Citations

ABSTRACTIntravenous immunoglobulin [IVIg], plasma exchange [PE], and corticosteroids are efficacious treatment in chronic inflammatory demyelinating polyneuropathy [CIDP]. IVIg is effective in multifocal motor neuropathy [MMN]. NIS, NIS‐weakness, sum scores of raw amplitudes of motor fiber (CMAPs) amplitudes, and Dyck/Rankin score provided reliable measures to detect and scale abnormality and reflect change; they are therefore ideal for office management of response‐based immunotherapy (R‐IRx) of CIDP. Using efficacious R‐IRx, a large early and late therapeutic response (≥ one‐fourth were in remission or had recovered) was demonstrated in CIDP. In MMN only an early improvement with late non‐significant worsening was observed. The difference in immunotherapy response supports a fundamental difference between CIDP (immune attack on Schwann cells and myelin) and MMN (attack on nodes of Ranvier and axons). Muscle Nerve 52: 488–497, 2015

Abstract Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48Cre/+, KrasG12D/+, p53F/+ mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors. Cancer Res; 75(14); 2907–15. ©2015 AACR.

Context Additional reviews of diagnostic surgical and cytology cases have been shown to detect diagnostic discrepancies. Objective To develop, through a systematic review of the literature, recommendations for the review of pathology cases to detect or prevent interpretive diagnostic errors. Design The College of American Pathologists Pathology and Laboratory Quality Center in association with the Association of Directors of Anatomic and Surgical Pathology convened an expert panel to develop an evidence-based guideline to help define the role of case reviews in surgical pathology and cytology. A literature search was conducted to gather data on the review of cases in surgical pathology and cytology. Results The panel drafted 5 recommendations, with strong agreement from open comment period participants ranging from 87% to 93%. The recommendations are: (1) anatomic pathologists should develop procedures for the review of selected pathology cases to detect disagreements and potential interpretive errors; (2) anatomic pathologists should perform case reviews in a timely manner to avoid having a negative impact on patient care; (3) anatomic pathologists should have documented case review procedures that are relevant to their practice setting; (4) anatomic pathologists should continuously monitor and document the results of case reviews; and (5) if pathology case reviews show poor agreement within a defined case type, anatomic pathologists should take steps to improve agreement. Conclusions Evidence exists that case reviews detect errors; therefore, the expert panel recommends that anatomic pathologists develop procedures for the review of pathology cases to detect disagreements and potential interpretive errors, in order to improve the quality of patient care.

Background: Peripheral nerve blocks (PNBs) have the potential to reduce postoperative pain. The use of ultrasound (US) to guide PNBs may be more beneficial than nerve stimulation (NS); however, very few studies have studied this technique in children. The objective of this study was to compare postoperative pain control in pediatric patients who had general anesthesia (GA) alone compared with those who had PNB performed by NS, or PNB with both NS and US guidance. Our hypothesis was that compared with NS, the US-guided PNB would result in reduced postoperative pain and opioid use, and that both PNB conditions would have improved outcomes compared with GA. Methods: A retrospective chart review of foot and ankle surgery included 103 patients who were stratified into 3 groups: GA, PNB with NS, and PNB with NS and US. Pain levels were measured with visual pain scales at 2, 4, 6, 8, 12, and 24 hours postoperatively. Days of hospitalization, morphine and oxycodone use by weight, and time to first PRN opioid use were also recorded. A repeated measure analysis of variance was used to compare the groups, and the proportion of patients who reported a visual analog scale score of 0 was calculated for each time point. Results: There were no significant differences in pain levels between groups for the first 12 hours, but the US group had higher pain levels at 24 hours. Both US and NS groups had a longer time to PRN opioid use and used significantly less morphine compared with GA. The US group had a significantly greater proportion of pain-free patients than the other 2 groups for the first 6 hours. Conclusions: The use of US guidance is beneficial in postoperative pain control. Both US-guided and NS-guided PNB are preferable to GA alone for lower extremity orthopaedic surgery in the pediatric population. Level of Evidence: III, retrospective comparative study.

