Citations

Abstract Patients diagnosed with germline mutations in MMR genes (Lynch Syndrome, LS) have up to 70-80% lifetime risk of colorectal cancer. Therefore, this high-risk population has the potential to benefit from effective chemopreventive strategies. Naproxen is an NSAID widely used for pain treatment with an excellent safety profile that has demonstrated to be more efficacious preventing colorectal cancer compared to aspirin in vivo using an intestinal tissue-specific mouse model of LS (VC-Msh2-LoxP). The ‘Naproxen trial' was designed to evaluate the modulation of PGE2 levels in colorectal mucosa, evaluate safety and tolerability, and discover novel molecular pathways involved in the chemopreventive activity of naproxen in LS patients. Methods: Participants were randomized to naproxen 440 mg (HD), 220 mg (LD) and placebo by mouth daily for 6 months. Modulation of prostaglandin levels, number of adverse events (AEs) observed in each treatment arm and gene expression profiles by next-generation sequencing (mRNAseq) in normal colorectal mucosa of LS patients after 6 months of intervention were examined. Results: Eighty participants diagnosed with LS were randomized, 25 participants to HD, 27 to LD, and 28 to placebo. From these patients, 54 were considered evaluable per-protocol analysis: 16 in the HD group, 15 in the LD and 23 in placebo. The level of prostaglandin E2 in the colorectal mucosa decreased significantly after treatment with both LD and HD naproxen when compared to placebo (-91.2%±14.1, -93.6%±7.9, and 23.8%±108.4, P-value<0.001, respectively). Moreover, levels of PGE2 urinary metabolite (PGE-M) were significantly changed in both treatment groups when compared to placebo (-47.7%±56.9, -41.1%±40.5, 7.6%±94.3, P-Value<0.018). The intervention was well tolerated, no severe AEs related to treatment were reported, and the total number of AEs was not different across treatment arms. LD and HD naproxen promoted the activity of the immune system by activating different immune cell types without any effect on lymphoid cellularity and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Conclusions: Naproxen is a promising strategy for immune interception in LS that induces immune-modulation coupled with changes in the dynamics of the intestinal crypt. We have also discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. Citation Format: Laura Reyes Uribe, Wenhui Wu, Ozkan Gelincik, Prashant V. Bommi, Alejandro Francisco-Cruz, Luisa M. Solis, Patrick M. Lynch, Ramona Lim, Elena Stoffel, Priyanka Kanth, N. Jewel Samadder, Maureen E. Mork, Melissa W. Taggart, Ginger L. Milne, Lawrence J. Marnett, Lana Vornik, Diane D. Liu, Maria Revuelta, Kyle Chang, Y. Nancy You, Levy Kopelovich, Ignacio I. Wistuba, J. Jack Lee, Shizuko Sei, Robert H. Shoemaker, Eva Szabo, Ellen Richmond, Asad Umar, Marjorie Perloff, Powell H. Brown, Steven M. Lipkin, Eduardo Vilar. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT111.

Glial fibrillary acidic protein (GFAP) is cleared by the Food and Drug Administration (FDA) to determine need for head computed tomography (CT) within 12 h after mild traumatic brain injury (TBI) (Glasgow Coma Score [GCS] 13–15); S100 calcium-binding protein B (S100B) serves this function in Europe. This phase 1 biomarker cohort analysis of the multi-center, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study compares GFAP's diagnostic performance, measured on a rapid point-of-care platform, against protein S100B to predict intracranial abnormalities on CT within 24 h post-injury across the spectrum of TBI (GCS 3–15). Head CT scan performed in TBI subjects and blood was collected for all consenting subjects presenting to 18 United States level 1 trauma centers. Plasma was analyzed on a point-of-care device prototype assay for GFAP and serum was analyzed for S100B. In 1359 patients with TBI (GCS 3–15), mean (standard deviation [SD]) age = 40.1 (17.0) years; 68% were male. Plasma GFAP levels were significantly higher in CT+ TBI subjects (median = 1358 pg/mL, interquartile range [IQR]: 472–3803) than in CT- TBI subjects (median = 116 pg/mL, IQR: 26–397) or orthopedic trauma controls ( n = 122; median = 13 pg/mL, IQR: 7–20), p < 0.001. Serum S100B levels were likewise higher in CT+ TBI subjects (median = 0.17 μg/L, IQR: 0.09–0.38) than in CT- TBI subjects (median = 0.10 μg/L, IQR: 0.06–0.18), p < 0.001. Receiver operating characteristic curves were generated for prediction of intracranial injury on admission CT scan; area under the curve (AUC) for GFAP was significantly higher than for S100B in the same cohort (GFAP AUC – 0.85, 95% confidence interval [CI] 0.83–0.87; S100B AUC – 0.67, 95% CI 0.64-0.70; p < 0.001). GFAP, measured on a point-of-care platform prototype assay, has high discriminative ability to predict intracranial abnormalities on CT scan in patients with TBI across the full injury spectrum of GCS 3–15 through 24 h post-injury. GFAP substantially outperforms S100B.

