Transforming the Future of Surgeon-Scientists.

OBJECTIVE: To create a blueprint for surgical department leaders, academic institutions, and funding agencies to optimally support surgeon-scientists. BACKGROUND: Scientific contributions by surgeons have been transformative across many medical disciplines. Surgeon-scientists provide a distinct approach and mindset toward key scientific questions. However, lack of institutional support, pressure for increased clinical productivity, and growing administrative burden are major challenges for the surgeon-scientist, as is the time-consuming nature of surgical training and practice. METHODS: An American Surgical Association Research Sustainability Task Force was created to outline a blueprint for sustainable science in surgery. Leaders from top NIH-sponsored departments of surgery engaged in video and in-person meetings between January and April 2023. A strength, weakness, opportunities, threats analysis was performed, and workgroups focused on the roles of surgeons, the department and institutions, and funding agencies. RESULTS: Taskforce recommendations: (1) SURGEONS: Growth mindset : identifying research focus, long-term planning, patience/tenacity, team science, collaborations with disparate experts; Skill set : align skills and research, fill critical skill gaps, develop team leadership skills; DEPARTMENT OF SURGERY (DOS): (2) MENTORSHIP: Chair : mentor-mentee matching/regular meetings/accountability, review of junior faculty progress, mentorship training requirement, recognition of mentorship (eg, relative value unit equivalent, awards; Mentor: dedicated time, relevant scientific expertise, extramural funding, experience and/or trained as mentor, trusted advisor; Mentee : enthusiastic/eager, proactive, open to feedback, clear about goals; (3) FINANCIAL SUSTAINABILITY: diversification of research portfolio, identification of matching funding sources, departmental resource awards (eg, T-/P-grants), leveraging of institutional resources, negotiation of formalized/formulaic funds flow investment from academic medical center toward science, philanthropy; (4) STRUCTURAL/STRATEGIC SUPPORT: Structural: grants administrative support, biostats/bioinformatics support, clinical trial and research support, regulatory support, shared departmental laboratory space/equipment; Strategic: hiring diverse surgeon-scientist/scientists faculty across DOS, strategic faculty retention/ recruitment, philanthropy, career development support, progress tracking, grant writing support, DOS-wide research meetings, regular DOS strategic research planning; (5) COMMUNITY AND CULTURE: Community: right mix of faculty, connection surgeon with broad scientific community; Culture: building research infrastructure, financial support for research, projecting importance of research (awards, grand rounds, shoutouts); (6) THE ROLE OF INSTITUTIONS: Foundation: research space co-location, flexible start-up packages, courses/mock study section, awards, diverse institutional mentorship teams; Nurture: institutional infrastructure, funding (eg, endowed chairs), promotion friendly toward surgeon-scientists, surgeon-scientists in institutional leadership positions; Expectations: RVU target relief, salary gap funding, competitive starting salaries, longitudinal salary strategy; (7) THE ROLE OF FUNDING AGENCIES: change surgeon research training paradigm, offer alternate awards to K-awards, increasing salary cap to reflect market reality, time extension for surgeon early-stage investigator status, surgeon representation on study section, focused award strategies for professional societies/foundations. CONCLUSIONS: Authentic recommitment from surgeon leaders with intentional and ambitious actions from institutions, corporations, funders, and society is essential in order to reap the essential benefits of surgeon-scientists toward advancements of science.

Integrative PTEN Enhancer Discovery Reveals a New Model of Enhancer Organization.

Enhancers possess both structural elements mediating promoter looping and functional elements mediating gene expression. Traditional models of enhancer-mediated gene regulation imply genomic overlap or immediate adjacency of these elements. We test this model by combining densely-tiled CRISPRa screening with nucleosome-resolution Region Capture Micro-C topology analysis. Using this integrated approach, we comprehensively define the cis-regulatory landscape for the tumor suppressor PTEN, identifying and validating 10 distinct enhancers and defining their 3D spatial organization. Unexpectedly, we identify several long-range functional enhancers whose promoter proximity is facilitated by chromatin loop anchors several kilobases away, and demonstrate that accounting for this spatial separation improves the computational prediction of validated enhancers. Thus, we propose a new model of enhancer organization incorporating spatial separation of essential functional and structural components.

