Citations

Objective The current study was designed to evaluate the translation of clinical trial outcomes and clinical guidelines for the treatment of fibromyalgia (FM) into an intensive multicomponent clinical program embedded in routine care delivery. The study aimed to assess the adaptation of these recommended strategies into routine clinical care while evaluating their effectiveness and durability in improving functional status and level of distress in a large clinical sample of FM patients. Methods Four hundred eighty-nine patients with FM completed a 2-day program that incorporated best practice recommendations for the treatment of FM. Patients completed the Fibromyalgia Impact Questionnaire–Revised, the Center for Epidemiologic Studies Depression Scale, and the Pain Catastrophizing Scale at admission to the program and at follow-up on average 5 months posttreatment. Results Significant improvements were seen in functional status (p < 0.0001), depressive symptoms (p < 0.0001), and pain catastrophizing (p < 0.0001) after participation in the intensive multicomponent treatment program. Conclusions The present study shows that an intensive multicomponent treatment program embedded in routine care delivery is effective in significantly improving functional status and psychological distress in a large sample of FM patients. The significant improvements were durable and maintained at follow-up.

Abstract Background: Focal adhesion kinase (FAK) is consistently hyperactivated in multiple tumor types including PDAC. Our preclinical work showed that FAK and PD-1 inhibitors elicit significant tumor regression, and that combining FAK and PD-1 inhibitors with gemcitabine achieves a maximal response. This suggests the need for a cytotoxic agent to bolster antigen presentation. Defactinib is an orally available, well-tolerated, potent FAK inhibitor. Methods: This study included a dose escalation phase (all solid tumors) and dose expansion phase (metastatic PDAC). A 3+3 design with five dose levels was used in the dose escalation phase. For the expansion phase, 10 PDAC patients with stable disease on front-line gemcitabine/nab-paclitaxel were enrolled in the Maintenance cohort (A), while 10 patients who progressed on at least one line of therapy were enrolled in the Refractory cohort (B). Pre and on-treatment biopsied were collected from all PDAC patients. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints included safety, toxicity, objective response rate, progression-free survival (PFS) and overall survival (OS). The exploratory endpoints included developing a molecular and immune profile for treatment response. Results: In dose escalation, the common low grade (G1/2) treatment-emergent adverse events included fatigue, anorexia, nausea and vomiting. No DLTs were seen. The RP2D was defactinib 400mg twice daily, gemcitabine 1000 mg/m2 days 1, 8 and pembrolizumab 200mg day 1 of a 21-day cycle. Safety and toxicity results in the escalation cohort were reported at the 2018 ASCO Annual Meeting. Among 8 evaluable PDAC patients enrolled on the dose escalation phase, we observed 1 (13%) partial response (PR), 3 (38%) stable disease (SD), 4 (50%) progressive disease (PD). In the Maintenance cohort, 1 (10%) PR, 6 (60%) SD, and 3 (30%) PD were observed. Two patients in the Maintenance cohort remain on study, and the median time on treatment was 4.6 months. In the Refractory cohort, 5 (50%) had SD, 4 (40%) PD, 1 not evaluable; median PFS was 2.9 months and median OS was 7.6 months. Interestingly, two confirmed PR patients both have MSS disease. Paired biopsies in PDAC patients show increased proliferating CD8+ T cells, while Tregs, macrophages, and stromal density decrease with treatment. Conclusions: The combination regimen was well tolerated. Encouraging efficacy signals were observed in both Maintenance and Refractory cohorts. Updated outcomes and correlative analyses are forthcoming. Citation Format: Andrea Wang-Gillam, Robert McWilliams, A. Craig Lockhart, Benjamin R Tan, Rama Suresh, Kian-Huat Lim, Katrina S. Pedersen, Nikolaos Trikalinos, Olivia Aranha, Haeseong Park, Lee Ratner, Nicholas Boice, David G. Denardo. Phase I study of defactinib combined with pembrolizumab and gemcitabine in patients with advanced cancer: Experiences of pancreatic ductal adenocarcinoma (PDAC) patients [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 CT118.

