Abdelrahman, Amro M.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US). Patients with MANEC-P were identified through the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries databases between 2000–2017. The primary outcomes included age-adjusted incidence rate, limited-duration prevalence, and CSS. A total of 630 patients were identified for the incidence analysis and 149 for the prevalence and CSS analyses. The MANEC-P incidence rate was 0.011 per 100,000 individuals, which was the lowest among pancreatic cancer histologic subtypes. The incidence rate was significantly higher in men and Black races and peaked at 75–79 years of age. The incidence rate was the lowest in the midwestern region (0.009) and the highest in the northeastern US (0.013). The 17-year prevalence was 0.00005%, indicating that 189 patients were alive in the United States at the beginning of 2018. The median CSS of MANEC-P was estimated to be 41 (23, 69) months. In conclusion, MANEC-P is very rare, and its incidence rate has been steady in the US over the last two decades. MANEC-P has a poor prognosis and is the 5th leading cause of pancreatic cancer-related death in the US.

591 Background: Cholangiocarcinoma (CCA) is a lethal disease with limited therapeutic options. We have demonstrated the interaction of Src-family kinase LCK with AXL, a TAM receptor tyrosine kinase (RTK), by phosphoproteomic analysis in CCA ( J Hepatol 2022). AXL is reported to act as a mechanism of acquired drug resistance in solid cancers. However, the role of AXL in CCA remains to be elucidated. Here, we investigated the significance of AXL expression as a potential therapeutic target in CCA. Methods: We first evaluated the expression levels of AXL in CCA and the associations with patient outcome using publicly available data from The Cancer Genome Atlas (TCGA). Next, to evaluate whether AXL inactivation sensitizes CCA cells to gemcitabine and cisplatin (GemCis) therapy as a standard therapy. AXL downregulation was achieved via siRNA approach and the selective inhibitor bemcentinib. We examined 50% inhibitory concentration (IC50) value of HuCCT1, a well characterized CCA cell line, on GemCis therapy with and without AXL knockdown using CellTiter-Glo cell viability assay. Then we assessed the efficacy of the combinatorial therapy of GemCis and bemcentinib utilizing Calcusyn software. Finally, apoptosis was evaluated by Annexin V assay. In vivo efficacy was assessed using a SB-1 (murine CCA cell line) and syngeneic murine model of CCA in C57Bl/6J mice treated with vehicle, GemCis, bemcentinib, and the combination of GemCis and bemcentinib. Results: In the TCGA cohorts, AXL is significantly expressed in CCA (P < 0.01), and disease-free survival and overall survival in low AXL expression group are significantly longer than those in high AXL expression group (P = 0.04, 0.01). In in vitro study, IC50 value of GemCis was decreased from 685nM to 129nM after AXL knockdown. Synergy effect was observed with the value of CI = 0.17 and Fa = 0.50 in the combinatorial therapy. The combinatorial therapy caused significantly increased apoptosis compared to GemCis or bemcentinib alone (P < 0.01, P < 0.01). In in vivo study, the combinatorial therapy significantly suppressed the tumor growth compared to GemCis or bemcentinib alone (P = 0.04, 0.01). Conclusions: Targeting AXL sensitizes CCA cell lines and preclinical models to standard of care GemCis combinatorial therapy. Our study suggests that the addition of AXL targeted therapy to cytotoxic chemotherapy can increase the response in CCA patients and is a promising combination.

Background: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival. Methods: We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS). Results: We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P <.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13–0.40), and was highly correlated ( P =.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor ( P <.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9–153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2–0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1–0.4). Conclusions: Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.

Abstract Background and aims Biliary tract cancers (BTCs) are uncommon, but highly lethal, gastrointestinal malignancies. Gemcitabine/cisplatin is a standard‐of‐care systemic therapy, but has a modest impact on survival and harbors toxicities, including myelosuppression, nephropathy, neuropathy, and ototoxicity. Whereas BTCs are characterized by aberrations activating the cyclinD1/cyclin‐dependent kinase (CDK)4/6/CDK inhibitor 2a/retinoblastoma pathway, clinical use of CDK4/6 inhibitors as monotherapy is limited by lack of validated biomarkers, diffident preclinical efficacy, and development of acquired drug resistance. Emerging studies have explored therapeutic strategies to enhance the antitumor efficacy of CDK4/6 inhibitors by the combination with chemotherapy regimens, but their mechanism of action remains elusive. Approach and results Here, we report in vitro and in vivo synergy in BTC models, showing enhanced efficacy, reduced toxicity, and better survival with a combination comprising gemcitabine/cisplatin and CDK4/6 inhibitors. Furthermore, we demonstrated that abemaciclib monotherapy had only modest efficacy attributable to autophagy‐induced resistance. Notably, triplet therapy was able to potentiate efficacy through elimination of the autophagic flux. Correspondingly, abemaciclib potentiated ribonucleotide reductase catalytic subunit M1 reduction, resulting in sensitization to gemcitabine. Conclusions As such, these data provide robust preclinical mechanistic evidence of synergy between gemcitabine/cisplatin and CDK4/6 inhibitors and delineate a path forward for translation of these findings to preliminary clinical studies in advanced BTC patients.

