Pleurectomy Decortication in the Treatment of Malignant Pleural Mesothelioma: Encouraging Results and Novel Prognostic Implications Based on Experience in 355 Consecutive Patients.

OBJECTIVE: We report a series of 355 consecutive patients treated over 9 years in a single institution with intended PDC. BACKGROUND: Surgery for MPM has shifted from extra-pleural pneumonectomy to PDC with the goal of MCR. METHODS: Clinical and outcome data were reviewed. Kaplan-Meier estimators and log rank test were used to compare the overall survival, and logistic regression models were used. RESULTS: MCR was achieved in 304. There were 223 males, median age was 69 and histology was epithelioid in 184. The 30 and 90-day mortality were 3.0% and 4.6%.Most complications were low grade. Prolonged air leak in 141, deep venous thrombosis in 64, Atrial fibrillation in 42, chylothorax in 24, Empyema in 23, pneumonia in 21, Hemothorax in 12 and pulmonary embolus in 8. Median/5-year survival were 20.7 months/17.9% in the intent-to-treat cohort and 23.2months/21.2% in the MCR group. The survivals were best for patients with Tlstage and epithelioid histology (69.8months/54.1%). In a multivariable analysis, factors that were found to be associated with longer patient overall survival included epithelioid histology, T stage, quantitative clinical stage/tumor volume staging, adjuvant chemotherapy, intraoperative heated chemo, female sex, and length of stay shorter than 14 days. CONCLUSIONS: PDC is feasible with low mortality and is associated with manageable complication rates. 5-year survival of patients undergoing PDC with MCR in multi-modality setting is approaching 25% depending on quantitative and clinical stage, sex and histological subtype and is better than PDC without- MCR.

Diagnostic Laparoscopy Improves Staging of Malignant Pleural Mesothelioma With Routine Positron Emission Tomography Imaging.

BACKGROUND: With a multimodal treatment strategy, cytoreductive surgery extends survival in malignant pleural mesothelioma. Improving the accuracy of staging can refine patient selection. Our objective was to determine whether diagnostic laparoscopy (DL) improves staging for patients with malignant pleural mesothelioma with the routine use of positron emission tomography (PET). METHODS: We performed a retrospective review of our prospectively maintained database from February 2014 to May 2019. Inclusion criteria were patients who had disease in the chest that was deemed potentially resectable by radiographic criteria and who underwent DL as part of the staging evaluation before surgery. RESULTS: Of 187 patients (71% men, 80% epithelial) who underwent DL during staging, 76% proceeded to surgery; 22% were unresectable at exploratory thoracotomy and 78% underwent resection (pleurectomy and decortication, 68%; extrapleural pneumonectomy, 32%). Also, 89% had a PET computed tomography (CT), and 11% had a preoperative CT without PET. DL revealed peritoneal disease in 17%. Among patients with pathologically proven disease at DL, 77% had negative PET-CT imaging. Based on the pathologic findings at DL the sensitivity, specificity, positive predictive value, and negative predictive value of PET-CT were 23%, 78%, 17%, and 83%, respectively. The accuracy of PET-CT was 68%. CONCLUSIONS: PET-CT has low sensitivity and diagnostic accuracy to identify peritoneal disease in malignant pleural mesothelioma. DL as part of the preoperative staging defines an important subset of patients with bicavitary disease. We recommend DL as a component of staging before surgery.

Preoperative prediction of unresectability in malignant pleural mesothelioma.

OBJECTIVE: Diffuse chest wall invasion (DCWI) is a common finding in patients undergoing intended resection for malignant pleural mesothelioma. We sought to determine the incidence and preoperative predictors of this finding, and to test our anecdotal impression that contraction of the ipsilateral hemithorax is associated with DCWI. METHODS: This was a single-institution retrospective study of 170 patients undergoing intended macroscopic complete resection for malignant pleural mesothelioma from 2014-2018. A novel metric of thoracic cage volume was calculated by preoperative chest computed tomography. Univariable analyses were performed to determine associations of preoperative variables with DCWI. RESULTS: Macroscopic complete resection was achieved by pleurectomy/decortication in 104 patients (61%) and by extrapleural pneumonectomy in 39 patients (23%). Unresectable disease was discovered at thoracotomy in 27 (16%) of patients; 24 (14%) by DCWI and 3 (2%) by intrathoracic organ invasion. In univariable analysis, decreased ipsilateral thoracic cage volume demonstrated the strongest association with unresectability by DCWI (P = .009) with >5% decrease in thoracic cage volume representing the optimal cutoff (P = .014; area under the curve, 0.67). Other preoperative variables associated with DCWI included preoperative chest pain requiring opioids (P = .028), prior pleurodesis (P = .036), decreased forced vital capacity (P = .023), decreased ipsilateral lung perfusion by ventilation/perfusion lung scan (P = .007), and magnetic resonance imaging findings of chest wall invasion (P = .035). CONCLUSIONS: Preoperative identification of DCWI will avoid unnecessary thoracotomy and accelerate initiation of nonsurgical therapy in malignant pleural mesothelioma. Our data suggest that contraction of thoracic cage volume has merit in predicting malignant pleural mesothelioma unresectability and should be validated in prospective studies.

