Citations

Abstract Purpose: Ovarian cancer has a high recurrence and mortality rate. A barrier to improved outcomes includes a lack of accurate models for preclinical testing of novel therapeutics. Experimental Design: Clinically relevant, patient-derived tumorgraft models were generated from sequential patients and the first 168 engrafted models are described. Fresh ovarian, primary peritoneal, and fallopian tube carcinomas were collected at the time of debulking surgery and injected intraperitoneally into severe combined immunodeficient mice. Results: Tumorgrafts demonstrated a 74% engraftment rate with microscopic fidelity of primary tumor characteristics. Low-passage tumorgrafts also showed comparable genomic aberrations with the corresponding primary tumor and exhibit gene set enrichment of multiple ovarian cancer molecular subtypes, similar to patient tumors. Importantly, each of these tumorgraft models is annotated with clinical data and for those that have been tested, response to platinum chemotherapy correlates with the source patient. Conclusions: Presented herein is the largest known living tumor bank of patient-derived, ovarian tumorgraft models that can be applied to the development of personalized cancer treatment. Clin Cancer Res; 20(5); 1288–97. ©2014 AACR.

Background— Reduced low forced expiratory volume in 1 second (FEV 1 ) is reportedly associated with an increased risk of atrial fibrillation (AF). Extant reports do not provide separate estimates for never smokers or for blacks, who incongruously have lower AF incidence than whites. Methods and Results— We examined 15 004 middle-aged blacks and whites enrolled in the Atherosclerosis Risk in Communities (ARIC) cohort study. Standardized spirometry data were collected at the baseline examination. Incident AF was identified from the first among the following: International Classification of Diseases codes for AF on hospital discharge records or death certificates or 12-lead ECGs performed during 3 triennial follow-up visits. Over an average follow-up of 17.5 years, a total of 1691 participants (11%) developed new-onset AF. The rate of incident AF was inversely associated with FEV 1 in each of the 4 race and sex groups. After multivariable adjustment for traditional cardiovascular disease risk factors and height, hazard ratios of AF comparing the lowest with the highest quartile of FEV 1 were 1.37 (95% confidence interval, 1.02–1.83) for white women, 1.49 (95% confidence interval, 1.16–1.91) for white men, 1.63 (95% confidence interval, 1.00–2.66) for black women, and 2.36 (95% confidence interval, 1.30–4.29) for black men. The above associations were observed across all smoking status categories. Moderate/severe airflow obstruction (FEV 1 /forced vital capacity <0.70 and FEV 1 < 80% of predicted value) was also associated with higher AF incidence. Conclusions— In this large population-based study with a long-term follow-up, reduced FEV 1 and obstructive respiratory disease were associated with a higher AF incidence after adjustment for measured confounders.

Purpose To determine the influence of modifiable lifestyle factors on the risk of cardiovascular disease after hematopoietic cell transplantation (HCT). Patients and Methods HCT survivors of ≥ 1 year treated from 1970 to 2010 (n = 3,833) were surveyed from 2010 to 2011 on current cardiovascular health and related lifestyle factors (smoking, diet, recreational physical activity). Responses (n = 2,362) were compared with those from a matched general population sample (National Health and Nutrition Examination Survey [NHANES]; n = 1,192). Results Compared with NHANES participants, HCT survivors (median age, 55.9 years; median 10.8 years since HCT; 71.3% allogeneic) had higher rates of cardiomyopathy (4.0% v 2.6%), stroke (4.8% v 3.3%), dyslipidemia (33.9% v 22.3%), and diabetes (14.3% v 11.7%; P < .05 for all comparisons). Prevalence of hypertension was similar (27.9% v 30.0%), and survivors were less likely to have ischemic heart disease (6.1% v 8.9%; P < .01). Among HCT survivors, hypertension, dyslipidemia, and diabetes were independent risk factors for ischemic heart disease and cardiomyopathy, and smoking was associated with ischemic heart disease and diabetes (odds ratios [ORs], 1.8 to 2.1; P = .02). Obesity was a risk factor for post-transplantation hypertension, dyslipidemia, and diabetes (ORs ≥ 2.0; P < .001). In contrast, lower fruit/vegetable intake was associated with greater risk of dyslipidemia and diabetes (ORs, 1.4 to 1.8; P ≤ .01), and lower physical activity level was associated with greater risk of hypertension and diabetes (ORs, 1.4 to 1.5; P < .05). Healthier lifestyle characteristics among HCT survivors attenuated risk of all cardiovascular conditions assessed. Conclusion Attention of clinicians to conventional cardiovascular risk factors and modifiable lifestyle characteristics offers hope of reducing serious cardiovascular morbidity after HCT.