Abstract Purpose: Mammographic breast density is an established and strong risk factor for breast cancer. Recently, a number of common genetic susceptibility loci have been identified as risk factors for breast cancer. We present the first report on the relative contribution of 76 validated breast cancer susceptibility loci, in the context of a polygenic risk score (PRS), to the breast density and breast cancer association. We also examine whether the PRS improves prediction of the Breast Cancer Surveillance Consortium (BCSC) 5-year risk model above and beyond breast density and clinical factors included in the model. Methods: The study population included 1643 cases and 2397 controls from three independent epidemiologic studies: the Mayo Mammography Health Study (MMHS), the Mayo Clinic Breast Cancer Study (MCBCS), and the Bavarian Breast Cancer Cases and Control Study (BBCC). Data collected on patients in each of the studies included clinical risk factor, BI-RADS breast density [a) almost entirely fat; b) scattered fibroglandular densities; c) heterogeneously dense; and d) extremely dense] and genotypes for the 76 breast cancer susceptibility loci known at the time of the study. We formed a PRS from the reported per-SNP odds ratios (OR) for 76 known breast cancer susceptibility loci, and evaluated whether BI-RADS density and the PRS were independent risk factors for breast cancer, when adjusted for age, 1/BMI and study. We also incorporated the PRS (OR) into the BCSC 5-year risk model and estimated 5-year risk for the MMHS nested case-control study of 339 invasive cases, 765 controls. Results: BI-RADS density (p<0.0001) and PRS (p<0.0001) were independent risk factors for breast cancer that together showed greater discrimination of risk (AUC=0.69) than density (AUC=0.66; ΔAUC=0.029) or PRS score alone (AUC=0.68; ΔAUC=0.013; p<0.001). Relative to those with scattered fibroglandular densities and average (2nd quartile) PRS, women with extremely dense breasts and in the highest PRS quartile, had a 2.7 fold (95%CI: 1.7-4.1) increased risk of breast cancer, while those with fatty breasts and in the lowest PRS quartile had a reduced risk (OR=0.30, 95%CI: 0.18-0.51). Incorporation of the PRS into the BCSC risk model improved discrimination (ΔAUC=0.031, p=0.001), for a net reclassification improvement of 20% (95%CI: 11%-28%), split equally among cases (9%) and controls (11%). Conclusion: BI-RADS density and the PRS are both important risk factors for breast cancer that can be included in breast cancer risk models to improve prediction of this disease. Using these models to identify high and low-risk risk groups will facilitate improved tailored screening and primary prevention interventions. Citation Format: Celine M. Vachon, V. Shane Pankratz, Christopher G. Scott, Lothar Haeberle, Elad Ziv, Matthew R. Jensen, Kathleen R. Brandt, Dana H. Whaley, Janet E. Olson, Katharina Heusinger, Carolin C. Hack, Sebastian M. Jud, Matthias W. Beckmann, Jeffrey A. Tice, Kristen S. Purrington, Thomas A. Sellers, Karla Kerlikowske, Peter A. Fasching, Fergus J. Couch. The contribution of common breast cancer susceptibility loci to the breast density and breast cancer association and the Breast Cancer Surveillance Consortium (BCSC) risk model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 940. doi:10.1158/1538-7445.AM2014-940

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of human cancer, due in large part to a high incidence of metastasis and resistance to conventional chemotherapies. As such, new therapies are needed to halt the metastatic process. The proto-oncogene Vav1 is ectopically expressed in over half of human pancreatic cancers, and its expression correlates with a poor prognosis in humans and promotes survival and transformation in isolated tumor cells. We have found that Vav1, through its GEF activity towards Rac1, also potently induces migration by pancreatic tumor cells. In addition, Vav1 also signals through Cdc42 to drive the formation of invadopodia and matrix degradation, which also promotes tumor cell invasion. Importantly, the activation of Vav1 circumvents the requirement for active Src in this process. Because Vav1 is ectopically expressed in pancreatic cancers and is a potent regulator of tumor cell survival, proliferation, and invasive migration, it could provide a specific therapeutic target for these tumors. Recently, the anti-inflammatory agent azathioprine was described as an inhibitor of Vav1/Rac1 activity in hematopoietic cells. Therefore, we hypothesized that azathioprine could also inhibit the Vav1-driven processes of proliferation and invasion in pancreatic tumor cells. Indeed, we have determined that azathioprine treatment of cultured human PDAC cells reduces viability and proliferation. Further, similar to siRNA-mediated depletion of Vav1, azathioprine treatment reduces cell migration, as well as the matrix degradation required for invasion. Vav1-expressing tumor cells were more sensitive to azathioprine than Vav1-negative cells, supporting the premise that the inhibitory effects of azathioprine are mediated through Vav1. Finally, azathioprine also reduces metastasis in a xenograft model of pancreatic cancer. Taken together, these data uncover a role for aberrantly expressed Vav1 in regulation of the cytoskeletal machinery required for migration and invasion, and in the promotion and metastasis of pancreatic cancer. Even with the expression of multiple Rho family GEFs, tumor cells that upregulate Vav1 have become dependent upon this exchange factor, implicating Vav1 as a potent node for therapeutic intervention. Supported by R01 CA104125 and R03 CA155778 to M.A.M. Citation Format: Gina L. Razidlo, Christopher Magnine, Arthur C. Sletten, Rachel M. Hurley, Mark A. McNiven. Attenuation of pancreatic cancer cell migration and invasion through a targeted inhibition of the Rac GEF Vav1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4026. doi:10.1158/1538-7445.AM2014-4026