Diagnostic value of biopsy sampling in predicting histology in patients with diffuse malignant pleural mesothelioma.

BACKGROUND: The classification of diffuse malignant mesothelioma into epithelioid, biphasic, and sarcomatoid types is based on histologic patterns. The diagnosis is made on biopsies, and because of intratumoral heterogeneity, they may not be representative of the entire tumor. The number and volume of biopsies needed to reach diagnostic accuracy in diffuse malignant mesothelioma and their prognostic value remain unclear. METHODS: This study examined 759 consecutive patients with pleural diffuse malignant mesothelioma treated by pleurectomy/decortication or extrapleural pneumonectomy for the presence of epithelioid and/or sarcomatoid histology and classified both the presurgery biopsies (core-needle or thoracoscopic) and surgical resection specimens. The number and volume of biopsies were correlated with pre- and postsurgery histologies and overall survival. RESULTS: Diffuse malignant mesothelioma was classified as epithelioid (76%), biphasic (18%), sarcomatoid (5%), or indeterminate (1%) in biopsies and as epithelioid (64%), biphasic (32%), and sarcomatoid (4%) in surgical resection specimens (overall concordance, 80.6%). The positive likelihood ratios were 2.4, 13.6, and 90.1 for biopsies with epithelioid, biphasic, and sarcomatoid histologies, respectively. Concordant histologies between biopsies and resections were associated with a higher number of biopsies (median tissue blocks for concordant histologies vs discordant histologies, 3 vs 2; P < .002) but were less associated with a higher volume (median, 1.2 vs 1.1 cm3 ; P = .06). In a multivariate analysis, overall survival was independently predicted by histology in the resection specimen (P < .0001) but not in the biopsy (P = .09). CONCLUSIONS: In contrast to epithelioid histology, sarcomatoid histology in biopsies is highly accurate. Despite intratumoral heterogeneity, the accuracy of histologic classification increases with the number of tissue blocks examined, emphasizing the diagnostic value of extensive sampling by presurgery biopsies.

A Proposed System Toward Standardizing Surgical-Based Treatments for Malignant Pleural Mesothelioma, From the Joint National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Taskforce.

This article is a joint effort arising from a task force formed at a National Cancer Institute-International Association for the Study of Lung Cancer-Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting, held at the NIH in March 2017. Malignant pleural mesothelioma remains one of the most virulent and recalcitrant malignancies, still considered incurable, and in desperate need of clinical trials in order to make progress for our patients. Although not standard of care, there is compelling evidence that a select subgroup of mesothelioma patients benefit from a surgery-based multimodal approach. As it is not possible to achieve a microscopically complete resection with mesothelioma, there appears to be no role for surgery alone. Thus, it is anticipated that significant strides in the surgery-based treatment of this cancer will require trials that determine which complementary treatments best augment the cytoreductive efficacy of surgery. Although lung-sacrificing surgery for mesothelioma is fairly standardized, approaches to lung-sparing surgery are highly variable and lung sparing surgery is emerging internationally as the dominant extirpative procedure for this cancer. It is not currently possible to rigorously assess the contribution of the adjuvant treatments combined with surgery because of the variability in procedures used to debulk this cancer, the extreme variability of the cancer itself, the variability in patient selection, the variability in treatment of the inevitable recurrence, and even the variability in follow up schedules. This article is an effort to address these problems by suggesting a more uniform approach to the surgical procedure and also proposing a series of data collection forms that could be adopted immediately, with any eye toward collecting the information that will be necessary to facilitate patient selection and determine which aspects of mesothelioma surgery can and should be standardized - with the goal being extension of life while maintaining quality of life as an equal priority. Furthermore, a completely original contribution in this manuscript is the proposal of a grading system that takes the information from the surgical procedure data forms and generates a completeness of resection score. This is the initial effort to establish a common denominator for mesothelioma surgery that will allow for more accurate comparison between surgical series and better assessment of the impact of the treatments combined with surgery.