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.

Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

Trends in Receipt of Adjuvant Chemotherapy and its Impact on Survival in Resected Biliary Tract Cancers.

BACKGROUND: Resection remains the cornerstone of curative-intent treatment for biliary tract cancers (BTCs). However, recent randomized data also support a role for adjuvant chemotherapy (AC). This study aimed to characterize trends in the use of AC and subsequent outcomes in gallbladder cancer and cholangiocarcinoma (CCA). METHODS: The National Cancer Database (NCDB) was queried for patients with resected, localized BTC from 2010 to 2018. Trends in AC were compared among BTC subtypes and stages of disease. Multivariable logistic regression was used to identify factors associated with receipt of AC. Survival analysis was performed with Kaplan-Meier and multivariable Cox proportional hazards methods. RESULTS: The study identified 7039 patients: 4657 (66%) with gallbladder cancer, 1159 (17%) with intrahepatic CCA (iCCA), and 1223 (17%) with extrahepatic CCA (eCCA). Adjuvant chemotherapy was administered to 2172 (31%) patients, increasing from 23% in 2010 to 41% in 2018. Factors associated with AC included female sex, year of diagnosis, private insurance, care at an academic center, higher education, eCCA (vs iCCA), positive margins, and stage II or III disease (vs stage I). Alternatively, increasing age, higher comorbidity score, gallbladder cancer (vs iCCA), and farther travel distance for treatment were associated with reduced odds of AC. Overall, AC was not associated with a survival advantage. However, subgroup analysis showed that AC was associated with a significant reduction in mortality among patients with eCCA. CONCLUSIONS: Among the patients with resected BTC, those who received AC were in the minority. In the context of recent randomized data and evolving recommendations, emphasis on guideline concordance with a focus on at-risk populations may improve outcomes.

Move It or Lose It - Intradialytic Exercise as Antidote to Functional Losses in Hemodialysis Patients?

Maintaining independence is the top health-related priority reported by older patients with advanced kidney disease.1 Unfortunately, functional losses such as fatigue, skeletal muscle loss, infection, cognitive decline, and diminished aerobic capacity are very common among patients receiving hemodialysis for chronic kidney failure. Such functional losses are associated with higher mortality2-4 and affect patients' physical activity level and overall quality of life. Indeed, symptom burden and mortality in patients receiving hemodialysis rival those in patients with cancer.5 Nephrology societies, clinicians, and above all patients and families are therefore interested in preserving quality of life and function for patients on dialysis.

Leveraging patient derived models of FGFR2 fusion positive intrahepatic cholangiocarcinoma to identify synergistic therapies.

Intrahepatic cholangiocarcinoma (ICC) remains a deadly malignancy lacking systemic therapies for advanced disease. Recent advancements include selective FGFR1-3 inhibitors for the 15% of ICC patients harboring fusions, although survival is limited by poor response and resistance. Herein we report generation of a patient-derived FGFR2 fusion-positive ICC model system consisting of a cell line, organoid, and xenograft, which have undergone complete histologic, genomic, and phenotypic characterization, including testing standard-of-care systemic therapies. Using these FGFR2 fusion-positive ICC models, we conducted an unbiased high-throughput small molecule screen to prioritize combination strategies with FGFR inhibition, from which HDAC inhibition together with pemigatinib was validated in vitro and in vivo as a synergistic therapy for ICC. Additionally, we demonstrate broad utility of the FGFR/HDAC combination for other FGFR fusion-positive solid tumors. These data are directly translatable and justify early phase trials to establish dosing, safety, and therapeutic efficacy of this synergistic combination.

Transposon Mutagenesis Reveals RBMS3 Silencing as a Promoter of Malignant Progression of BRAFV600E-Driven Lung Tumorigenesis.

