Citations

Abstract Background National guidelines recommend genomic profiling of tumor tissue to guide precision therapy. We compared the specimen adequacy for genomic profiling and yield of DNA between endoscopic ultrasound (EUS)-guided fine-needle biopsy (FNB) and EUS-guided fine-needle aspiration (FNA). Methods In our tandem, randomized controlled trial, consecutive patients undergoing EUS for evaluation of pancreatic masses underwent both conventional EUS-FNA with a 25-gauge needle and paired EUS-FNB (19 or 22-gauge needle), with the order randomized (EUS-FNA first followed by EUS-FNB, or vice versa). A minimum of one pass with each needle was obtained for histology. Second and third passes were performed to collect DNA. Specimens were evaluated by a cytopathologist blinded to the needle type. Specimen adequacy for genomic profiling was calculated based on FoundationOne clinical diagnostic (CDx) adequacy requirements. We compared the adequacy for genomic profiling DNA (quantity) and histology yields with both needles. Results Analysis included 50 patients (25 men; mean age 68 [standard deviation (SD) 13] years), with a mean lesion size of 38 (SD 17) mm; 37 lesions (74 %) were pancreatic ductal adenocarcinoma (PDAC). The mean DNA concentrations in PDAC by FNB and FNA needles were 5.930 (SD 0.881) µg/mL vs. 3.365 (SD 0.788) µg/mL, respectively (P = 0.01). The median standardized histology score per pass with EUS-FNB was 5 (sufficient for histology) and for EUS-FNA was 2 (enough for cytology). Specimen adequacy for genomic profiling and yield of DNA was significantly higher with FNB than with FNA needles. Conclusions In this study, adequacy for genomic profiling, DNA, and histology yield were considerably superior using an EUS-FNB needle compared with an EUS-FNA needle.

9017 Background: Bevacizumab is a humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF-A) that has demonstrated significant growth inhibition in several pre-clinical models of pediatric solid tumors. However, the agent has never been tested in pediatric patients. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the dose limiting toxicities (DLTs), and to determine the pharmacokinetics (PK) and recommended phase II dose of bevacizumab administered by IV infusion every 2 weeks in 28-day cycles. Cohorts were enrolled at dose levels of 5, 10, and 15 mg/kg; the final dose level was expanded to include at least 3 children <6 years of age. Serial blood samples were collected for PK, plasma VEGF concentration, and circulating mature and progenitor endothelial cells (CECs/CEPs). Results: 20 patients (10 male), median age 13 yrs (range 1–21), were enrolled at dose levels 5 (n=3), 10 (n=3), and 15 (n=14) mg/kg. 18 patients were fully evaluable for toxicity (one withdrew consent prior to treatment and the second was removed for rapid disease progression). A total of 67 cycles were administered with a median of 3 per patient (range 1–16). Treatment was well tolerated and no DLTs were observed. Only one grade 3 toxicity, lymphopenia, was attributed to drug. Non-dose limiting, grade 1–2 toxicities included infusional reaction (n=3), rash (n=3), mucositis (n=2), and proteinuria (n=3). There was no hypertension, hemorrhage or thrombosis reported. There were no partial or complete responses; 3 pts with Ewings and 2 pts with soft tissue sarcoma had disease stabilization for > 3 months. The serum exposure to bevacizumab as measured by AUC appeared to increase in proportion to dose. The median clearance of bevacizumab was 4.1 ml/day/kg (range 3.2–15.9), and the median T1/2 was 11.8 days (range 3.9–14.6). In some patients, a rapid rate of rise in plasma VEGF, increase in mature CECs or decrease in CEPs was observed. Conclusion: Bevacizumab at doses up to 15mg/kg every two weeks is well tolerated in children with solid tumors. No significant financial relationships to disclose.

ABSTRACTCell‐based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell‐based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web‐based marketing and patient testimonials supporting cell‐based therapy. Both the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS) are committed to ensuring that the potential of cell‐based therapies is realized through rigorous, reproducible, and clinically meaningful scientific discovery. The two organizations convened a multidisciplinary and international Task Force composed of physicians, surgeons, and scientists who are recognized experts in the development and use of cell‐based therapies. The Task Force was charged with defining the state‐of‐the art in cell‐based therapies and identifying the gaps in knowledge and methodologies that should guide the research agenda. The efforts of this Task Force are designed to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell‐based therapies for skeletal tissues. The design and implementation of rigorous, thorough protocols will be critical to leveraging these innovative treatments and optimizing clinical and functional patient outcomes. In addition to providing specific recommendations and ethical considerations for preclinical and clinical investigations, this report concludes with an outline to address knowledge gaps in how to determine the cell autonomous and nonautonomous effects of a donor population used for bone regeneration. © 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:485–502, 2020

