Citations

Introduction: Menorrhagia is a common health problem affecting ∼5-10% of women. The optimal management of menorrhagia among women with abnormal laboratory hemostasis is uncertain. The goal of this study was to determine the effect of intranasal desmopressin (IN-DDAVP) vs. oral tranexamic acid (TA) on menstrual blood loss (MBL) and quality of life (QOL). Methods: In a cross-over study design, 117 consenting women 18–50 years of age with menorrhagia (defined as subjective report of heavy bleeding and a pictorial blood assessment chart [PBAC] score > 100) with a negative gynecological evaluation and abnormal laboratory hemostasis (62% platelet dysfunction, 15% von Willebrand disease, 23% other coagulation defect or combined) were randomly assigned to initial IN-DDAVP or TA therapy each for two menstrual cycles, followed by cross-over to the second study drug for an additional two cycles. MBL by PBAC was measured at baseline and after each menstrual cycle while QOL was assessed by four validated instruments: Health Related Quality of Life (HRQOL), SF-36®, Center for Epidemiologic Studies Depression Scale (CES-D) and the Ruta menorrhagia questionnaire. Results: There was a statistically significant decrease in the PBAC for both treatments. On average, the estimated decrease in the PBAC from baseline for IN-DDAVP was −66.0 (CI = (−89.5, −42.6)) and for TA, −107.8 (CI = (−131.5, −84.1)). The decrease in the PBAC score was larger for TA with a difference of 41.8 (p-value = 0.0002, CI = (20.4, 63.2)) between the two treatments. In the multivariable analysis, the test for treatment-cycle number interaction was not significant, suggesting no carry-over effect. The test for a treatment type effect was significant (p<0.0001) suggesting a greater reduction in PBAC score with TA compared to IN-DDAVP. Both IN-DDAVP and TA generally improved QOL as assessed by each of the four instruments. Over-all, the Ruta Menorrhagia Questionnaire and the Center for Epidemiologic Studies Depression Scale measurements showed the most statistically significant improvements. Conclusion: Both TA and IN-DDDAVP reduce MBL and improve QOL in females with menorrhagia and abnormal laboratory hemostasis.The significance of these findings are underscored by the fact that prior studies of menorrhagia treatment in these patients have not included validated QOL instruments. The marked improvement in MBL and QOL noted with TA and IN-DDAVP appears to justify hemostasis screening in women presenting with menorrhagia for whom no gynecological cause can be found.

