Citations

Objective: To describe a novel case of congenital profound bilateral sensorineural hearing loss in a patient with bilateral nodular internal auditory canal and labyrinthine enhancement and temporal bone dysplasia. Patients: A 76-day-old female was referred to the authors’ center for evaluation of congenital deafness. Behavioral observations and objective audiometric evaluation demonstrated bilateral profound sensorineural hearing loss and a comprehensive multidisciplinary evaluation identified compound heterozygous pathogenic variants in MYO7A , a gene associated with Usher Syndrome Type 1B or DFNB2. Computed tomography and contrast-enhanced magnetic resonance imaging studies demonstrated bilateral temporal bone anomalies with unique middle and inner ear malformations, as well as unique contrast enhancement in the membranous labyrinth, internal auditory canals, and cranial nerves, which have not been previously described with MYO7A variants. Interventions: Given the potential risk for progressive bilateral labyrinthitis ossificans, bilateral simultaneous cochlear implantation was performed at 4 months of age. Main Outcome Measures: Subsequent audiologic follow up after implantation shows significantly improved access to auditory information and increased vocalizations. At last testing, speech and language skills for both receptive and expressive language abilities were found to be commensurate with her chronological age. Conclusion: We report a novel presentation and imaging findings of congenital bilateral profound sensorineural hearing loss in a patient with nodular internal auditory canal and labyrinthine enhancement and coexisting inner ear dysplasia. Despite the multiple radiologic abnormalities, the patient has demonstrated good benefit from cochlear implantation. Future study of rare variants of congenital deafness, such as this, is critical toward defining new disease processes and determining optimal treatment.

104 Background: Lymphedema (LE), a side effect of BC treatment, affects 8%–56% of women. The study tested the effectiveness of an education only vs education + exercise intervention on LE incidence in a group randomized trial (NCT00376597) of 38 cooperative group sites. Methods: Newly diagnosed women with stage I-III BC were consented and arm circumference and range of motion were measured pre-surgery. After surgery, patients (pts) were enrolled based on the randomization assignment of their treating institution, stratified by their type of node dissection (sentinel or axillary), and received either: education only: its causes, signs, symptoms and risk reduction strategies, or education + personalized exercise instruction from a physical therapist, with elastic compression garments to wear during heavy arm use and air travel. Pts completed surveys and arm measurements at baseline (BL), 12 and 18 months with the LE endpoint defined as ≥ 10% difference in limb volume at any time from BL to 18 months or physician diagnosis of LE. Cochran-Mantel-Haenszel (CMH) tests were used to compare the LE-free rate between arms, adjusted for type of biopsy. Logistic regression assessed predictors of LE. Results: 568 pts were enrolled, 45% in education only, and 55% in education + exercise, with 554 (98%) included in the analyses. Pts were on average 57.7 years, White (83%), non-Hispanic (92%) and married (62%). 47% only had sentinel node dissection, 35% had mastectomy, and 37% had chemotherapy. The LE-free rate was 58% in education only vs 55% in education + exercise (CMH p = 0.73). Predictors of LE included surgery type (lumpectomy vs mastectomy, OR = 2.22, p < 0.001) and chemotherapy (no vs yes, OR = 1.73, p = 0.02), after adjusting for BMI and type of node dissection. Only one-third wore the sleeve at least 75% of the time and only 50% did LE exercises at least weekly. Conclusions: There was no difference by intervention arm in LE incidence by 18 months. Poor adherence in the education + exercise arm may have been a factor. Additional analyses will assess quality of life, body image and knowledge about LE by arm. Further research is needed to effectively prevent LE in pts after BC surgery. Research Support: UL1TR001409; U10CA037447, UG1CA189823 Clinical trial information: NCT00376597.

