Citations

Abstract Background This study compared the ergonomics of surgeons during deep inferior epigastric perforator (DIEP) flap surgery using either baseline equipment (loupes, headlights, and an operating microscope) or an exoscope. Plastic surgeons may be at high risk of musculoskeletal problems. Recent studies indicate that adopting an exoscope may significantly improve surgeon postures and ergonomics. Methods Postural exposures, using inertial measurement units at the neck, torso, and shoulders, were calculated in addition to the surgeons' subjective physical and cognitive workload. An ergonomic risk score on a scale of 1 (lowest) to 4 (highest) was calculated for each of the postures observed. Data from 23 bilateral DIEP flap surgeries (10 baseline and 13 exoscope) were collected. Results The neck and torso risk scores decreased significantly during abdominal flap harvest and chest dissection, while right shoulder risk scores increased during the abdominal flap harvest for exoscope DIEP flap procedures compared with. Exoscope anastomoses demonstrated higher neck, right shoulder, and left shoulder risk scores. The results from the survey for the “surgeon at abdomen” showed that the usage of exoscopes was associated with decreased performance and increased mental demand, temporal demand, and effort. However, the results from the “surgeon at chest” showed that the usage of exoscopes was associated with lower physical demand and fatigue, potentially due to differences in surgeon preference. Conclusion Our study revealed some objective evidence for the ergonomic benefits of exoscope; however, this is dependent on the tasks the surgeon is performing. Additionally, personal preferences may be an important factor to be considered in the ergonomic evaluation of the exoscope.

Two attending surgeons (surgeon at abdomen and surgeon at chest) and nine surgical trainees completed electronic surveys after deep inferior epigastric perforator (DIEP) flap surgical procedures. The survey included workload and teamwork subscales. The results indicated that DIEP flap surgery is a highly demanding surgical procedure both physically and cognitively. For the surgeon at abdomen, most of workload subscales were significantly higher than the paired trainees (p<0.05), while their teamwork subscales were not significantly different. The surgical trainees should know that the attending surgeon’s self-perceived workload could be higher than theirs even when their self-perceived teamwork is similar. For the surgeon at chest, most of teamwork subscales were significantly higher than the paired trainees (p<0.05), while their workload subscales were not significantly different. The attending surgeons should know that even when their self-evaluation of workload is similar to their trainees, the trainee’s evaluation of teamwork could be less than theirs.

Zusammenfassung Hintergrund Die Brustrekonstruktion mittels autologem Gewebe ist fester Bestandteil eines ganzheitlichen Therapiekonzeptes bei Patientinnen mit Mammakarzinom. Während zahlreiche Studien den körperlichen und psychischen Gesundheitszustand von Patientinnen mit Brustkrebs nach Mastektomie und konsekutiver Brustrekonstruktion untersuchen, mangelt es an objektiven Daten zur Beurteilung des Einflusses von Ablatio und Brustrekonstruktion auf die Wahrnehmung von externen Beobachtern. Diese Studie untersucht die Blickmuster bei Betrachtung einer Brust in verschiedenen Stadien der Brustrekonstruktion mittels DIEP Lappenplastik. Material und Methoden Mittels Eye-Tracking-Technologie wurden die Augenbewegungen von 58 Studienteilnehmer*in- nen beim Betrachten von 2D-Fotografien einer Patientin in den verschiedenen Stadien der Brustrekonstruktion (1. Ablatio, 2. Aufbau mittels DIEP Lappenplastik, 3. MAK Rekonstruktion) analysiert. Die Zeit bis zur ersten Fixierung und die Dauer der Fixierung wurde in jedem Bild für die rechte und linke Brust aufgezeichnet. Ergebnisse Die Dauer der kompletten Fixierung der operierten Brust zeigte über die verschiedenen Stadien der Brustrekonstruktion insgesamt eine signifikante Abnahme mit p<0,001. Gleichzeitig zeigte sich keine statistisch signifikante Veränderung der Blickdauer auf der nicht-operierten Gegen- seite mit p=0,174. Die Zeit bis zur ersten Blickfixierung der betroffenen Brust zeigte eine signifikante Zunahme über die verschiedenen Rekonstruktionsschritte, mit p<0,001. Bei der Gegenseite zeigte sich kein statistisch signifikanter Unterschied in der Zeit bis zur ersten Fixierung, mit p=0,344. Schlussfolgerung Die Ablatio mammae und die einzelnen Schritte der Brustrekonstruktion verändern die äußerliche Wahrnehmung von Patientinnen. Im Laufe der einzelnen re- konstruktiven Teilschritte kommt es zu einer zunehmenden Aufhebung der Blickdeviation in Richtung erkrankte Brust.

