Citations

Rationale Use of matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOFMS) to monitor serum and urine samples for endogenous monoclonal immunoglobulins. MALDI‐TOFMS is faster, fully automatable, and provides superior specificity compared to protein gel electrophoresis (PEL). Methods Samples were enriched for immunoglobulins in 5 min using Melon Gel™ followed by reduction with dithiothreitol for 15 min to separate immunoglobulin light chains and heavy chains. Samples were then desalted using C4 ZipTips, mixed with sinapinic acid matrix, and analyzed on a Bruker Biflex III MALDI‐TOF mass spectrometer. Results Monoclonal immunoglobulin light chains were identified in serum and urine samples from patients with a known monoclonal gammopathy using MALDI‐TOFMS with minimal sample preparation. Conclusions MALDI‐TOFMS can identify a monoclonal immunoglobulin in serum and urine samples. The molecular mass of the monoclonal immunoglobulin light chain is obtained providing unprecedented specificity compared to PEL. In addition, the methodology can be automated, making it a practical alternative to PEL. Copyright © 2015 John Wiley & Sons, Ltd.

Study Design Retrospective study. Objective Efficient use of operating room time is important, as delays during induction or recovery increase time not spent operating while in the operating room. We identified factors that increase anesthetized, nonoperative time by utilizing a database of over 5,000 consecutive neurosurgical spine cases. Methods Surgical records were searched to identify all spine surgeries performed between January 2010 and July 2012. Anesthetized, nonoperative time was calculated from the anesthesia record and compared with both patient and procedure characteristics to determine any significant relationships Results There were 5,515 surgical cases with a mean age of 60.5 and mean body mass index (BMI) of 29.7; 3,226 (58%) were male subjects. There were 1,176 (21%) fusion cases, and level of pathology was predominantly lumbar (4,010 cases, 73%). Fusion cases had a significantly longer total anesthetized, nonoperative time (fusion: 98 minutes, nonfusion: 76 minutes, mean difference: 22 minutes, p < 0.0001). Significant factors affecting anesthetized, nonoperative time in nonfusion cases include age greater than 65 years (mean difference 5 minutes, p < 0.0001), American Society of Anesthesiologists (ASA) grade, and BMI (BMI < 25: 72 ± 1.2 minutes, BMI 25 to 29: 74 ± 0.6 minutes, BMI 30 to 39: 79 ± 0.6 minutes, BMI 40 + : 87 ± 1.8 minutes, p < 0.0001). Similarly, for fusion operations, age > 65 years significantly increased nonoperative time (mean difference 6 minutes, p < 0.01), as did increasing ASA (mean difference 9 minutes, p < 0.0001) and increasing BMI. Conclusion Patient and surgical factors, including ASA grade, BMI, level of pathology, and surgical approach, have noticeable effects on anesthetized, nonoperative times in spine surgery.

We tested the hypothesis that markers of coagulation activation are greater during lower body negative pressure (LBNP) than those obtained during blood loss (BL). We assessed coagulation using both standard clinical tests and thrombelastography (TEG) in 12 men who performed a LBNP and BL protocol in a randomized order. LBNP consisted of 5-min stages at 0, −15, −30, and −45 mmHg of suction. BL included 5 min at baseline and following three stages of 333 ml of blood removal (up to 1,000 ml total). Arterial blood draws were performed at baseline and after the last stage of each protocol. We found that LBNP to −45 mmHg is a greater central hypovolemic stimulus versus BL; therefore, the coagulation markers were plotted against central venous pressure (CVP) to obtain stimulus-response relationships using the linear regression line slopes for both protocols. Paired t-tests were used to determine whether the slopes of these regression lines fell on similar trajectories for each protocol. Mean regression line slopes for coagulation markers versus CVP fell on similar trajectories during both protocols, except for TEG α° angle (−0.42 ± 0.96 during LBNP vs. −2.41 ± 1.13°/mmHg during BL; P < 0.05). During both LBNP and BL, coagulation was accelerated as evidenced by shortened R-times (LBNP, 9.9 ± 2.4 to 6.2 ± 1.1; BL, 8.7 ± 1.3 to 6.4 ± 0.4 min; both P < 0.05). Our results indicate that LBNP models the general changes in coagulation markers observed during BL.