AbstractWe analyzed the outcomes following initial relapse or refractory disease in systemic light chain amyloidosis (AL) and the impact of type of therapy employed.A total of 1327 patients with AL seen at Mayo Clinic within 90 days of diagnosis, between 2006 and 2015, were reviewed. The study included 366 patients experiencing a documented hematological or organ relapse or refractory disease requiring start of second line therapy. Overall survival (OS) and time to next treatment (TTNT) were calculated from start of second line treatment.The median time to require second line treatment was 16.2 months (1‐93) from the start of first line therapy. At relapse, patients received proteasome inhibitors (PI; 45.1%), immunomodulators (IMiD; 22.7%), alkylators (9%), PI and IMiD combination (4.1%), autologous transplant (3.8%), steroids and other therapies (4.9%). Among these, 124 (33.9%) required change or reinstitution of therapy. The median time to require third line treatment was 31 months (95% CI; 24, 40.5) and the median overall survival (OS) was 38.8 months (95% CI; 29.6, 52.6) from the start of second line treatment. Retreatment with same therapy at relapse significantly reduced TTNT (22 m vs 32.3 m; P = .01) as compared to different therapy; but did not have any impact OS (30.8 m vs 51.1 m; P = .5). In conclusion, this study provides important information about outcomes of patients with AL who require second line treatment for relapsed/refractory disease . Treatment with a different therapy at relapse improves time to next therapy but does not impact OS.

The optimal surveillance for patients with resected high-risk melanoma is controversial. Select locoregional or oligometastatic recurrences can be cured with salvage resection. Data on the ability of PET/CT to detect such recurrences are sparse. We evaluated whether surveillance PET/CT in patients with resected stage III–IV melanoma led to detection of clinically occult recurrences amenable to curative-intent salvage treatment. We retrospectively identified 1429 melanoma patients who underwent PET/CT between January 2008 and October 2012 at Mayo Clinic (Rochester, Minnesota). A total of 1130 were excluded because of stage I–II, ocular or mucosal melanoma, incomplete resection, PET/CT not performed for surveillance or performed at a different institution, and records not available. A total of 299 patients were eligible. Overall, 162 (52%) patients developed recurrence [locoregional: 77 (48%), distant: 85 (52%)]. The first recurrence was clinically occult in 98 (60%) and clinically evident in 64 (40%). Clinically evident recurrences were more often superficial (skin, subcutaneous, or nodal) or in the brain, whereas clinically occult recurrences more often visceral. Overall, 90% of all recurrences were detected by 2.8 years. In all, 70% of patients with recurrence underwent curative-intent salvage treatment (locoregional: 94%, distant: 48%), with similar rates for clinically occult versus clinically evident recurrences (66 vs. 75%, P=0.240). Overall survival was superior among those who underwent curative-intent salvage treatment [5.9 vs. 1.2 years; hazard ratio=4.27, 95% confidence interval (CI)=2.68–6.80; P<0.001], despite 79% developing recurrence again. PET/CT had high sensitivity (88%, 95% CI=79.94–93.31%), specificity (90%, 95% CI=88.56–91.56%), and negative predictive value (99%, 95% CI=98.46–99.52%). However, the positive predictive value was only 37% (95% CI=31.32–43.68%). In patients with resected stage III–IV melanoma, surveillance PET/CT detected a large proportion of clinically occult recurrences amenable to curative-intent salvage treatment. Despite a high rate of second relapse, curative-intent salvage treatment was associated with superior overall survival. Even though PET/CT had high sensitivity, specificity, and negative predictive value, positive predictive value was poor, highlighting the need for histologic confirmation of PET/CT-detected abnormalities.

ABSTRACTHuman cerebral malaria (HCM) is a serious complication ofPlasmodium falciparuminfection. The most severe outcomes for patients include coma, permanent neurological deficits, and death. Recently, a large-scale magnetic resonance imaging (MRI) study in humans identified brain swelling as the most prominent predictor of fatal HCM. Therefore, in this study, we sought to define the mechanism controlling brain edema through the use of the murine experimental cerebral malaria (ECM) model. Specifically, we investigated the ability of CD8 T cells to initiate brain edema during ECM. We determined that areas of blood-brain barrier (BBB) permeability colocalized with a reduction of the cerebral endothelial cell tight-junction proteins claudin-5 and occludin. Furthermore, through small-animal MRI, we analyzed edema and vascular leakage. Using gadolinium-enhanced T1-weighted MRI, we determined that vascular permeability is not homogeneous but rather confined to specific regions of the brain. Our findings show that BBB permeability was localized within the brainstem, olfactory bulb, and lateral ventricle. Concurrently with the initiation of vascular permeability, T2-weighted MRI revealed edema and brain swelling. Importantly, ablation of the cytolytic effector molecule perforin fully protected against vascular permeability and edema. Furthermore, perforin production specifically by CD8 T cells was required to cause fatal edema during ECM. We propose that CD8 T cells initiate BBB breakdown through perforin-mediated disruption of tight junctions. In turn, leakage from the vasculature into the parenchyma causes brain swelling and edema. This results in a breakdown of homeostatic maintenance that likely contributes to ECM pathology.