AbstractIntellectual disability is a heterogeneous disorder with a wide phenotypic spectrum. Over 1,700 OMIM genes have been associated with this condition, many of which reside on the X‐chromosome. The IQSEC2 gene is located on chromosome Xp11.22 and is known to play a significant role in the maintenance and homeostasis of the brain. Mutations in IQSEC2 have been historically associated with nonsyndromic X‐linked intellectual disability. Case reports of affected probands show phenotypic overlap with conditions associated with pathogenic MECP2, FOXG1, CDKL5, and MEF2C gene mutations. Affected individuals, however, have also been identified as presenting with additional clinical features including seizures, autistic‐behavior, psychiatric problems, and delayed language skills. To our knowledge, only 5 deleterious mutations and 2 intragenic duplications have been previously reported in IQSEC2. Here we report two novel IQSEC2 de novo truncating mutations identified through diagnostic exome sequencing in two severely affected unrelated male probands manifesting developmental delay, seizures, hypotonia, plagiocephaly, and abnormal MRI findings. Overall, diagnostic exome sequencing established a molecular diagnosis for two patients in whom traditional testing methods were uninformative while expanding on the mutational and phenotypic spectrum. In addition, our data suggests that IQSEC2 may be more common than previously appreciated, accounting for approximately 9 % (2/22) of positive findings among patients with seizures referred for diagnostic exome sequencing. Further, these data supports recently published data suggesting that IQSEC2 plays a more significant role in the development of X‐linked intellectual disability with seizures than previously anticipated.

BACKGROUNDAngiogenesis contributes to the progression of urothelial carcinoma (UC). In the current study, the authors investigated the role of maintenance sunitinib in patients with advanced UC.METHODSPatients with locally recurrent/metastatic UC and adequate organ function who achieved stable disease or a partial or complete response after 4 to 6 chemotherapy cycles were randomized to sunitinib at a dose of 50 mg/day (28 days on and 14 days off) or placebo. The primary endpoint was the 6‐month progression rate. Secondary endpoints were safety, survival, change in serum vascular endothelial growth factor (VEGF)/soluble VEGF receptor‐2 (sVEGFR2), and the activity of sunitinib in patients who developed disease progression while receiving placebo. A total of 38 eligible patients per treatment arm were required to select better therapy with 90% probability (α = .05).RESULTSA total of 54 eligible patients were randomized to either the sunitinib arm (26 patients) or the placebo arm (28 patients). The median number of cycles received was 2 cycles per treatment arm. The most common grade 3 to 4 adverse events (graded according to version 3.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) among patients receiving sunitinib were thrombocytopenia, diarrhea, mucositis, fatigue, and hypertension. There were no grade 3 or 4 adverse events noted among > 5% of patients receiving placebo. The 6‐month progression rate was 72% versus 64%. The median progression‐free survival (PFS) was 2.9 months (range, 0.5 months‐32.5 months) versus 2.7 months (range, 0.8 months −65 months) for the sunitinib versus placebo arms, respectively. Patients receiving placebo were found to have no changes in their serum VEGF/sVEGFR2 levels over time. Patients treated with sunitinib had no significant change in their VEGF level, but the sVEGFR2 level significantly decreased after cycles 1 and 2 (P < .0001) and at the time of disease progression (P = .0002). A baseline VEGF level that was at or greater than the median was found to be correlated with a longer PFS. Sixteen patients who were receiving placebo received sunitinib at the time of disease progression, with the best responses being 1 partial response (6.3%), 6 cases of stable disease (37.5%), and 5 cases of progressive disease (31.3%); 4 patients were not evaluable for response. The median PFS was 3.7 months (range, 0.1 months‐22 months).CONCLUSIONSThe current multicenter study was limited by premature closure and a small sample size. Maintenance sunitinib did not appear to improve the 6‐month progression rate. Open‐label sunitinib was found to have only modest activity. The sVEGFR2 level decreased among patients receiving sunitinib. Cancer 2014;120:692–701. © 2013 American Cancer Society.