Mutationally activated BRAF is detected in approximately 7% of human lung adenocarcinomas, with BRAFT1799A serving as a predictive biomarker for treatment of patients with FDA-approved inhibitors of BRAFV600E oncoprotein signaling. In genetically engineered mouse (GEM) models, expression of BRAFV600E in the lung epithelium initiates growth of benign lung tumors that, without additional genetic alterations, rarely progress to malignant lung adenocarcinoma. To identify genes that cooperate with BRAFV600E for malignant progression, we used Sleeping Beauty-mediated transposon mutagenesis, which dramatically accelerated the emergence of lethal lung cancers. Among the genes identified was Rbms3, which encodes an RNA-binding protein previously implicated as a putative tumor suppressor. Silencing of RBMS3 via CRISPR/Cas9 gene editing promoted growth of BRAFV600E lung organoids and promoted development of malignant lung cancers with a distinct micropapillary architecture in BRAFV600E and EGFRL858R GEM models. BRAFV600E/RBMS3Null lung tumors displayed elevated expression of Ctnnb1, Ccnd1, Axin2, Lgr5, and c-Myc mRNAs, suggesting that RBMS3 silencing elevates signaling through the WNT/ß-catenin signaling axis. Although RBMS3 silencing rendered BRAFV600E-driven lung tumors resistant to the effects of dabrafenib plus trametinib, the tumors were sensitive to inhibition of porcupine, an acyltransferase of WNT ligands necessary for their secretion. Analysis of The Cancer Genome Atlas patient samples revealed that chromosome 3p24, which encompasses RBMS3, is frequently lost in non-small cell lung cancer and correlates with poor prognosis. Collectively, these data reveal the role of RBMS3 as a lung cancer suppressor and suggest that RBMS3 silencing may contribute to malignant NSCLC progression. SIGNIFICANCE: Loss of RBMS3 cooperates with BRAFV600E to induce lung tumorigenesis, providing a deeper understanding of the molecular mechanisms underlying mutant BRAF-driven lung cancer and potential strategies to more effectively target this disease.

Sclerotherapy in Aesthetic Medicine: Myths and Realities.

BACKGROUND: Sclerotherapy is commonly performed for elimination of reticular and telangiectatic leg veins. There are several variations in practice, from the preparation to post-therapy directives. OBJECTIVE: To critically examine the misconceptions of sclerotherapy for aesthetic indications. MATERIALS AND METHODS: This review assesses evidence for and against each of the most common myths regarding sclerotherapy for aesthetic indications. RESULTS: Sclerotherapy can be safely used to treat veins in areas other than the lower extremities, with the exception of the face. Laser therapy is not superior to sclerotherapy for the treatment of small telangiectatic veins on the lower extremities. The type of syringe used to produce foam sclerotherapy is an important procedural consideration. After sclerotherapy, graduated compression stocking usage is a vital part of the procedure. Detergent sclerotherapy agents are similar, but not equivalent. Touch-up treatments after sclerotherapy should not be performed for 2 months post-treatment. Foam sclerotherapy does not have a high risk for air emboli. It is not advisable to treat the leg veins in "sections." Finally, one cannot reliably treat the telangiectatic veins without treating the feeding reticular veins for a satisfactory result. CONCLUSION: Many aspects of sclerotherapy have existing evidence to dictate best clinical practice.

Patterns and Impact of Fragmented Care in Stage II and III Gastric Cancer.