Abstract Background: Persons of African ancestry (AA) experience a 1.5-2-fold risk of multiple myeloma (MM) compared to persons of European ancestry (EA). We assembled a set of MM patients with self-reported AA in order to evaluate the contribution of genetics to etiology in this high-risk group. Methods: Here we present the results of a meta-analysis of two GWAS in 1,813 cases and 8,871 controls of AA. We also conducted an admixture mapping scan to identify risk alleles associated with local ancestry, fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA, and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. Finally, we conducted an eQTL analysis measuring gene expression in those genes harboring a risk variant in malignant plasma cells from 292 of the patients from a single site. Results: In GWAS analysis, we identified two suggestive novel loci located at 9p24.3 and 9p13.1 at P&lt;1 × 10-6, but no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. 20 of the 23 known EA risk variants showed directional consistency and 9 replicated at P&lt;0.05 in AA individuals. In eight regions, we identified markers that better capture MM risk in persons of AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95%CI: 1.56, 2.11) increased MM risk compared to those with average risk (25-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P= 5.1 × 10–12). Conclusion: Our study shows that common genetic variation contributes to MM risk individuals of AA. This abstract is also being presented as Poster C040. Citation Format: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristen A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael Press, John David Carpten, Stephen Chanock, Jayesh Mehta, Graham A Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association study and eQTL analysis of multiple myeloma among African Americans [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR05.

Study Design: Retrospective case series. Objective: Sacral insufficiency fracture is a rare and serious complication following lumbar spine instrumented fusion. The purpose of this study was to describe the patient characteristics, presentation, evaluation, treatment options, and outcomes for patients with sacral insufficiency fracture after short-segment lumbosacral fusion. Methods: Six patients from our institutional database and 16 patients from literature review were identified with a sacral insufficiency fracture after short-segment (L4-S1 or L5-S1) lumbar fusion within 1 year of surgery. Results: Patients were 55% female with a mean age of 58 years and body mass index of 30 kg/m 2 . Osteoporosis or osteopenia was the most common comorbidity (85%). Half of patients sustained a sacral fracture after surgery from a posterior approach, while the others had anterior or anterior-posterior surgery. Mean time to fracture was 42 days with patients clinically presenting with new sacral pain (86%), radiculopathy (60%), or neurologic deficit (5%). Ultimately, 73% of patients underwent operative fixation often involving extension of the construct (75%) and fusion to the pelvis (69%). Men ( P = .02) and patients with new radicular pain or neurologic deficit ( P = .01) were more likely to undergo revision surgical treatment while women over 50 years of age were more likely to be treated conservatively ( P = .003). Conclusions: Spine surgeons should monitor for sacral insufficiency fracture as a source of new-onset pain in the postoperative period in patients with a short segment fusion to the sacrum. The recognition of this complication should prompt an assessment of bone health and management of underlying bone fragility.

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.

AbstractBackgroundOligodendroglioma is genetically defined by concomitant IDH (IDH1/IDH2) mutation and whole-arm 1p/19q codeletion. Codeletion of 1p/19q traditionally evaluated by fluorescence in situ hybridization (FISH) cannot distinguish partial from whole-arm 1p/19q codeletion. Partial 1p/19q codeletion called positive by FISH is diagnostically a “false-positive” result. Chromosomal microarray (CMA) discriminates partial from whole-arm 1p/19q codeletion. Herein, we aimed to estimate the frequency of partial 1p/19q codeletion that would lead to a false-positive FISH result.MethodsFISH 1p/19q codeletion test probe coordinates were mapped onto Oncoscan CMA data to determine the rate of partial 1p/19q codeletion predicted to be positive by FISH. Diffuse astrocytic gliomas with available CMA data (2015–2018) were evaluated and classified based on IDH1-R132H/ATRX/p53 immunohistochemistry, IDH/TERT promoter targeted sequencing, and/or CMA according to classification updates. Predicted false-positive cases were verified by FISH whenever possible.ResultsThe overall estimated false-positive FISH 1p/19q codeletion rate was 3.6% (8/223). Predicted false positives were verified by FISH in 6 (of 8) cases. False-positive rates did not differ significantly (P = .49) between IDH-mutant (4.6%; 4/86) and IDH-wildtype (2.9%; 4/137) tumors. IDH-wildtype false positives were all WHO grade IV, whereas IDH-mutant false positives spanned WHO grades II-IV. Testing for 1p/19q codeletion would not have been indicated for most false positives based on current classification recommendations.ConclusionSelective 1p/19q codeletion testing and cautious interpretation for conflicting FISH and histopathological findings are recommended to avoid potential misdiagnosis.