ABSTRACT Cell-based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell-based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web-based marketing and patient testimonials supporting cell-based therapy. Both the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS) are committed to ensuring that the potential of cell-based therapies is realized through rigorous, reproducible, and clinically meaningful scientific discovery. The two organizations convened a multidisciplinary and international Task Force composed of physicians, surgeons, and scientists who are recognized experts in the development and use of cell-based therapies. The Task Force was charged with defining the state-of-the art in cell-based therapies and identifying the gaps in knowledge and methodologies that should guide the research agenda. The efforts of this Task Force are designed to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell-based therapies for skeletal tissues. The design and implementation of rigorous, thorough protocols will be critical to leveraging these innovative treatments and optimizing clinical and functional patient outcomes. In addition to providing specific recommendations and ethical considerations for preclinical and clinical investigations, this report concludes with an outline to address knowledge gaps in how to determine the cell autonomous and nonautonomous effects of a donor population used for bone regeneration. © 2019 American Society for Bone and Mineral Research.

SummaryBackgroundBecause most pancreatic intraductal papillary mucinous neoplasms (IPMNs) will never become malignant, currently advocated long‐term surveillance is low‐yield for most individuals.AimTo develop a score chart identifying IPMNs at lowest risk of developing worrisome features or high‐risk stigmata.MethodsWe combined prospectively maintained pancreatic cyst surveillance databases of three academic institutions. Patients were included if they had a presumed side‐branch IPMN, without worrisome features or high‐risk stigmata at baseline (as defined by the 2012 international Fukuoka guidelines), and were followed ≥ 12 months. The endpoint was development of one or more worrisome features or high‐risk stigmata during follow‐up. We created a multivariable prediction model using Cox‐proportional logistic regression analysis and performed an internal‐external validation.Results875 patients were included. After a mean follow‐up of 50 months (range 12‐157), 116 (13%) patients developed worrisome features or high‐risk stigmata. The final model included cyst size (HR 1.12, 95% CI 1.09‐1.15), cyst multifocality (HR 1.49, 95% CI 1.01‐2.18), ever having smoked (HR 1.40, 95% CI 0.95‐2.04), history of acute pancreatitis (HR 2.07, 95% CI 1.21‐3.55), and history of extrapancreatic malignancy (HR 1.34, 95% CI 0.91‐1.97). After validation, the model had good discriminative ability (C‐statistic 0.72 in the Mayo cohort, 0.71 in the Columbia cohort, 0.64 in the Erasmus cohort).ConclusionIn presumed side branch IPMNs without worrisome features or high‐risk stigmata at baseline, the Dutch‐American Risk stratification Tool (DART‐1) successfully identifies pancreatic lesions at low risk of developing worrisome features or high‐risk stigmata.

Objective This study aimed to evaluate a deep learning protocol to identify neoplasia in intraductal papillary mucinous neoplasia (IPMN) in comparison to current radiographic criteria. Methods A computer-aided framework was designed using convolutional neural networks to classify IPMN. The protocol was applied to magnetic resonance images of the pancreas. Features of IPMN were classified according to American Gastroenterology Association guidelines, Fukuoka guidelines, and the new deep learning protocol. Sensitivity and specificity were calculated using surgically resected cystic lesions or healthy controls. Results Of 139 cases, 58 (42%) were male; mean (standard deviation) age was 65.3 (11.9) years. Twenty-two percent had normal pancreas; 34%, low-grade dysplasia; 14%, high-grade dysplasia; and 29%, adenocarcinoma. The deep learning protocol sensitivity and specificity to detect dysplasia were 92% and 52%, respectively. Sensitivity and specificity to identify high-grade dysplasia or cancer were 75% and 78%, respectively. Diagnostic performance was similar to radiologic criteria. Areas under the receiver operating curves (95% confidence interval) were 0.76 (0.70–0.84) for American Gastroenterology Association, 0.77 (0.70–0.85) for Fukuoka, and 0.78 (0.71–0.85) for the deep learning protocol ( P = 0.90). Conclusions The deep learning protocol showed accuracy comparable to current radiographic criteria. Computer-aided frameworks could be implemented as aids for radiologists to identify high-risk IPMN.