BACKGROUND: Optimal management of stage II/III gastric cancer requires multidisciplinary care, often necessitating treatment at more than one facility. We aimed to determine patterns of "fragmented" care and its impact on outcomes, including concordance with National Comprehensive Cancer Network (NCCN) guidelines and overall survival. METHODS: The 2006-2016 National Cancer Database was queried for patients with clinical stage II/III gastric adenocarcinoma who received preoperative therapy in addition to surgery. Patients were stratified based on whether surgery and chemotherapy/chemoradiation were performed at one versus multiple facilities (termed "coordinated" and "fragmented" care, respectively). Multivariable logistic regression was performed to identify factors associated with fragmented care. Survival was compared using Kaplan-Meier and Cox proportional hazards methods. RESULTS: Overall, 2033 patients met study criteria: 1043 (51.3%) received coordinated care and 990 (48.7%) fragmented care. There was no significant difference in time to surgery or pathologic upstaging by care structure. On adjusted analysis, factors associated with receipt of fragmented care included increasing age and distance traveled to the treating facility. Factors associated with coordinated care included metropolitan residence and treatment at academic and high-volume centers. Fragmented care was associated with a reduction in guideline-preferred perioperative chemotherapy (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.63-0.97, p = 0.02) and increased mortality (HR 1.16, 95% CI 1.00-1.34, p = 0.05). CONCLUSIONS: For patients with stage II/III gastric cancer, fragmented care is associated with inferior outcomes, including a reduction in preferred perioperative treatment and survival. Further work is needed to ensure equitable outcomes among patients as complex cancer care becomes more regionalized.

Discovery of an Allosteric, Inactive Conformation-Selective Inhibitor of Full-Length HPK1 Utilizing a Kinase Cascade Assay.

Achieving selectivity across the human kinome is a major hurdle in kinase inhibitor drug discovery. Assays using active, phosphorylated protein kinases bias hits toward poorly selective inhibitors that bind within the highly conserved adenosine triphosphate (ATP) pocket. Targeting inactive (vs active) kinase conformations offers advantages in achieving selectivity because of their more diversified structures. Kinase cascade assays are typically initiated with target kinases in their unphosphorylated inactive forms, which are activated during the assays. Therefore, these assays are capable of identifying inhibitors that preferentially bind to the unphosphorylated form of the enzyme in addition to those that bind to the active form. We applied this cascade assay to the emerging cancer immunotherapy target hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase that negatively regulates T cell receptor signaling. Using this approach, we discovered an allosteric, inactive conformation-selective triazolopyrimidinone HPK1 inhibitor, compound 1. Compound 1 binds to unphosphorylated HPK1 >24-fold more potently than active HPK1, is not competitive with ATP, and is highly selective against kinases critical for T cell signaling. Furthermore, compound 1 does not bind to the isolated HPK1 kinase domain alone but requires other domains. Together, these data indicate that 1 is an allosteric HPK1 inhibitor that attenuates kinase autophosphorylation by binding to a pocket consisting of residues within and outside of the kinase domain. Our study demonstrates that cascade assays can lead to the discovery of highly selective kinase inhibitors. The triazolopyrimidinone described in this study may represent a privileged chemical scaffold for further development of potent and selective HPK1 inhibitors.

Postoperative Outcomes of Local Skin Flaps Used in Oncologic Reconstructive Surgery of the Nasal Ala: A Systematic Review.

BACKGROUND: Despite numerous options for nasal ala reconstruction, advantages and disadvantages of each method are unclear. OBJECTIVE: To summarize reported outcomes of local flaps without the use of grafts for nasal ala oncologic reconstructive surgery. METHODS: A nasal ala-specific protocol was adapted from a previous head- and neck-specific PROSPERO submission (CRD42017071596). The search was conducted in MEDLINE, EMBASE, and CENTRAL on December 23, 2017 and updated on May 10, 2019. Two reviewers screened 9,313 results from head and neck literature. Study bias was evaluated with the ROBINS-I tool. RESULTS: Subunit-based categorization of included studies identified 12 nasal ala-specific publications. Complications (flap necrosis, hematoma, wound infections, trapdoor deformities, and dehiscence), functional (nasal valve or respiratory dysfunction), and cosmetic (alar rim distortion/asymmetry/notching, secondary/revisionary procedures, and patient satisfaction) outcomes were extracted. CONCLUSION: Generally favorable outcomes are seen in all flaps. Careful consideration of donor sites for interpolation flaps is needed for optimal cosmetic outcomes. Transposition flaps, including laterally based bilobed and trilobed flaps, created good outcomes, although melolabial transposition flaps may produce poorer outcomes compared with melolabial island pedicle advancement flaps. Caution is needed for rotation flaps to prevent nasal valve/respiratory dysfunction due to alar crease contracture or ridge elevation. Further research is needed.