10522 Background: The limited therapeutic options and dismal prognosis for patients (pts) with angiosarcomas (AS) provide a strong rationale for the evaluation of new therapies. Preclinical studies in AS tumor models have shown antitumor effects of antiangiogenic agents. We conducted a phase II study to determine the antitumor effect of bevacizumab in AS. Methods: The study was a two-stage design in which patients with newly diagnosed or relapsed/refractory AS and epithelioid hemangioendotheliomas were treated with bevacizumab 15 mg/kg IV every 3 weeks. Treatment was continued until progression or unacceptable toxicity. Response was assessed by RECIST criteria. Results: To date, of 29 pts enrolled, 28 received treatment. Baseline data on 29 pts are: M:F= 12:17 and median age 62 (range 18–94). Three pts are not evaluable (1 too early, 2 full treatment not given). Among 26 pts evaluable for response so far: 3 have PR (range 3–16 cycles), 13 have SD (3–32 cycles) and 10 have PD. ORR 3/26 (12%). After 141 cycles of therapy, only 1 grade 4 adverse event occurred (thrombocytopenia) and 5 patients experienced a grade 3 adverse event (anemia, pleural effusion, congestive heart failure, pain, headache, and nausea). Conclusions: Bevacizumab monotherapy for AS resulted in a response rate of 12% and tumor stabilization achieved by 62% of pts. Further studies with bevacizumab in combination with chemotherapy should be explored in this disease. No significant financial relationships to disclose.

6587 Background: Increasing numbers of clinical trials include optional or mandatory pharmaco-dynamic and -kinetic assays. Since little is known about patients’ (pts) perceived willingness to undergo specific tests and the number of tests pts would tolerate on a single trial, this study was conducted. Secondary purposes included correlating test number and type with demographics, prior test experience, coverage, and inconvenience. Methods: Exploratory correlative study using a multi-item self-report questionnaire to measure pts willingness (0–10 scale, 0 = not willing, 10 = very willing) to undergo imaging (e.g., MRI, ECHO), invasive (e.g., tumor, skin biopsies [bx]) and less invasive tests (e.g., blood, urine). 61 pts (22 female, 39 male) with advanced malignancies participating in phase I or II trials at one institution were enrolled from June 2008-December 2008. Descriptive and non-parametric statistics were used. Results: Statistically significant (p < 0.01) inverse relationships were found between the number of imaging studies (e.g., CT, ECHO), tests required (e.g., tumor, skin bx, blood draws) and pts reported willingness to undergo these tests. Pts were least willing to undergo tumor bx (median 5.5, interquartile range [IQR] 3.5–10), skin bx (6.8, 3.1–10), and unexpectedly MRIs (8, 4–10) (all p < 0.01). Surprisingly, inconvenience and prior negative experiences for the more invasive tests (e.g., skin bx) did not negatively affect willingness to undergo these tests in the future as opposed to most imaging studies. College-educated were more willing to undergo tests than non-college educated. Few pts were unwilling to undergo tests/procedures at all, if mandatory for enrollment. Conclusions: Results provide improved understanding of pts willingness to undergo trial requirements and suggest that adequate explanation (e.g., MRI) and test rationale may affect willingness to undergo tests. Findings can be used to improve study design and consent procedures to minimize patient discomfort and inconvenience. The overall willingness of advanced stage cancer pts to undergo study specific tests/procedures is high. No significant financial relationships to disclose.