Abstract Background: Cholangiocarcinoma is an aggressive malignancy with limited systemic therapeutics. We have recently identified LCK, a non-receptor tyrosine kinase, as a potential therapeutic target in select subtypes of cholangiocarcinoma. Proteomic profiling in other cancer types has proven beneficial in predicting response to systemic therapies. Herein, we present proteomic profiling of cholangiocarcinoma can predict sensitivity to a novel LCK inhibitor in patient derived xenograft models. Methods: Proteins from 28 unique cholangiocarcinoma patient derived xenograft models (PDX) were isolated, labeled with tandem mass tags (TMT) and then analyzed by liquid chromatography and mass spectroscopy (LC/MS). Phosphopeptides were separately evaluated both by Immobilized Metal Affinity Chromatography and pY-enrichment techniques. Following normalization, the global proteome, serine/threonine phosphoproteome, and tyrosine phosphoproteome were analyzed and a proteomic signature was created for each tumor. These signatures were compared to PDX models with known response profiles to NTRC0652-0, an LCK inhibitor (1 resistant and 1 sensitive). The top 200 differentially abundant proteins (log2FC 2.6) were then utilized to develop a sensitive and a resistant signature. Correlation indices were then calculated across the 28 PDX model library. An additional predicted resistant and predicted sensitive model was expanded. Tumor bearing mice were randomized based on tumor volume to either treatment with NTRC (30mg/kg PO daily), n=5, or vehicle, n=4, (10% Kolliphor, 10% DMSO, 80% Water, 2 mol equivalents HCl). Tumors were measured weekly with calipers and then weighed at the end of the study. Results: In the top 200 differentially abundant proteins that represented the proteomic signature there was over representation of proteins with decreased abundance. There were only 12 proteins with higher abundance in the sensitive model as compared to the resistant. Utilizing the signature developed from the global proteomics data, nine tumors were predicted to be sensitive while 17 were predicted to be resistant to NTRC. PDX115 is a an intrahepatic CCA PDX known to contain an IDH1 mutation and was predicted to be resistant by modeling. The model was resistant to single agent NTRC with no demonstrable effect on tumor growth in vivo. PDX175 is a distal CCA PDX and was predicted to be sensitive by modeling. In vivo growth was inhibited by NTRC as compared to vehicle treated mice following two weeks of treatment (983% vs 435%, p=0.03). Additionally, final tumor weight was significantly lower in NTRC treated mice (0.651 g vs 0.317 g, p=0.04). Conclusion: Cholangiocarcinoma proteomic signatures can be used to predict therapeutic response to a novel LCK inhibitor in preclinical models. Whether or not this could be applied to other treatment modalities in cholangiocarcinoma remains to be determined. Citation Format: Ryan Watkins, Roberto Alva-Ruiz, Caitlin Conboy, Dong-Gi Mun, Erik Jessen, Diep Vu, Jos de Man, Rogier Buijsman, Akhilesh Pandey, Mitesh Borad, Gregory Gores, Rory Smoot. Proteomic profiling of cholangiocarcinoma predicts response to a novel small molecule inhibitor in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3094.