Lower eyelid xanthelasma following hyaluronic acid filler injections to the tear troughs.

INTRODUCTION: Adverse effects from dermal fillers are uncommon. We report a case of filler-induced xanthelasma at the bilateral infraorbital region in a 43-year-old woman after multiple injections of hyaluronic acid to correct tear trough depression. MATERIAL AND METHODS: We report a case of a 43-year-old woman with a chief complaint of skin discoloration of the bilateral lower eyelids. Her history was significant for ten sessions of hyaluronic acid filler for tear trough deformity between December 2008 and May 2016. On clinical examination, she exhibited thin, soft, and yellow papules to her lower medial infraorbital hollows. A punch biopsy showed foamy histiocytes with a background of hypervascularization and focal extracellular lipid in the superficial dermis, consistent with xanthelasma. RESULTS: Xanthelasma was treated with multiple passes of Er:YAG laser (Sciton Contour TRL) with a 4 mm spot size, fluence 7.5 J/cm2, and ablate/coagulate 50/50 at 6 Hz until clearance occurred. The perilesional skin was treated with 1-2 passes, fluence 7.5 J/cm2, ablate/coagulate 50/0 to blend in the cosmetic unit. Six-month follow-up showed notable improvement of all lesions. DISCUSSION: There is a paucity of treatments described for filler-induced xanthelasma reaction. While broad conclusions cannot be drawn from one case, our experience indicates that complete resolution can be achieved with Er:YAG ablation. We hypothesize that this laser is an optimal treatment, as it can vaporize the lipid contents while minimizing adverse effects, such as scars and hyperpigmentation.

Postoperative Outcomes of Local Skin Flaps Used in Oncologic Reconstructive Surgery of the Upper Cutaneous Lip: A Systematic Review.

BACKGROUND: Despite many options for upper lip reconstruction, each method's advantages and disadvantages are unclear. OBJECTIVE: To summarize complications and functional and aesthetic outcomes of localized skin flaps for oncological reconstruction of the upper cutaneous lip (PROSPERO CRD42020157244). METHODS: The search was conducted in Ovid MEDLINE, Ovid EMBASE, and CENTRAL on December 14, 2019. Two reviewers screened 2,958 results for eligibility. Bias assessment was conducted using ROBINS-I criteria. RESULTS: Our search identified 12 studies reporting outcomes of V-Y advancement, ergotrid, rotation, Karapandzic, alar crescent, and propeller facial artery perforator flaps. Flap complications (infection, hemorrhage/hematoma, wound dehiscence, and flap necrosis) ranged from 0% to 7.69%. Functional outcomes (salivary continence, microstomia, and paresthesia) were poorest for Karapandzic flaps. Aesthetic outcomes, when reported, stated satisfaction rates greater than 90%. V-Y advancement flaps reported the highest rates of poor scarring (0%-20%) and need for revision surgery (0%-46.7%). CONCLUSION: Our results provide dermatologic surgeons an overview of upper cutaneous lip flap outcomes reported in the literature. In general, we noted high patient satisfaction rates and low complication rates. Additional research into outcomes of other commonly used flaps is needed. Standardization of reported outcomes could allow further comparison across different flaps or across studies of the same flap.

Outcomes of Staged Excision With Circumferential en Face Margin Control for Lentigo Maligna of the Head and Neck.

