HCT). Methods This is a retrospective cohort study of 475 pediatric blood cancer and noncentral nervous system solid tumor survivors screened for low BMD with dual-energy X-ray absorptiometry (DXA) as per the COG-LTFU Guidelines from 2003 to 2010. Risk factors for low BMD (DXA Z-score ≤–2) were evaluated by univariate and multivariate analysis. Results The mean DXA Z-score was –0.1 for both whole body and lumbar spine measurements. Among at-risk survivors, 8.2% (39/475) had low BMD. Multivariate analysis of survivors with low BMD showed significant association with male gender (odds ratio [OR] 3.4, 95% confidence interval [CI], 1.3–9.0), exposure to total body irradiation (TBI), cranial, or craniospinal radiation (OR 5.2, 95% CI, 1.8–14.9), and gonadal dysfunction (OR 4.3, 95% CI, 1.4–13.0). Methotrexate exposure was not significantly associated with low BMD. Survivors receiving HCT had a reduced risk of low BMD (OR 0.2, 95% CI, 0.1–0.9). Conclusion The highest risk factors for low BMD were male gender, exposure to TBI, cranial, or craniospinal radiation, and gonadal dysfunction. Survivors receiving methotrexate or HCT therapy have the lowest risk for low BMD among those screened. Future studies should investigate risk of low BMD for survivors receiving HCT without radiation exposure.

Tumour lysis syndrome (TLS), because of its low proliferative activity, is thought to only rarely complicate the treatment of patients with multiple myeloma. However, as more aggressive therapeutic approaches are increasingly used in the management of this disease, it is conceivable that clinicians will encounter this complication more frequently. A retrospective analysis of > 800 patients with multiple myeloma treated at the University of Arkansas identified nine patients who developed a marked tumour lysis syndrome following intermediate- or high-dose chemotherapy. Evaluation of disease characteristics revealed association with high tumour mass, high proliferative activity, increased lactic dehydrogenase levels, plasmablastic morphology, and unfavourable cytogenetic abnormalities. Recognition of multiple myeloma patients at high risk for the development of tumour lysis syndrome and prompt intervention are required especially in the presence of abnormal baseline renal function frequently complicating the clinical course of these patients.

For nearly all natural waters, planktonic organisms will be distributed discretely in the fluid mechanical sense. This means that the dynamics of planktonic ecosystems occur among discrete particles, not continuous scalar fields. This idea was first suggested by Hurlburt (1990) as an explanation for the paradox of the plankton. However, the discrete nature of organism distributions has many important implications for the interpretation and modeling of planktonic ecosystems. In particular, mass conservation relationship approaches to the modeling of planktonic populations (i.e., resource competititon and its result, competitive exclusion) will not be valid for all natural conditions. A microscale model of competition among individual phytoplankton cells was used to investigate the role of discreteness on phytoplankton competitition for a single, limiting nutrient substrate. This scaling analysis demonstrates that rates of competitition should increase with cellular abundance and phytoplankton size. For a typical eutrophic planktonic ecosystem (relatively large cell abundances and cell sizes), resource competitition among individual phytoplankters appears to be likely. However, for oligotrophic conditions (low cell abundances and small cells), rates of competitive displacement should be greatly reduced. The microscale competition model does not predict that the final outcome of competition will differ from resource competition theory when evaluated over thousands of division cycles. However the time required for this outcome to occur may be so long that other processes, such as episodic nutrient inputs, imposed diel cycles, and specialization of the grazer assemblage, are likely to have a dominant role in determining the species composition of an oligotrophic phytoplankton community. This seeming violation of the principle of competitive exclusion occurs because nutrient competition in oligotrophic environments is governed by interactions among discrete individuals rather than entire populations. Discreteness in plankton distributions also creates an ecological subgrid scale (SGS) problem that must be solved as part of most mathematical descriptions of plankton population dynamics. Approaches towards solution of the ecological SGS problem are suggested; however, a great deal of theoretical and experimental work remains.