463 Background: Molecularly targeted therapy is gaining traction in cholangiocarcinoma with the first FDA approval of a targeted agent in 2020, the FGFR inhibitor pemigatinib. Yet response rates and efficacy are modest, and most cholangiocarcinoma patients still lack targeted therapy options. The hippo pathway effector, YAP, is an oncogene that is activated in the majority of cholangiocarcinoma, yet attempts to develop YAP inhibitors have not yet been clinically successful. Recently, we described a novel mechanism of YAP regulation, via tyrosine phosphorylation by the Src-family kinase LCK. Therefore we hypothesized that LCK inhibition by may be therapeutic in cholangiocarcinoma through suppression of YAP activity. Methods: NTRC 0652-0 is a novel tyrosine kinase inhibitor with specificity for LCK. In vitro pharmacodynamics were defined. In cholangiocarcinoma cells, specificity for LCK inhibition was determined by mass spectrometry-based unbiased analysis of the tyrosine phosphoproteome following treatment with NTRC 0652-0 or genetic deletion of LCK. YAP phosphorylation and cotranscriptional activity, cell viability, and apoptosis were assessed. A panel of eight cholangiocarcinoma patient derived organoids (PDO) were characterized and tested for sensitivity to NTRC 0652-0. Two patient-derived xenograft (PDX) models bearing FGFR2-rearrangements were utilized for in vivo assessment of pharmacokinetics, toxicity, and efficacy. Results: NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in cholangiocarcinoma cells. NTRC 0652-0 treatment led to YAP inhibition and apoptotic cell death in cholangiocarcinoma cell lines, associated with inhibition of MCL1 expression. PDOs demonstrated variable sensitivity to NTRC 0652-0, correlated with basal YAP tyrosine phosphorylation and drug-induced suppression of YAP co-transcriptional activity. FGFR2-altered cholangiocarcinoma was also identified as a subset with enrichment of YAP target genes. Cells from an FGFR2-altered PDX were sensitive to NTRC 0652-0 despite being primarily resistant to pemigatinib. In two PDX models of FGFR2-altered cholangiocarcinoma, daily oral treatment with NTRC 0652-0 inhibited YAP tyrosine phosphorylation, and resulted in stable plasma and tumor drug levels, acceptable toxicity, and significantly decreased tumor growth. Conclusions: A novel LCK inhibitor, NTRC 0652-0, reduced YAP signaling and demonstrated preclinical efficacy in multiple patient-derived models of cholangiocarcinoma. LCK is a novel therapeutic target in cholangiocarcinoma, and YAP activation or FGFR2-alteration are potential biomarkers for response.

The goal of this study was to evaluate residents’ workload and teamwork and the correlation between their workload and teamwork subscales during deep inferior epigastric perforator (DIEP) flap surgery. Ten residents who assisted during DIEP flap procedures completed an electronic survey following each DIEP flap procedure from July 2019 to August 2020. The survey contained items from the NASA-TLX and SURG-TLX and questions to measure teamwork subscales. Across 29 surgical cases, 38 surveys were recorded. Overall, the means of workload subscales were mostly greater than 10 and less than 15 (range=020) and the means of all teamwork subscales were greater than 15 (range=0-20). Good teamwork was correlated with lower distractions (Rs= -0.36 to -0.48) and better performance (Rs=0.35 to 0.52). Also, all the teamwork subscales were highly correlated (Rs= 0.59 to 0.92). Our findings suggest that good teamwork, low distractions, and successful performance are generally observed together; however, a causative relationship could not be established based on these results.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Abstract Background The deep inferior epigastric perforator (DIEP) flap is the most common perforator flap for microsurgical breast reconstruction. Contrary to the conventional open approach, robotic-assisted DIEP flap harvest intends to preserve ARS integrity, thereby reducing the morbidity. We assessed the feasibility and compared performance outcomes of a robotic, cadaveric training model for DIEP flap harvest using two approaches: transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP). Methods A robotics system (da Vinci Xi) was applied in conjunction with a cadaveric training model. Ports were placed in the abdominal wall to triangulate each DIEP flap. Surgical time and technical characteristics were recorded. Values were analyzed and compared. Results Eight female cadavers (16 hemi-DIEP flaps) were dissected: 50% TAPP and 50% TEP approaches. Mean harvest time was 56 minutes (range: 48–74 minutes) and 65 minutes (range: 60–83 minutes) for TAPP versus TEP groups, respectively (p < 0.05). Mean pedicle dissection time was 36 minutes (range: 25–40 minutes) and 39 minutes (range: 30–42 minutes) for TAPP versus TEP groups, respectively (p > 0.05). Intra-abdominal contents were manipulated twice on average in the TAPP group versus 0 times in the TEP group (p < 0.05). One TAPP case had an injury to the bowel, and one TEP case was converted to conventional open due to pneumoperitoneum. Conclusion Robotic-assisted DIEP flap harvest represents a technological enhancement for advanced regenerative plastic surgery. Our model demonstrated both TAPP and TEP are feasible, with TEP less invasive, preserving the posterior rectus sheath, and decreasing complication risks. However, there is a steeper and longer learning curve for TEP.