Prognostic value of neoadjuvant treatment response in locally advanced esophageal adenocarcinoma.

OBJECTIVE: To determine the association between neoadjuvant chemotherapy and chemoradiation therapy on completeness of pathologic response and to assess the impact of primary tumor versus nodal response on survival after esophagectomy. METHODS: Patients aged 18 to 80 years in the National Cancer Data Base (2006-2016) with clinically staged, locally advanced (cT2-4 or cN+) esophageal adenocarcinoma who underwent an R0 esophagectomy after neoadjuvant chemotherapy or chemoradiation therapy were included. Multivariable Cox proportional hazards regression models were constructed to assess the association between treatment response and survival. RESULTS: Among 2870 patients, there was a significant dose-response association between completeness of response and overall survival: no response (reference), partial response (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.72-0.91), and complete response (HR, 0.55; 95% CI, 0.47-0.65). Compared with neoadjuvant chemotherapy alone, neoadjuvant chemoradiation was associated with higher pathologic primary tumor (33.9% vs 21.3%; P < .001) and pathologic nodal response rates (55.9% vs 32.7%; P < .001). Both a primary and nodal response were associated with improved survival. However, among patients with a primary but no nodal response, primary tumor response was not associated with risk of death (HR, 0.88; 95% CI, 0.69-1.11). In contrast, among patients who had a nodal but no primary response, the survival benefit of a nodal response was maintained (HR, 0.66; 95% CI, 0.58-0.76). CONCLUSIONS: Pathologic nodal (rather than primary tumor) response to neoadjuvant therapy is associated with improved survival. These data suggest a need to optimize neoadjuvant strategies associated with more complete nodal response rates and to consider more aggressive adjuvant treatment for patients with residual nodal disease after esophagectomy.

Povidone-iodine results in rapid killing of thymic epithelial tumour cells through cellular fixation†.

OBJECTIVES: Hyperthermic pleural lavage with povidone-iodine (PVP-I) is utilized to control micrometastatic disease following cytoreductive surgery for thymic epithelial tumours (TETs). Our objective was to investigate whether PVP-I demonstrates direct cytotoxicity against human TET cells. METHODS: Human Met-5A (immortalized mesothelial cell), IU-TAB-1 (thymoma) and Ty-82 (thymic carcinoma) cell lines were treated with serial dilutions of PVP-I (0.01-10%) for 5, 30 and 60 min at 37°C and 42°C. MTT assays and flow cytometry were used to evaluate cell death and apoptosis. Membrane permeability was assayed by intracellular staining of cleaved poly-ADP-ribose polymerase. Cellular fixation was evaluated by membrane disruption of dead cells by dimethylsulphoxide and by comparing cleaved poly-ADP-ribose polymerase staining following PVP-I with known fixatives. RESULTS: MTT assays demonstrated that PVP-I concentrations greater than 0.5% led to rapid cell death in both TET cell lines regardless of temperature. IC50 values following 5 min of exposure to PVP-I were 8.4 mM (0.3%) and 13.3 mM (0.48%) for IU-TAB-1 and Ty-82, respectively and 8.9 mM (0.32%) for MeT-5A. Flow cytometry demonstrated that 5-min exposure of either cell line to 1% PVP-I resulted in profound cell death: 74% and 58% at 5 min and 97% and 95% at 30 min, for IU-TAB-1 and Ty-82 cells, respectively. Resistance of PVP-I-treated cells to dimethylsulphoxide lysis and similar cleaved poly-ADP-ribose polymerase expression following PVP-I and known fixatives revealed cellular fixation as the mechanism of death following PVP-I exposure. CONCLUSIONS: PVP-I results in rapid death of human TET cells and normal mesothelial cells through a cellular fixation mechanism and may, therefore, favourably impact the control of micrometastatic disease following resection of TETs with pleural dissemination.

A Phase I Trial of Surgical Resection and Intraoperative Hyperthermic Cisplatin and Gemcitabine for Pleural Mesothelioma.