Abstract Background. We recently identified an in-frame ESR1 translocation in a tumor and PDX pair from a patient with endocrine therapy resistant advanced disease. The fusion gene preserved the N-terminal 365aa of ESR1 containing the intact activation function 1 (AF1), DNA-binding domain (DBD) and hinge, followed by the C-terminal transactivation domain of YAP1. The ESR1-365>YAP1 fusion drove estrogen-independent and anti-estrogen-resistant tumor cell growth (Cell Reports 4:1116, 2013). We therefore sought to further investigate the role of ESR1 fusion genes in breast cancer. Methods. 711 cases from TCGA, 82 ER+ cases from neoadjuvant endocrine therapy trials and 25 ER+ systemic relapse samples were screened for fusion genes using RNAseq. Fusion genes involving ESR1 were subsequently assayed for estrogen response element (ERE)-mediated transcriptional activity and ability to drive estradiol independent breast cancer cell growth. Results. Multiple ESR1 fusions were identified in mostly luminal B cancers. ESR1 fusions resulted most frequently from rearrangements involving another gene on Chromosome (Chr) 6 but also fusions with genes on other chromosomes. The fusions involving partners on Chr6 that retained an intact N terminal AF1 and DNA binding domain (DBD) of ESR1 (≥1-253aa) included an Out-of-Frame (OF) fusion event with CCDC170 (a gene immediately centromeric to ESR1), POLH (in-frame or IF), AKAP12 (IF), PCMT1 (OF), SYNE1 (OF) and GPR126 (OF). Also identified were inter-chromosomal translocations involving Chr12p-NOP2 (IF) and ChrX-PCDH11X (IF) and Chr7q-AKR1D1 (OF). The ESR1 fusions with transcriptional potential (because of a retained DNA binding domain) included variable 5’ ESR1 exons that preserved 253aa, 365aa, 412aa or 458aa of ESR1 sequence: in all cases disrupting ligand binding though loss of C terminal sequence. The effect of the IF and OF 3’ sequences on the transcriptional activity of the relevant ESR1 fragment was highly variable. The most transcriptionally active fusion (more active than the relevant ESR1 fragment alone) was the ESR1-365>YAP1 as well as ESR1-365>PCDH11X and ESR1-253>CCDC170. This is remarkable since PCDH11X is not considered a transcription factor and the CCDC170 sequence was OF – in both cases suggesting the activity of the fusion was due to "neomorphic" properties. Two fusions, NOP2 and POLH were inactive in the ERE reporter assay, yet both stimulated estradiol independent growth. In these cases we suggest that the ESR1 locus can function as a "promoter trap" which allows the identification of genes with previously unknown functions in endocrine therapy resistance. Conclusions: In luminal-type breast cancer the ESR1 gene was fused to multiple 3’ partners with remarkably heterogeneous functions. The two most transcriptionally active, ESR1-365>YAP1 and ESR1-365>PCDH11X, were both identified in endocrine therapy refractory advanced disease – suggesting a role in fatal disease progression. Citation Format: Jieya Shao, Jin Zhang, Robert J Crowder, Rodrigo Goncalves, Chanpheng Phommaly, Breast AWG and Network, Charles M Perou, Christopher A Maher, E Aubrey Thompson, Matthew J Ellis. ESR1 gene fusions implicated in endocrine therapy resistance of ER+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD6-4.