Abstract Background: Immunoglobulin light chain (AL) amyloidosis is a fatal complication of B-cell clonal proliferation. Currently, the best biomarker for treatment monitoring is serum free light chain (FLC) assay. Despite its higher sensitivity, it cannot distinguish clonality thus ultralow levels of monoclonal gammopathy can be missed. Urinary exosomes (UExs) are the smallest members of the extracellular vesicle family that are excreted in the urine. They exhibit different characteristics in patients with AL amyloidosis vs multiple myeloma. This study was undertaken to determine if urinary exosomes have different characteristics in patients AL amyloidosis who progress despite being in complete response (CR) vs those who have a renal response. Methods: UEx were extracted from 4 patients at different stages of AL (Table 1). Immunoglobin light chains (LC) were identified in the UEx using western blotting. Intact immunoglobulin light chains were identified in plasma, UEx, and kidney biopsy amyloid deposits using mass spectrometry (MS). cDNAs from bone marrow plasma cells (BMPC) collected at the time of diagnosis from patient 4 were sequened. Results: Oligomeric LC (250 kd) were identified in the UEx of patient 1 (newly diagnosed, Fig 1a) and 4 (renal progression in CR, Fig 1d) but only monomeric LC (25 kd) were detected in patient 2 (Fig 1b) and 3 (CR and renal response, Fig 1c). MS of the UEx and plasma of patient 4 detected 2 monoclonal λ LC. The mass of one of the LC was consistent with a lambda 6a LC which is also the most common cDNA (IGLV-6-57) found in the BMPC. Amino acid sequences derived from the tryptic digestion of the amyloid deposits matched the predicted sequence of the cDNA. The calculated weight of the peptide produced by the cDNA (23,304 Da ) was within margin of error of the mass of the lambda 6a LC (23,306 Da). The mass of the second LC (23,092 Da) was consistent with a λ4/λ5 LCs. A search of the amino acid and cDNA sequences failed to identify any similarity. The density ratio of the oligomeric LC to monomeric LC in the UEx was 0.47 which was similar to the intensity ratio by MS of the lambda 6a LC (23,306 Da) to the 23,092 Da LC in the blood (0.43). Discussion: Urinary EXs identified oligomeric LC in a patient with progressive renal disease despite achieving a CR. The mass one of the λ LC matched the predicted peptide product of the cDNA obtained from BMPC. The amino acid sequence predicted by the cDNA matched the trypsin digested sequences from the amyloid deposits. This strongly suggests the oligomeric LC represents the amyloidogenic λ6a LC detected in the blood which was being produced by the BMPC clone which is being deposited as amyloid in the kidney. The origin of the second λ LC is unknown but is likely a new monoclonal gammopathy of undetermined significance that developed after the initial bone marrow biopsy. The blood and urine samples were obtained 3 years after the BMPC. The development of a new monoclonal gammopathy in patients with plasma cell dyscrasia is not uncommon. Unfortunately, bone marrow biopsy collected at the time of the urine and blood sample had insufficient number of plasma cells (CR) for analysis. Conclusion: UEx can identify amyloidogenic LC even when current standard methods could not. The persistent presence of the amyloidogenic LC helps explain why patients can progress despite being in CR. The presence of a second λ LC which was not part of the amyloid deposit also has clinical implication. It may explain why some patients do well despite having a persistent monoclonal protein. If these results are confirmed, UEx may have a powerful role in the determination of organ and hematologic response in patients with AL amyloidosis. Disclosures Dispenzieri: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Celgene: Research Funding.

INTRODUCTION: Functional Dyspepsia (FD) is a common functional GI disorder in the upper abdomen (above the navel). The estimated prevalence is 15-30% worldwide. There are currently no FDA-approved medications for the treatment of FD. Proton pump inhibitors (PPIs) are commonly prescribed off-label. However, long-term use of these drugs has been associated with serious health concerns. Prokinetic agents are also often used off-label. However, many are associated with significant side effects (e.g. metoclopramide). A safe, effective, and readily available treatment option for FD is greatly needed. This study describes an important 24-month post-marketing point on an option for FD that has already demonstrated good efficacy and low side effects in RCTs. These RCTs have demonstrated that the combination of caraway oil and peppermint oil improves FD symptoms. Caraway oil plus L-menthol (the major component of peppermint oil) with site-specific targeting (COLM-SST) is a novel delivery system of triple-coated, solid-state microspheres designed to target the duodenum, the main center of disturbance in FD. This study was conducted to report on the overall safety profile of COLM-SST and to determine if any unexpected pattern of side effects emerged. METHODS: A call-in number for reporting adverse events (AEs) was provided on all boxes containing COLM-SST. An independent call center with pharmacovigilance-trained health care personnel, in accordance with the FDA and global regulatory guidelines on properly reporting AEs, was retained to receive and record customer AEs. The AEs for this study were collected and processed from July 8, 2016 to July 8, 2018. RESULTS: An estimated 558,345 individual patients used COLM-SST during the surveillance. An analysis of the data showed that there were no serious AEs reported. Additionally, the self-reporting rate of non-serious AEs was low, with only 148 events received (from 127 patients), a 0.023% event rate for COLM-SST. The top reported, non-serious AEs were abdominal pain/discomfort/distension (18; 0.0032%), which were consistent with the pattern of commonly reported symptoms of FD, and headache (7; 0.0013%). CONCLUSION: 24 months of monitoring in-market, real-world use of caraway oil and L-menthol with site-specific targeting, for the treatment of FD demonstrates an extremely low rate of self-reported AEs. These data, combined with earlier RCT data, indicates that COLM-SST is a safe and effective therapy for FD, and is a viable alternative to PPIs and prokinetics.