Abstract Background: Mixed acinar neuroendocrine carcinoma (MANEC) of the pancreas is an extremely rare histopathologic subtype. MANEC is an amphicrine malignancy composed of at least 25% of acinar cell carcinoma (PACC) and neuroendocrine carcinoma (pNET). No standard systemic treatment is available for MANEC and current recommendations are derived from standard of care for PACC or pNET. Platinum based regimens have been approved for PACC while targeted agents (sunitinib and everolimus) are approved for pNET. This study aimed to investigate the antitumor effect and toxicities of both platinum based and targeted agents on a successfully first described patient derived xenograft (PDX) of metastatic MANEC of the pancreas. Methods: Several generations of PDX from a surgically resected metastatic MANEC of the pancreas was histologically validated. PDX-MANEC tumors were heterotopically implanted into NOD/SCID mice and randomized into 6 groups (4 mice each) as in table 1. The study continued for 3 weeks. Antitumor efficacy was determined based on change in the tumor volume. Toxicity was assessed change in mice weights. Results: Table 1 shows the changes in tumor volume and mouse weight in all study arms compared to controls end point. Only FOLFIRINOX and gemcitabine/cisplatin arms revealed overall decrease in tumor volume lower than starting volume in controls. All arms other than sunitinib, led to decrease in overall tumor volume compared to control tumor volumes over time. All treatment arms led to lower trending mouse weights (toxicities) except sunitinib, however only the everolimus arm had statistical significance. Conclusion: Both platinum-based regimens and everolimus revealed significant tumor control. No synergistic effect observed in sunitinib/everolimus. Preclinical studies are undergoing to investigate other effective and less toxic therapeutics for MANEC. Table 1.Delta in tumor volumes of PDX-MANEC-P after multiple platinum-based chemotherapy regimens and targeted therapeutics from the standard of care for other pancreatic cancer subtypes including PACC and pNET.ControlFOLFIRINOXGemcitabine and CisplatinSunitinibEverolimusSunitinib and EverolimusDelta in tumor volume in mm3 at the study end (mean ± standard deviation)3225 ± 2054-609.3 ± 351.8-654.7 ± 92.561583 ± 950.3-178.1 ± 61.58-160.8 ± 86.55P value (column group vs. control)&lt;0.0010.0030.0950.0010.001Delta in mice weight in grams at the study end (mean ± standard deviation)0.84 ± 1.68-1.26 ± 0.84-8.5 ± 1.630.86 ± 1.22-2.2 ± 1.61-1.42 ± 1.27P value (column group vs. control)0.058&lt;0.0010.9810.0070.050 Citation Format: Amro M. Abdelrahman, Jennifer A. Yonkus, Roberto Alva-Ruiz, Jennifer L. Leiting, Nellie A. Campbell, Lewis R. Roberts, Michael L. Kendrick, David M. Nagorney, Sean P. Cleary, Travis E. Grotz, Gregory J. Gores, Jun Yin, Rondell P. Graham, Thorvardur R. Halfdanarson, Rory L. Smoot, Mark J. Truty. Preclinical efficacy of platinum based chemotherapy regimens and targeted therapeutics in the first successful described patient derived xenograft model of mixed acinar neuroendocrine carcinoma of the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 413.

Abstract Objective The American College of Surgeons (ACS) encourages clinicians to provide training to laypeople on tourniquet application. It is unclear whether clinicians are confident in their abilities and equipped with adequate knowledge, skills, and resources. This study aimed to determine surgical trainee knowledge and attitudes regarding tourniquet application and compare the effectiveness of instructions. Methods Thirty surgical trainees performed a tourniquet application simulation using a Combat Application Tourniquet and one of the three instructions sets developed by ACS, Department of Homeland Security, and the tourniquet manufacturer. Participants reported tourniquet knowledge, attitudes, and confidence and discussed the instructions. One instruction set was updated and compared to the original set with 20 new trainees. Results Participants with ACS instructions passed the greatest number of steps (p &lt; 0.01) and completed the task significantly faster compared to those with manufacturer instructions (p &lt; 0.01). Participants (80%) reported favorable views toward tourniquets but 30–60% did not align with to ACS tourniquet guidelines. Focus group participants suggested revisions to the ACS instructions. Comparing the original and revised version of these instructions resulted in no significant improvements. Conclusions ACS instructions provide guidance; however, improvements to tourniquet instruction are needed for success in controlling exsanguinating hemorrhage.