Abstract Background Renal imaging examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) patients. TKV has become the gold-standard image biomarker for ADPKD progression at early stages of the disease and is used in clinical trials to characterize treatment efficacy. Automated methods to segment the kidneys and measure TKV are desirable because of the long time requirement for manual approaches such as stereology or planimetry tracings. However, ADPKD kidney segmentation is complicated by a number of factors, including irregular kidney shapes and variable tissue signal at the kidney borders. Methods We describe an image processing approach that overcomes these problems by using a baseline segmentation initialization to provide automatic segmentation of follow-up scans obtained years apart. We validated our approach using 20 patients with complete baseline and follow-up T1-weighted magnetic resonance images. Both manual tracing and stereology were used to calculate TKV, with two observers performing manual tracings and one observer performing repeat tracings. Linear correlation and Bland–Altman analysis were performed to compare the different approaches. Results Our automated approach measured TKV at a level of accuracy (mean difference ± standard error = 0.99 ± 0.79%) on par with both intraobserver (0.77 ± 0.46%) and interobserver variability (1.34 ± 0.70%) of manual tracings. All approaches had excellent agreement and compared favorably with ground-truth manual tracing with interobserver, stereological and automated approaches having 95% confidence intervals ∼±100 mL. Conclusions Our method enables fast, cost-effective and reproducible quantification of ADPKD progression that will facilitate and lower the costs of clinical trials in ADPKD and other disorders requiring accurate, longitudinal kidney quantification. In addition, it will hasten the routine use of TKV as a prognostic biomarker in ADPKD.

BackgroundRecently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi‐incident Mennonite family.MethodsIn the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD).ResultsOur sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed.ConclusionOur results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

Abstract Background. Non-steroidal anti-inflammatory drugs (NSAIDs) and statin drugs have been suggested as protective agents against the development of non-Hodgkin lymphoma (NHL), but data are limited, particularly for NHL subtypes. Further, some in vitro, animal and epidemiologic data suggest there may be a synergistic effect of these two agents in cancer prevention, but there has been no test of this hypothesis in NHL. Methods. We evaluated the use of NSAIDs and statins in a clinic-based study of 1683 newly diagnosed cases and 2168 frequency matched controls enrolled from 2002-2012. Regular use (at least once/week for at least one year) of low dose (baby) aspirin, standard or extra strength aspirin, ibuprofen, other NSAIDs (e.g., naproxen, etc), COX-2 inhibitors, as well as statins or other cholesterol lowering drugs, was ascertained using a self-administered questionnaire. Frequency, amount and duration of use were also collected. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, education, body mass index, smoking history, alcohol use, and history of rheumatoid arthritis and osteoarthritis. Pathologic classification of NHL subtypes was centrally reviewed, and subtype-specific NHL risks were estimated using polychotomous logistic regression for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, N = 495), diffuse large B-cell (DLBCL, N = 326), follicular (FL, N = 410) and marginal zone (MZL, N = 134) lymphomas. Results. The mean age of cases was 61.8 years and 59% were men, while the mean age of controls was 61.6 years and 53% were men. We observed an inverse association of low dose aspirin use with risk of NHL (OR = 0.82; 95% CI 0.70-0.96), with stronger associations for more pills per day, longer duration of use and greater number of pill-years. In contrast, we observed no evidence of an association with NHL risk with use of regular or extra-strength aspirin, ibuprofen, other NSAIDs, or COX-2 inhibitors, nor use of statins or other cholesterol-lowering drugs. When we modeled the joint use of low dose aspirin and statins, the strongest inverse association was observed for low dose aspirin use only, followed by use of both aspirin and statins; there was no association with statin use only and no evidence for any interaction of low dose aspirin and statins on NHL risk. For low dose aspirin, the strongest inverse trends were observed for DLBCL, followed by FL and MZL, while there were no consistent associations for CLL/SLL. Conclusions. We found a strong inverse association of low dose aspirin use with risk of NHL and the subtypes of DLBCL, FL, and MZL, but no association for regular/extra strength aspirin, other NSAIDs or statin use. While confirmation is needed, our findings for low dose aspirin but not use of other NSAIDs suggest that anti-platelet or other effects of low dose aspirin may be of etiologic significance in lymphomagenesis. Citation Format: James R. Cerhan, Megan M. O'Bryne, Grzegorz S. Nowakowski, Timothy G. Call, Carrie A. Thompson, Tait D. Shanafelt, William R. Macon, Neil E. Kay, Thomas M. Habermann, Susan L. Slager, Mark Liebow. Aspirin and other nonsteroidal anti-inflammatory drugs, statins, and risk of non-Hodgkin lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 877. doi:10.1158/1538-7445.AM2015-877