Although intelligibility deficits are common across various forms of dysarthria, it was hypothesized that the causes of intelligibility reductions depend on the ways the degraded signal challenges listener cognitive-perceptual strategies. This hypothesis was confirmed by analyzing the lexical boundary errors (LBE) elicited by 44 speakers with one of four forms of dysarthria (ataxic, hypokinetic, hyperkinetic, mixed spastic-flaccid). Error patterns from 60 listener transcripts revealed reliance on metrical stress to segment the 80 six-syllable phrases. However, reductions and disturbances in the acoustic cues to syllabic stress associated with each form of dysarthria resulted in different LBE patterns. Explanations for these unique patterns are found, in part, in the metrical structures of the dysarthric speech. For example, the temporal relationships among stressed and unstressed syllables varied widely in hyperkinetic speech, which ostensibly prevented listeners from optimally exploiting metrical stress as a cue for segmentation. The equal-even temporal structure of the spastic-flaccid speech resulted in the highest proportion of boundary insertions. The presence of interword pauses facilitated the assignment of word onset to strong syllables. Results will be presented relative to models of lexical segmentation and clinical implications for targets of remediation in the dysarthrias. [Work supported from NIH-NIDCD 5R01 DC6859.]

The detrimental effect of speaker variability on word recognition has been reported using a wide variety of tasks and stimuli. In this study, the use of dysarthric speech alongside unimpaired speech allowed us to examine the effect of indexical variability from a new perspective. We compared voice-specificity effects in words produced by healthy speakers and the same words produced by dysarthric patients suffering from Huntington’s disease (HD). The speech of persons with HD is particularly suited to this issue because of its idiosyncratic and variable manifestation. Reaction time and accuracy results provided confirmatory evidence for Luce et al.’s (2003) time-course hypothesis: The slower responses occasioned by processing dysarthric stimuli were accompanied with greater reliance on surface details of the stimuli. Thus, specificity effects can be seen as resulting from a coping strategy called upon when the system is presented with an input that is highly dissimilar from canonical lexical representations. In addition, we found some evidence that the time-course hypothesis holds even when intelligibility is controlled. This finding confirms that time, rather than processing effort, is the cause of specificity effects, with activation confined to abstract representations in an early stage and spreading to episodic traces later on.

Disturbances in speech rhythm are common in dysarthria, and deficit patterns vary among dysarthria subtypes. Attempts to quantify differences in disordered rhythm patterns have met with limited success. Here, we attempt to differentiate various forms of dysarthria using metrics designed to quantify linguistic rhythm on a stress-timed versus syllable-timed continuum. Speakers with hypokinetic, ataxic, hyperkinetic, or mixed flaccid-spastic dysarthria read sentences. Rhythm metrics were calculated for these utterances based on vocalic and consonantal interval durations. Differences among groups were discovered for %V (percentage of utterance duration comprised of vocalic intervals), VarcoV (rate-normalized standard deviation of vocalic interval durations), and nPVI-V (normalized pairwise variability index for vocalic intervals). Differences were independent of variable speaking rates among groups. All dysarthric groups produced rhythm patterns less stress-timed than the control American English speakers, with lower VarcoV and nPVI-V and higher %V. Those with flaccid-spastic dysarthria secondary to amyotrophic lateral sclerosis exhibited a syllable-timed pattern more extreme than even control Spanish speakers, indicating minimal differentiation of stressed and unstressed syllables. These results show that the various types of rhythmic disturbance accompanying dysarthria can be effectively described and distinguished within a stress-/syllable-timed continuum and relative to healthy speech.

Key PointsAmino acid substitution at peptide-binding residues of the HLA class I molecule is associated with graft-versus-host disease and mortality. Avoidance of donor-recipient combinations that result in amino acid substitution at peptide-binding residues may improve transplant outcomes.