AimsThe aims of this study were to review our 5‐year experience with clinical FISH testing for TP63 rearrangements using both TP63 break‐apart (BAP) and TBL1XR1/TP63 dual‐fusion (D‐FISH) probes to evaluate the frequency of TP63 rearrangements and the distribution of TBL1XR1 vs. alternate partner loci, and to assess whether both probe sets are necessary in all cases undergoing FISH testing.Methods and resultsA retrospective review of the Mayo Clinic cytogenetic database identified 470 patients evaluated by FISH testing for TP63 rearrangements in formalin‐fixed paraffin‐embedded (FFPE) tissue using both BAP and D‐FISH probes. Of these, 25 (5.3%) had TP63 rearrangements. All samples were being investigated for anaplastic large‐cell lymphoma or other T cell lymphoma subtypes. A TBL1XR1 partner was identified by D‐FISH in 12 (48%) of 25 cases. All cases positive by TBL1XR1/TP63 D‐FISH were also positive by TP63 BAP FISH.ConclusionThis is the largest series of TP63 rearrangements to date. The frequency of positive results among cases referred to a large reference laboratory for TP63 FISH testing was 5.3%. Approximately half of TP63 rearrangements have a TBL1XR1 partner. TP63 BAP FISH testing is sufficient for up‐front testing of FFPE tissue samples. However, because of the genomic proximity of the TP63 and TBL1XR1 loci, we recommend reflex TBL1XR1/TP63 D‐FISH testing in positive and equivocal cases.

Abstract Aims Pathogenic gain-of-function variants in CACAN1C cause type-8 long QT syndrome (LQT8). We sought to describe the electrocardiographic features in LQT8 and utilize molecular modelling to gain mechanistic insights into its genetic culprits. Methods and results Rare variants in CACNA1C were identified from genetic testing laboratories. Treating physicians provided clinical information. Variant pathogenicity was independently assessed according to recent guidelines. Pathogenic (P) and likely pathogenic (LP) variants were mapped onto a 3D modelled structure of the Cav1.2 protein. Nine P/LP variants, identified in 23 patients from 19 families with non-syndromic LQTS were identified. Six variants, found in 79% of families, clustered to a 4-residue section in the cytosolic II–III loop region which forms a region capable of binding STAC SH3 domains. Therefore, variants may affect binding of SH3-domain containing proteins. Arrhythmic events occurred in similar proportions of patients with II–III loop variants and with other P/LP variants (53% vs. 48%, P = 0.41) despite shorter QTc intervals (477 ± 31 ms vs. 515 ± 37 ms, P = 0.03). A history of sudden death was reported only in families with II–III loop variants (60% vs. 0%, P = 0.03). The predominant T-wave morphology was a late peaking T wave with a steep descending limb. Exercise testing demonstrated QTc prolongation on standing and at 4 min recovery after exercise. Conclusion The majority of P/LP variants in patients with CACNA1C-mediated LQT8 cluster in an SH3-binding domain of the cytosolic II–III loop. This represents a ‘mutation hotspot’ in LQT8. A late-peaking T wave with a steep descending limb and QT prolongation on exercise are commonly seen.