Abstract Introduction: The use of multi-drug regimens, including taxanes (T), has increased survival for breast cancer patients. However, T-induced neuropathy, one of the most common side effects, cannot be predicted, prevented or effectively treated. Using genome wide analyses (GWA), we sought to identify common genetic variants that infer susceptibility to clinical and self-reported neuropathy. Methods: Women with high risk breast cancer were enrolled in SWOG 0221, a trial of dosing schedules for AC and T. Genotyping was performed using the Illumina 1M chip and SNPs examined in relation to CTCAE grade 3 and 4 neurotoxicity and self-reported symptoms (FACT-TAXANE) among women providing blood samples. Significant associations were tested for replication in CALGB40101. Results: Among 1269 European Americans (EA) and 139 African Americans (AA) in S0221, there were 147 and 31 grade 3+ neuropathies, respectively. In CALGB40101, grade 3 toxicity was less frequent (59/855 EA and 15/117 AA). In S0221 EA patients, loci on chromosomes 7, 10, 16 and 17 showed associations with grades 3 and 4 neuropathy at p&lt;5×10e-06, with the most significant genetic association on chromosome 17, rs910920, p = 6.8×10e-08, odds ratio (OR) = 0.44 (95% confidence interval (CI), 0.32-0.61); this SNP is a cis eQTL, thought likely to affect transcription factor binding and linked to expression of VPS53 in lymphoblastoid cell lines. While the rs910920 association was specific to EA, the A allele in rs1858826 on chromosome 7 was associated with reduced odds of neuropathy in both EA (p = 7×10e-07) and AA (p = .02) groups. The S0221 associations at p&lt;5×10e-06 did not replicate in CALGB40101. A subset of patients (n = 677 EA and n = 42 AA) completed the FACT-TAXANE. The most significant associations with this neuropathy phenotype (p&lt;5×10e-07) were on chromosomes 2 (rs4267555 and rs4443044) and 3 (rs2421468). Of the 168 SNPs tested for association with neuropathy in previous studies, rs1695 in GSTP1 (p = 0.0009) and rs228591 in ATM (p = 0.0006), showed some evidence of association with FACT-TAXANE scores; the latter SNP was significant at p = .005 in ordinal regression analysis of neuropathy grades 0-4 in CALGB40101. None of these SNPs were significantly associated with grade 3 CTCAE neuropathy at p&lt;.05, nor were the top CTCAE associations in relation to FACT-TAXANE scores. Replication of the most significant S0221 FACT-TAXANE findings in CALGB40101 is ongoing. Conclusions: Failure to replicate S0221 in CALGB40101, and the lack of coherence between self-report and clinical grade in S0221 could be attributable to differences in trial designs as well as differences in defining a complex phenotype. Larger homogeneous trials with similar dosing and criteria for defining neuropathy are needed to assess the relationship of genetics and the neuropathy symptom spectrum. Citation Format: Lara Sucheston-Campbell, Alyssa Clay, William E. Barlow, G Thomas Budd, Dan Stram, Chris Haiman, Li Yan, Gary Zirpoli, Song Yao, Dawn Hershman, Kathy S. Albain, Daniel F. Hayes, Halle Moore, Timothy J. Hobday, James A. Stewart, Claudine Isaacs, Muhammad Salim, Julie R. Gralow, Gabriel N. Hortobagyi, Robert B. Livingston, Xin Sheng, Deanna L. Kroetz, Christine B. Ambrosone. A genome-wide association study identifies novel loci associated with taxane-related sensory neuropathy in breast cancer patients enrolled in a cooperative group clinical trial (SWOG S0221). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5489. doi:10.1158/1538-7445.AM2015-5489