Citations

Background OnabotulinumtoxinA has been demonstrated to be effective for the preventive treatment of headache in individuals with chronic migraine and has been approved and recommended for this patient population. While the therapeutic effect of onabotulinumtoxinA on migraine headache is well documented, there is limited information on the effect of onabotulinumtoxinA on migraine aura. Objective Given the prolonged and often debilitating nature of aura in patients with hemiplegic migraine, our group sought to examine the effect of onabotulinumtoxinA on aura frequency and severity in this specific subset of migraine patients. Methods All clinical notes from July 1, 1994 to December 1, 2017 at our institution were retrospectively reviewed to identify patients diagnosed with hemiplegic migraine who received at least one set of onabotulinumtoxinA injections. Thirty‐four patients were identified; and of those, 23 were excluded due to incomplete documentation regarding aura symptoms at follow‐up visits. The clinical notes of the remaining 11 patients (4 with familial hemiplegic migraine [FHM] and 7 with sporadic hemiplegic migraine [SHM]) were reviewed, and the frequency and description of their headaches and aura before and after receiving onabotulinumtoxinA were recorded. Results Nine of the 11 patients in our series noted a decrease in the frequency, severity, and/or duration of their aura after receiving onabotulinumtoxinA. Of the 2 non‐responders, one was FHM and one was SHM. Of the 9 that noticed improved aura symptoms, 6 described a “wearing off” effect of onabotulinumtoxinA around week 9 or 10 of the 12‐week cycle, with subsequent improvement after the next round. Conclusion For 9 of 11 patients with hemiplegic migraine, onabotulinumtoxinA was helpful not only in reducing the frequency and severity of headaches but also in reducing the frequency and severity of the aura. In this manuscript, we speculate on potential pathophysiologic mechanisms that could have contributed to this effect.

Premise Migraine can present with a wide range of neurological symptoms. Problem Based on currently available data, the symptoms of typical migraine aura are most likely related to cortical spreading depression (CSD), and evidence supports that CSD can lead to trigeminovascular activation resulting in the headache phase of migraine. Potential Solution An alternative diagnosis to migraine aura should be considered if migrainous headaches present with transient neurological symptoms that have features inconsistent with aura.

Abstract Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

Objective Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs. Design Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats. Results Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17β-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis. Conclusions PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool.

Objective To report a retrospective analysis of patients with migraine headaches treated with rimabotulinumtoxin B as preventive treatment, investigating an association between clinical responsiveness with migraine directionality and migrainous aura. Background The P hase III R esearch E valuating M igraine P rophylaxis T herapy studies demonstrated onabotulinumtoxin A is effective in the preventive management of chronic migraine headaches. J akubowski et al reported greater response to onabotulinumtoxin A in migraine patients reporting inward‐directed head pain (imploding or ocular) compared with outward‐directed head pain (exploding), suggesting subpopulations of patients may be better candidates for its use. No correlation was found between those reporting migrainous aura and onabotulinumtoxin A responsiveness. Methods One hundred twenty‐eight migraine patients were identified who had received rimabotulinumtoxin B injections over an average of 22 months, or 7 injection cycles. Migraine directionality was reported as inward directed (imploding, n = 72), eye centered (ocular, n = 28), outward directed (exploding, n = 16), and mixed (n = 12). Results One hundred two out of one hundred twenty‐eight patients (80%) improved; of these, 58 (57%) demonstrated a >75% reduction in monthly headache frequency (“>75%‐responders”), 76% of which noted sustained benefits >12 months with repeated injections every 10‐12 weeks. Those reporting ocular‐ and imploding‐directed headaches were significantly more likely to be >75%‐responders, compared with exploding‐ and mixed‐directed headaches ( P < .0025). Patients with ocular‐directed headaches were most likely to be sustained >75%‐responders. Patients reporting migrainous aura were more likely to be >75%‐responders ( P = .0007). Those reporting exploding‐ and mixed‐directed headaches were more likely to be nonresponders ( P < .0001). Conclusions Reported migraine directionality and presence of migrainous aura predict migraine headache responsiveness to rimabotulinumtoxin B injections.

Abstract Background: Preliminary results from the Success and Remagus trials showed that CTC detection by CellSearch® has adverse prognostic value in non-metastatic breast cancer. Moreover, several investigators have characterized HER2 expression on CTCs in early breast cancer. Since the majority of CTC-positive women with non-metastatic breast cancer have only 1 CTC detected / blood volume analyzed, we wanted to evaluate the inter-reader variability in this setting. This is a crucial step before moving forward with multi-lab/multi-center prospective testing of the clinical utility of the CellSearch® technology in non-metastatic breast cancer. Methods: Five galleries of CellSearch® images from 3 European and one US institution (a total of 307 images) were mailed to 22 independent readers from 14 European and US academic laboratories and 8 readers from two CellSearch® Veridex laboratories in a blinded fashion. These images came mainly from studies on CTC and/or HER2−positive CTC detection in breast cancer and included healthy women (negative controls), women with metastatic (positive controls) and non-metastatic disease (Pierga et al SABCS 2010, Pierga et al ASCO 2011, Riedthorf et al CCR 2010, Ignatiadis et al PLoS ONE 2011). Each reader reported the images as either CTC-negative or CTC-positive/HER2−negative or CTC-positive/HER2−positive. Kappa statistics were used to assess inter-reader agreement. The 8 Veridex readers were summarized by a majority voting system to derive a gold standard in order to compare each independent reader using discordance rates. Results: Kappa statistics showed moderate to good agreement between independent readers depending on the gallery evaluated (gallery 1 K: 0.55, gallery 2 K:0.57 gallery 3 K:0.64, gallery 4 K:0.72, gallery 5 K:0.85). These differences were attributed to differences in scoring difficulty of each gallery. Discordances in CTC-positive vs CTC-negative events between each reader and the gold standard ranged from 2.3%-31.3% with 7 readers showing discordance rates &lt;5%, 11 readers between 5–10%, 10 readers between 10–14% and only 2 readers showing discordance rates &gt;14% as compared to the gold standard (median discordance rate: 9.3%). Image analysis showed that investigators with high discordance rates compared to the Veridex gold standard were not always taking into account “morphological characteristics” for defining an event as CTC-positive. Discordant results between readers were mainly due to discordance in CTC definition and to a lesser extent in the definition of HER2−positivity. Indeed, discordances in assigning a CTC-positive event as either HER2−negative or HER2−positive ranged from 0.3−13.7% with 19 readers showing discordance rates &lt;5%, 7 readers between 5–10% and 4 readers with discordance rates &gt;10% (median discordance rate: 3.9%). Conclusion: In non-metastatic breast cancer, we observed low discordance between most independent readers and the gold standard for defining a CellSearch® event as CTC with very few readers showing high discordance rates. Concordance can be improved through appropriate training and the use of all the tools provided by the CellSearch® system for image interpretation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-07-14.