Abstract Background: Epidemiologic associations of leukocyte telomere length (LTL) and pancreatic ductal adenocarcinoma (PDAC) have been inconsistent owing, in part, to variation in telomere length (TL) assessment across studies. To overcome this limitation and address concerns of potential reverse causation, we used carriage of telomere-related alleles to genetically predict TL and examined its association with PDAC. Methods: A case–control study of 1,500 PDAC cases and 1,500 controls, frequency-matched on age and sex was performed. Eight of nine polymorphisms previously associated with variation in LTL were analyzed. Genetic risk scores (GRS) consisting of the TL-related polymorphisms were computed as the number of long TL alleles carried by an individual scaled to published kilobase pairs of TL associated with each allele. Participants were further categorized on the basis of the number of short TL alleles they carry across all eight SNPs. Associations were examined in additive and dominant models using logistic regression to calculate ORs and 95% confidence intervals (CI). Results: In age- and sex-adjusted models, one short TL allele (rs10936599, T) was associated with reduced risk, whereas another short TL allele (rs2736100, A) was associated with increased risk, with per-allele ORs of 0.89 (95% CI, 0.79–0.99) and 1.13 (95% CI, 1.01–1.24), respectively. No association was observed with GRS or short TL allele counts, and no associations were observed in the dominant models. Conclusions: Findings suggest that genetically predicted short TL is not associated with PDAC risk. Impact: Common genetic determinants of short TL do not appear to influence PDAC risk. Cancer Epidemiol Biomarkers Prev; 26(6); 971–4. ©2017 AACR.