Abstract Purpose: Statins may mediate suppression of molecular pathways conferring benefit in cancer. Statins have shown anti-tumor effects in preclinical studies and have been associated with decreased recurrence and improved disease-specific survival. While designed to target cholesterol biosynthesis, statins can also have liver, bone and brain effects. We collected data on statin use in the S0307 adjuvant bisphosphonate trial to test the hypothesis that statin use may decrease risk of recurrence to liver, bone and brain as well as second primary (contralateral) breast cancers, and may act synergistically with bisphosphonates to decrease the risk of recurrence to bone. Patients and Methods: In S0307, 6097 patients diagnosed with Stage I-III breast cancer who had undergone surgery and were receiving adjuvant systemic therapy were randomized to receive zoledronic acid, clodronate, or ibandronate for 3 years. No significant difference was found in disease-free survival (DFS) among the 3 groups, including a sub-analysis of patients &gt; age 55. Statin use was infrequent in younger women in S0307, consequently we analyzed statin use in those &gt; age 55. Cox proportional hazard models were used to determine which variables were independently associated with DFS and to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among women aged ≥ 55 years, 684 (27%) reported taking a statin at baseline and 1,848 did not. Both groups were similar in terms of hormone receptor and HER2 status (p = 0.82). Median age in the statin group was 64.3 versus 61.0 years in the no statin group, mean BMI 31.2 v. 29.5, mean tumor size 2.1cm v. 2.3cm, negative lymph nodes 60% v. 54%, Stage I disease 47% v. 36%, and receipt of chemotherapy 62% v. 71% (all p &lt; 0.01). In the statin group, 122 (17.8%) experienced a DFS event compared to 313 (16.9%) in the no statin group (HR 1.18, CI 0.95-1.46). No difference was observed by statin use in overall recurrence (p=0.28), distant recurrence (p=0.64), or recurrences to the bone (p=0.64), liver (p=0.38) or brain (p=0.65) at initial recurrence. There was no synergy between statin use and specific bisphosphonates. Recurrence and statin useOutcomeGroup 1: On stan at baseline n=684Group 2: No statin at baseline n=1848DFS events122 (17.8%)313 (16.9%)Died without recurrence51 7.5%)97 (5.2%)Recurrence71 (10.4%)216 (11.7%)Contralateral breast cancer9 (1.3%)17 (0.9%)Distant recurrence48 (7%)157 (8.5%)Bone as 1st site of distant recurrence (% distant recurrence)31 (65%)76 (48%)Liver as 1st site of distant recurrence (% distant recurrence)6 (13%)24 (16%)Brain/CNS as 1st site of distant recurrence (% distant recurrence)5 (10%)17 (11%) Conclusions: We found no evidence that statins reduce risk of second primary breast cancers or distant metastases among post-menopausal women with early-stage breast cancer. Despite promising preclinical data, they did not appear to act in synergy with a specific bisphosphonate. Though women in the statin group had less advanced disease at study entry, statin use was not associated with improved DFS. Results are limited by lack of information about type of statin used, adherence, or initiation of statin in control group. Citation Format: Kizub D, Miao J, Stopeck A, Thompson P, Paterson AH, Clemons M, Dees EC, Ingle JN, Falkson CI, Barlow W, Hortobagyi GN, Gralow JR. Statin use, site of recurrence, and survival among post-menopausal women taking bisphosphonates as adjuvant therapy for breast cancer (SWOG S0307) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-03.

Background: Cerebral cavernous malformation is a genetic neurovascular disorder causing aberrant angiogenesis and lesion development within capillary beds. Lesions exhibit impaired endothelial barrier function, causing blood-brain barrier leakage and hemorrhage. Quantitative MRI biomarkers (dynamic contrast-enhanced quantitative permeability (DCEQP) and quantitative susceptibility mapping (QSM)) have been shown to correlate with CCM disease progression as measures of barrier leakage and hemorrhagic iron deposition, and there is interest in utilizing these biomarkers as endpoints in clinical trials. However, their consistencies across multiple platforms and institutions has not yet been rigorously verified. Materials and Methods: Instruments used were a 3T Philips Ingenia at University of Chicago and a 3T Siemens Prisma at Northwestern University. QSM was assessed by five balloons filled with varying concentrations of MultiHance, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8, surrounded by an agarose gel. Permeability was assessed by the injection of a bolus of MultiHance through a coiled hose inside a water-filled shell, and the consistency of the peak-to-peak ratio of the curves at the input and output was measured. Each biomarker was assessed by accuracy (to expected values, Pearson correlation), precision (between repeated measurements, paired t-test), and reproducibility (between instruments, paired t-test). Results: QSM measured with an accuracy of r 2 = 0.997 on the Philips Achieva and r 2 = 0.999 on the Siemens Prisma. Each scanner had adequate precision between measurements, showing no significant difference by a paired t-test (p = 0.66 Achieva, p = 0.45 Prisma), and the reproducibility between scanners also showed no significant difference (p = 0.89). The peak-to-peak ratio on DCEQP scans was accurate (r 2 = 0.998), precise between measurements (p = 0.54), and repeatable between instruments (p = 0.49). Conclusion: Quantitative imaging biomarkers DCEQP and QSM are accurate, consistent across multiple measurements, and between platforms and will be useful for future clinical trials in CCM.