BACKGROUND: Treatment practices vary for lentigo maligna (LM). Staged excision with circumferential margin control (SECMC) has the potential to achieve low recurrence rates. OBJECTIVES: To evaluate the clinical outcomes of SECMC using permanent, paraffin-embedded sections and delayed reconstruction. METHODS: We conducted a retrospective, uncontrolled, observational cohort study involving patients who underwent staged excision for LM of the head and neck at Women's College Hospital in Toronto, Canada, from September 2010 to March 2013. Recurrence and infection rates were ascertained from patient charts and postal surveys. RESULTS: One hundred and two patients (45 female, 57 male) were included with a median follow-up time of 1410.5 (IQR 260-1756) days. The median age was 69 (IQR 61-79) years. Approximately one-fifth (21%, 21/102) of patients required greater than 0.5 cm margins to achieve histological clearance. One patient (1/102) upstaged to invasive melanoma based on the initial stage of excision. The infection rate was 6% (6/102) and the 5-year cumulative recurrence rate was 1.4% (95% CI 0.2-9.6%). CONCLUSION: SECMC using permanent sections and delayed reconstruction appears to be a safe and effective treatment method for LM on the head and neck. Randomized trials are needed to help define the optimal treatment.

A Study of High-Grade Serous Ovarian Cancer Origins Implicates the SOX18 Transcription Factor in Tumor Development.

Fallopian tube secretory epithelial cells (FTSECs) are likely the main precursor cell type of high-grade serous ovarian cancers (HGSOCs), but these tumors may also arise from ovarian surface epithelial cells (OSECs). We profiled global landscapes of gene expression and active chromatin to characterize molecular similarities between OSECs (n = 114), FTSECs (n = 74), and HGSOCs (n = 394). A one-class machine learning algorithm predicts that most HGSOCs derive from FTSECs, with particularly high FTSEC scores in mesenchymal-type HGSOCs (padj < 8 × 10-4). However, a subset of HGSOCs likely derive from OSECs, particularly HGSOCs of the proliferative type (padj < 2 × 10-4), suggesting a dualistic model for HGSOC origins. Super-enhancer (SE) landscapes were also more similar between FTSECs and HGSOCs than between OSECs and HGSOCs (p < 2.2 × 10-16). The SOX18 transcription factor (TF) coincided with a HGSOC-specific SE, and ectopic overexpression of SOX18 in FTSECs caused epithelial-to-mesenchymal transition, indicating that SOX18 plays a role in establishing the mesenchymal signature of fallopian-derived HGSOCs.

Recurrence, death, and secondary malignancy after ovarian conservation for young women with early-stage low-grade endometrial cancer.

OBJECTIVE: To examine the association between ovarian conservation and oncologic outcome in surgically-treated young women with early-stage, low-grade endometrial cancer. METHODS: This multicenter retrospective study examined women aged <50 with stage I grade 1-2 endometrioid endometrial cancer who underwent primary surgery with hysterectomy from 2000 to 2014 (US cohort n = 1196, and Japan cohort n = 495). Recurrence patterns, survival, and the presence of a metachronous secondary malignancy were assessed based on ovarian conservation versus oophorectomy. RESULTS: During the study period, the ovarian conservation rate significantly increased in the US cohort from 5.4% to 16.4% (P = 0.020) whereas the rate was unchanged in the Japan cohort (6.3-8.7%, P = 0.787). In the US cohort, ovarian conservation was not associated with disease-free survival (hazard ratio [HR] 0.829, 95% confidence interval [CI] 0.188-3.663, P = 0.805), overall survival (HR not estimated, P = 0.981), or metachronous secondary malignancy (HR 1.787, 95% CI 0.603-5.295, P = 0.295). In the Japan cohort, ovarian conservation was associated with decreased disease-free survival (HR 5.214, 95% CI 1.557-17.464, P = 0.007) and an increased risk of a metachronous secondary malignancy, particularly ovarian cancer (HR 7.119, 95% CI 1.349-37.554, P = 0.021), but was not associated with overall survival (HR not estimated, P = 0.987). Ovarian recurrence or metachronous secondary ovarian cancer occurred after a median time of 5.9 years, and all cases were salvaged. CONCLUSION: Our study suggests that adoption of ovarian conservation in young women with early-stage low-grade endometrial cancer varies by population. Ovarian conservation for young women with early-stage, low-grade endometrial cancer may be potentially associated with increased risks of ovarian recurrence or metachronous secondary ovarian cancer in certain populations; nevertheless, ovarian conservation did not negatively impact overall survival.