Abstract Introduction: We have previously identified a 9p24.1 amplicon targeting PD-L1/JAK2 (PDJ) in subset (26.7%) of triple negative breast cancer (TNBC) patients. The PDJ amplicon is common in newly diagnosed and chemotherapy treated TNBCs and is associated with a worse prognosis. Our goal in this study was to determine whether immunohistochemistry (IHC) evaluation could identify those patients who harbor the PDJ amplicon. Methods: TNBC patients from 1999 to 2015 whose tumors were flow-sorted and evaluated by array-based comparative genomic hybridization (CGH) were identified; paraffin slides were obtained for IHC staining evaluation of JAK-2, phosphorylated STAT3 (pSTAT3), and PD-L1. Pathologic analysis consisted of scoring the stains for intensity (0-3+) and the relative percent of tumor cells with positive staining; positive score was defined as 3+ for any percent staining. Statistical analysis of IHC staining was performed to determine association with the PDJ amplicon defined by focal 9p24.1 copy number gain with CGH log2ratios of &gt;1.0 for each sorted TNBC sample. Results: Eleven of 43 TNBC patients evaluable by IHC had the PDJ amplicon. There was no association between PDJ amplification and IHC staining for JAK-2, pSTAT3, or PD-L1 regardless of staining intensity or percentage tumor cells positive. Table 1 describes PDJ amplicon status and positivity for JAK2, pSTAT3 and PD-L1. Of PDJ-positive samples, 64%, stained positive for JAK2, 27% positive for pSTAT3, but 0% for PD-L1 in tumor cells. However, in the PDJ-negative group, 69% still stained positive for JAK2, 19% positive for pSTAT3, and 9% for PD-L1. Table 1: PDJ amplicon status and IHC staining JAK2 (3+) (n;%)pSTAT3 (3+) (n;%)PD-L1 (3+) (n;%)PDJ - (n=32)22;69%6;19%3;9%PDJ + (n=11)7;64%3;27%0;0% JAK2: Most PDJ-positive samples (10/11, 91%) showed some JAK-2 staining. Although one had only 1+ staining at 5% of the cells, the majority (7/11, 64%) had staining of 3+ and &gt;10% of the cells with 2 patients demonstrating 3+ staining of 75% and 90% of the cells. However, those patients without the PDJ amplicon also exhibited JAK2 staining, with 66% (n= 22) of PDJ-negative cases staining strongly for JAK-2 (3+) and &gt; 10% of cells. pSTAT3: All but one PDJ-positive case demonstrated some staining (1+ or greater) for pSTAT3; the staining intensity and percent positivity were much less than the JAK-2 staining with only 2 cases (18%) having 3+ staining of &gt; 10%. Similar staining was seen in the PDJ-negative cohort; 75% of PDJ-negative patients had some pSTAT3 staining (1+ or greater) and 1 patient (5%) exhibited 3+ staining &gt; 10%. PD-L1: Finally, the PD-L1 staining was low overall with only 18% of PDJ-positive cases demonstrating some staining for PD-L1. Notably, only one case stained 3+ with 20% positivity while the majority of the samples had a 2+ intensity encompassing 5-50% of the cells. Conclusions: IHC staining for JAK2, pSTAT3, or PD-L1 was not associated with the presence of the PDJ amplicon. Notably positive IHC staining for JAK2 was observed for both PDJ-positive and PDJ-negative tumor cells, thereby nullifying its application as a screening tool for PDJ amplification. Alternative methods, such as fluorescence in situ hybridization, are needed to identify PDJ-positive patients for further study. Citation Format: Linnaus ME, Kosiorek H, Ocal IT, Dixon L, Barrett MT, Gawryletz CD, Anderson KS, McCullough AE, McEachron TA, Pockaj BA. Immunohistochemistry cannot be used to detect PD-L1/JAK-2 amplification [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-03-13.

CRA1002 Background: Weekly P is superior to q 3 week (wk) dosing, and adding B improves progression free survival (PFS) (E2100). Ix is a potent epothilone that can be effective after microtubule inhibitor resistance. NP is a novel albumin-bound formulation of P with promising activity in the first-line MBC setting. In this phase III trial, the efficacy of weekly Ix or NP is compared to P, in combination with B in patients (pts) with chemotherapy (CTX) naïve MBC. Toxicity including >Grade 2 sensory neuropathy (SN) is compared to P. Methods: Pts were randomized 1:1:1 to receive P (90 mg/m2), Ix (16 mg/m2) or NP (150 mg/m2) on a 3 wk on, 1 wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all pts, but became optional in 3/2011 and was added to stratification. The primary end point of PFS is defined as time from randomization to progression or all-cause death. With a target N=900 pts, the study was powered to detect a hazard ratio (HR) of 1.36 (median PFS 10 vs 13.6 mos). Eligibility included no prior CTX for MBC, >12 mos from adjuvant P and measurable disease. Results: 799 pts were enrolled between 11/08-11/11 (283 to P, 271 to NP, 245 to Ix); 98% received B. 72% had ER+ disease, 44% received adjuvant P. At the 1st interim analysis (165 events) the comparison of Ix to P crossed the futility boundary (FB) and accrual to Ix was closed. At the 2nd interim analysis (236 events), NP to P crossed the FB and the study was closed on 11/30/11. Median PFS was 10.4, 9.6 and 7.6 mos for P, NP and Ix, with HRs (95% CIs) of 0.94 (0.73-1.22) and 0.66 (0.51-0.84) for P to NP and Ix respectively. Grade 2+ SN was 48% for NP, 44% for Ix and 37% for P; Grade 3+ hematologic toxicity was 49% for NP, 20% for Ix, and 12% for P. Conclusions: In pts with CTX naive MBC, both NP and Ix are highly unlikely to be superior to P for PFS (when all are combined with B), and in combination with B, weekly P is the better tolerated drug. Toxicity including SN was greater in each experimental arm compared to P. Updated data will be presented, and correlative studies will be reported at a future date.