Microsurgery is considered one of the most demanding surgical techniques. In a recent American Society of Reconstructive Microsurgeons survey, respondents reported that about half their procedures lasted 8 hours or longer and 8% had tremor during their surgery. Thus, the aim of this study was to define user centered design requirements for a microsurgery armrest, create low-fidelity armrest design concepts and evaluate microsurgeons’ perspectives on the advantages/disadvantages of five potential design concepts. Direct and videotaped observations of microsurgery, user brainstorming during a co-creation workshop and semi-structured interviews were used. The resulting five microsurgery armrest concepts were presented pictorially through semi-structured interviews, where microsurgeons defined armrest design requirements as: a) an armrest that allows the surgeons to be as close as possible to the patient; b) adjustable to accommodate different procedures sites and surgeon preferences; c) rigid enough to support arms; d) is not difficult to set up; nor e) large or bulky; and f) complies with operative sterility rules. This study illustrated how involving the users (microsurgeons) early in the design process provides useful perspectives on design requirements and implementation barrier for a cost-effective ergonomic microsurgery armrest to foster sound ergonomic surgical practice and reduce musculoskeletal health risk factors during microsurgery.

Periodic intraoperative microbreaks with calesthenic exercises performed within the sterile field improved self-reported mental focus (38%) and physical performance (57%) for 56 surgeons. Therefore, targeted stretching exercises and a web-application (web-app) leading the stretches with a reminder system were developed and piloted using user-centered design principles. A focus group with 10 users was conducted to refine the developed app. Seven surgeons (4 females) at a quaternary medical institute piloted the periodic stretching web-app in their operating rooms. At the end of each surgical day, the surgeons completed a short survey about the intraoperative stretching exercises web-app impact on their physical performance, mental focus and workflow disruption. Non-Routine Events were captured during the procedures. Twelve surgical days were followed with a median of 6 microbreaks/day/surgeon. Results showed that better physical performance and lower fatigue were reported (91.7%) across the surgical days, also better mental focus was reported (83.3%) across the surgical days, and less pain/discomfort was reported (100%) across the surgical days, with others reporting no change. The web-app leading sterile field microbreak stretches helped reduce physical pain, discomfort/pain, fatigue, and improve mental focus with minimal disruption for a small sample. The web-app is a promising tool for improving surgeon mental focus and physical performance and potentially musculoskeletal health.

With advancements in surgical techniques, patients have experienced improvements in health and recovery outcomes. However, about 87% of laparoscopic surgeons [1] and an increasing number of surveyed allied health professionals [2, 3] report musculoskeletal symptoms. Medical practitioners and human factors engineers have highlighted the “hostile” and “dangerous” operating room (OR) environment [1, 4, 5]. With increasing technology and surgical case complexity, physical demands for surgical team members will continue to increase due to circumstances such as technology restricting posture, taking up working space and more team members working around smaller surgical incisions [6]. There is widespread concern that these medical professionals’ work is unsustainable for safe and healthy patients and surgical team members. Surgical team members can benefit from posture improvement during surgery; however, direct postural feedback may be difficult during their work due to the high visual and auditory stimuli during surgery. The tactile modality has been recently explored as a method to provide additional information without interfering with cognitive resources dedicated to visual and auditory pathways [7]. Tactile devices have successfully been implemented in high-stress environments, e.g., military, healthcare, and rehabilitation with a resulting improvement in performance [8–11]. Vibrotactile feedback has been specifically implemented in the healthcare field for improved performance by 31–75% anesthesiologists during simulated tasks [10]. Additionally, it has contributed to improved postural control in rehabilitation patients[11]. Despite success in other application areas, the potential of tactile devices for improving healthcare workers’ safety and performance remains unexplored. This study is a part of a larger project to design a wearable device that provides realtime vibrotactile feedback for preventing fatigue and musculoskeletal disorders for healthcare workers in the workplace. This specific aim of this study is to measure distraction, frustration, and performance during a surgical simulation task performed with and without vibrotactile feedback. This is a test of initial feasibility of vibrotactile feedback for use in training proper ergonomics for surgical team members. The researchers hypothesize that there will be some distraction with the vibrotactile feedback wearable but no frustration or performance degradation during the basic simulation task.

The American College of Surgeons (ACS) and the Department of Homeland Security (DHS) encourage the use of tourniquets as part of the “Stop the Bleed” campaign. Both have provided instructions for layperson tourniquet application in order to save the life of a hemorrhaging trauma victim. This study sought to compare the impact of using ACS and DHS instructions with manufacturer-provided instructions for the completion of simulated tourniquet application steps. Thirty surgical trainees completed a simulated tourniquet application with one of the three instruction sets. Their completion time and success for each step were measured. Participants that received ACS instructions failed the fewest number of steps (p < 0.01) and completed the task faster (Mean (SD) = 70 (33) seconds) compared to those with the manufacturer-provided instructions (p < 0.01). Tourniquet instruction sets need to be refined in order to optimize the success rate of just-in-time guidance for tourniquet application.