BackgroundChronic exertional compartment syndrome (CECS) is a type of leg pain related to elevated intracompartmental pressure with activity in one or more of the four compartments of the leg. Open fasciotomy is the definitive treatment for CECS but has a reported complication rate of up to 15.7% and return to full activity reported up to 16 weeks. Ultrasound‐guided (USG) fasciotomy of the anterior and lateral compartments has been translated into clinical practice.ObjectiveTo determine the safety and feasibility of a USG fasciotomy of the deep posterior compartment (DPC) and superficial compartment (SPC) of the leg in a fresh‐frozen cadaveric model.DesignProspective, cadaveric laboratory investigation.SettingProcedural skills laboratory at an academic institution.Cadaveric CohortTen fresh‐frozen cadaveric knee‐ankle‐foot specimens from five female and five male donors aged 58 to 93 years (mean 77.4 years) with body mass indexes of 18.1 to 33.5 kg/m2 (mean 25.1 kg/m2).Methods or InterventionsOne experienced operator performed 10 USG DPC and SPC fasciotomies. A clinical anatomist performed dissections of each.Main Outcome MeasuresAchievement of target length and continuity of release was recorded. Target lengths of 10 cm for the superficial posterior compartment (SPC) and 15 cm for the deep posterior compartment (DPC) were established based on previous studies. Tendinous and neurovascular structures were assessed for damage.ResultsNo tendon or neurovascular injuries were observed. In the SPC, target length was achieved in 90% and continuous release was observed in 80%. In the DPC, target length was achieved in 60% and continuity observed in 30%.ConclusionsThese findings suggest that SPC USG fasciotomies using the technique described in this study are feasible, may be safe, and warrant further translational research; however, DPC USG fasciotomies are more challenging and require more technical refinement prior to clinical translation.

11063 Background: Dacetuzumab (SGN-40) is a humanized IgG1 monoclonal antibody that binds to CD40, mediates effector cell functions, and activates downstream apoptosis signaling pathways. Dacetuzumab has shown single-agent activity in relapsed/refractory DLBCL in phase I and phase II trials, with multiple objective responses and 1/3 of patients demonstrating tumor shrinkage, defined as a decrease in tumor volume (SPD) of at least 10%. We previously reported a 14-gene signature (ASH 2008 #1593) that was strongly associated with dacetuzumab sensitivity in DLBCL cell lines. Here, we report an initial evaluation of the gene signature as a classifier of patients likely to demonstrate tumor shrinkage after dacetuzumab therapy. Methods: The original 14 microarray probes were chosen for high correlation with in vitro dacetuzumab sensitivity (IC25) in 31 NHL cell line models. Matching qRT-PCR probes were developed and confirmed to correlate with the microarray probes in paired cell line samples. In this retrospective analysis, archived paraffin blocks from a 26 patient subset of the phase I and II trials, with a diagnosis of DLBCL and available tumor measurements, were assayed by qRT-PCR. Results: Overall, 42% of patients (11/26) exhibited decreased SPD of at least 10%. Of those who were marker +, 10 out of 13 (78%) had 10% or better decreases in SPD, whereas only 1 of 13 patients who were marker - demonstrated tumor shrinkage (8%). The overall accuracy for predicting tumor shrinkage was 85% (one-sided P=0.002, by permutation test). Among the 14 genes contributing to the multivariate signature, CD22 and VNN2 were the most strongly down-regulated in specimens from patients without at least a 10% decrease in SPD (P=0.14 and P=0.10, respectively), while IGF1R and CTSC were the most strongly up-regulated (P=0.05 and P=0.08, respectively). Conclusions: A 14-gene signature appears to predict tumor shrinkage in DLBCL patients receiving dacetuzumab in single-agent clinical trials (P=0.002). A larger clinical data set will be analyzed to further evaluate the correlation of this gene signature with objective clinical response rates.. [Table: see text]

9513 Background: Hot flashes are a major problem in many women for which better treatment options are needed. Given the known efficacy of gabapentin for decreasing hot flashes, it was decided to evaluate pregabalin, with hopes that it would work better and/or with fewer toxicities. Methods: A three-arm, double-blinded, placebo-controlled randomized trial was developed. Women with bothersome hot flashes (at least 28/week) were randomized to receive either a placebo or target pregabalin oral doses of 75 mg bid or 150 mg bid (starting at 50 mg/d and then increasing the dose at weekly intervals to 50 mg bid, then 75 mg bid, and then, in the higher dose arm, 150 mg bid); patients were treated for 6 weeks. Hot flash numbers and scores (hot flash number times mean severity) were measured using a validated daily hot flash diary. A one-week baseline period preceded initiation of study tablets. The primary endpoint was the average intra-patient difference in hot flash score between baseline and week six, comparing the higher dose pregabalin arm and the placebo arm. With the planned sample size of 55 patients per arm, there was an 80% power and two-sided 5% Type I error rate to detect a difference of 0.54 standard deviations, or 1.08 hot flashes per day, or 2.7 units of hot flash score per day. Results: 207 patients were randomized between 6/20/2008 and 8/21/2008. The study arms were well balanced. Mean/median daily hot flash scores and frequencies for all pts at baseline were 15.7/13.4 and 8.3/7.7, respectively. The table shows the decreases in hot flashes from the baseline to the sixth treatment week. Larger numbers illustrate greater hot flash reductions. Toxicity information, quality of life information, and information regarding the effects of hot flashes on subjective symptoms will be available at the meeting time. Conclusions: Pregabalin reduces hot flashes in women. There appears to be similar effects with both studied doses. [Table: see text] No significant financial relationships to disclose.

520 Background: Targeted therapy using trastuzumab (an anti-HER-2 receptor monoclonal antibody) has significantly improved survival in breast carcinoma patients (pts), but determining which pts will respond to this therapy remains a challenge. We previously reported (Miller DV, ASCO 2004 abstract #568) a subset of pts with breast cancers demonstrating focal HER-2 amplified clones (FHAC) amidst otherwise nonamplified tumor cells by fluorescence in-situ hybridization. These accounted for 21% of the HER-2 amplified but immunohistochemistry (IHC) negative cases and 30% of the HER-2 amplified but IHC equivocal cases. The clinical significance of this phenomenon was unclear at that time. We now report the disease-free survival (DFS) data on 91 FHAC pts with a comparison to the diffusely amplified (DA) cases in this trial group. Methods: Breast tumors were evaluated for HER-2 gene amplification using PathVysion™. FHAC cases demonstrated 2–40% of cells with >10 HER-2 signals and HER-2:CEP17 ratio >5.0, regardless of the overall HER-2:CEP17 ratio. Patient and disease characteristics were compared using chi-square tests. Cox regression models compared DFS between pts randomized to arms A (standard chemotherapy) and C (standard chemotherapy with concurrent trastuzumab) within 91 FHAC and 1571 DA cases. Median follow up was 4.0 years. Results: Age, race, menopausal status, surgical procedure, nodal status, histologic type and grade, and tumor size, were not significantly different between pateints with FHAC and DA. Pateints with FHAC had more frequent hormone receptor positivity compared to DA cases (66% vs 50%; p = 0.004). Hazard ratios between pts with FHAC and DA showed that both groups of pts had similar DFS (A: HR = 0.86, p = 0.65; C: HR = 0.72, p = 0.57). Hazard ratios between arms within FHAC and DA groups demonstrated similar benefit from trastuzumab in each group (FHAC: HR = 0.50, p = 0.30; DA: HR = 0.59, p < 0.0001). Results remained consistent when including hormone receptor status in the model. Conclusions: Based on a small number (n = 91) of pts with FHAC, benefit from trastuzumab appears to be similar whether the population of HER-2 amplified cells with breast carcinomas is focal or diffuse. [Table: see text]

Purpose: Radiotherapy (RT) is an effective treatment for localized gastric mucosa-associated lymphoid tissue (MALT) lymphomas unresponsive to antibiotic therapy; however, irradiating the stomach can result in significant radiation to the heart, a risk factor for cardiac disease. We analyzed the Surveillance, Epidemiology, and End Results database to evaluate outcomes related to cardiac disease among patients treated with RT for stage I gastric MALT. Materials and Methods: We identified adult patients treated between 1993 and 2014. The relationship between treatment modality (RT, chemotherapy, combination, and no treatment) and overall survival (OS), mucosa-associated lymphoid tissue-specific survival (MSS), non-mucosa-associated lymphoid tissue-specific survival (non-MSS), and cardiac-specific survival (CSS) was assessed using the Kaplan-Meier estimator and Cox proportional hazards analyses. Results: A total of 2996 patients (median follow-up, 5.6 y) were analyzed: 27.5% had received RT alone, 12.1% chemotherapy alone, 3.9% chemoradiotherapy, and 56.5% no/unknown treatment (including antibiotic therapy). Compared with RT alone, patients who received chemotherapy alone exhibited worse OS (hazard ratio [HR]: 1.67; 95% confidence interval [CI]: 1.32-2.10; P<0.001) and MSS (HR: 2.10; 95% CI: 1.36-3.23; P=0.001). Although CSS appeared worse in patients who received chemotherapy (HR: 1.56; 95% CI: 0.92-2.66; P=0.10), it was not statistically significant. When comparing orbital and gastric MALT patients, there was no significant difference in CSS (HR: 0.80; 95% CI: 0.49-1.31; P=0.38). Conclusions: RT improved survival among patients with stage I gastric MALT without increasing the risk of cardiac death. Those with gastric MALT exhibited similar CSS to those with orbital MALT. Although we cannot analyze nonfatal cardiac toxicity, these results suggest that, absent antibiotic therapy, RT should remain first-line treatment for early-stage gastric MALT.

AbstractIntroductionCerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood‐brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases.MethodsWe performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin‐5 (CLDN5) and occludin (OCLN), and major AD‐related molecules (amyloid beta [Aβ40], Aβ42, tau, p‐tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.ResultsHigher levels of soluble tau, insoluble p‐tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.DiscussionRefining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.