INTRODUCTION: The primary objective of this single-institution phase I clinical trial was to establish the maximum tolerated dose of gemcitabine added to cisplatin and delivered as heated intraoperative chemotherapy after resection of malignant pleural mesothelioma. METHODS: The extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) treatment arms were based on investigators' assessment of patient fitness and potential for macroscopic complete resection. Previously established intracavitary dosing of cisplatin (range 175-225 mg/m2) with systemic cytoprotection was used in combination with escalating doses of gemcitabine, following a 3-plus-3 design from 100 mg/m2 in 100-mg increments. RESULTS: From 2007 to 2011, 141 patients were enrolled and 104 completed treatment. The median age of those completing treatment was 65 years (range 43-85 years), and 22 (21%) were female. In the EPP arm (n = 59), 31 patients (53%) had the epithelioid histologic type and the median radiographic tumor volume was 236 cm3 (range 16-4285 cm3). In the P/D arm (n = 41), 29 patients (71%) had the epithelioid histologic type and the median tumor volume was 79 cm3 (range 6-1107 cm3). The operative mortality rate was 2%, and 35 and 22 serious adverse events were encountered among 27 patients (46%) and 16 patients (39%) in the EPP and P/D arms, respectively. Dose-limiting toxicity (grade 3 leukopenia) was observed in two patients who were receiving 1100 mg/m2 of gemcitabine, thus establishing the maximum tolerated dose at 1000 mg/m2, in combination with 175 mg/m2 of cisplatin. The median overall and recurrence-free survival times in treated patients were 20.3 and 10.7 months, respectively. CONCLUSIONS: Combination cisplatin and gemcitabine heated intraoperative chemotherapy can be administered safely and feasibly in the context of complete surgical resection of malignant pleural mesothelioma by EPP or P/D.

Comprehensive immunoproteogenomic analyses of malignant pleural mesothelioma.

We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides.

Matrix metalloproteinase 12 promotes tumor propagation in the lung.

OBJECTIVE: Past studies are inconsistent with regard to the role of matrix metalloproteinase 12 in lung tumorigenesis. This is due, in part, to differential tumorigenesis based on tumor-derived versus immune-derived matrix metalloproteinase 12 expression. Our study aims to thoroughly dissect the role of matrix metalloproteinase 12 in lung tumorigenesis. METHODS: We tested matrix metalloproteinase 12 expression and the association with prognosis using a tissue array and a published non-small cell lung cancer gene expression database. In addition, we characterized the contribution of matrix metalloproteinase 12 to tumor propagation in the lung using a series of in vitro and in vivo studies. RESULTS: Tumor cells of a diverse set of human lung cancers stained positive for matrix metalloproteinase 12, and high matrix metalloproteinase 12 mRNA levels in the tumor were associated with reduced survival. The lung microenvironment stimulated endogenous production of matrix metalloproteinase 12 in lung cancer cells (human 460 lung cancer cell line, Lewis lung carcinoma). In vitro, matrix metalloproteinase 12 knockout Lewis lung carcinoma and Lewis lung carcinoma cells had the same proliferation rate, but Lewis lung carcinoma showed increased invasiveness. In vivo, deficiency of matrix metalloproteinase 12 in Lewis lung carcinoma cells, but not in the host, reduced tumor growth and invasiveness. CONCLUSIONS: We suggest that tumor cell-derived matrix metalloproteinase 12 promotes tumor propagation in the lung and that in the context of pulmonary malignancies matrix metalloproteinase 12 should further be tested as a potential novel therapeutic target.

Postoperative Chylothorax After Thoracoabdominal Aortic Aneurysm Repair.

Chylothorax is a potentially deadly complication that can occur after thoracoabdominal aortic aneurysm (TAAA) repair. We describe our contemporary experience (2005-2014) with this complication, our efforts to identify perioperative variables associated with it, and our attempts to assess treatment outcomes. We reviewed the records of 1092 consecutive patients who underwent TAAA repair between 2005 and 2014. Standard bivariate analysis was used to test for between-group differences. Eleven patients (0.9%) developed postoperative chylothorax. Nonoperative management was used in 8 of these patients (73%); 1 patient died after a lengthy hospital stay (297 days). The other 3 patients required thoracotomy with direct ligation; 1 of these patients required a second operation. Patients who developed chylothorax appeared to be similar to other patients in age, sex, extent of aneurysm, and metabolic or cardiovascular comorbidities. Patients who developed postoperative chylothorax were more likely to require drainage of a pleural effusion (P = 0.005), tracheostomy (P = 0.02), and longer stays in the intensive care unit (median, 6 [2-24] days, P < 0.001) and the hospital (median, 35 [24-88] days, P = 0.001), and these patients were more likely to develop a graft infection (n = 2, P < 0.001). The extent of TAAA repair (Crawford I-IV), reoperation, and clamping proximal to the left subclavian artery were not significantly associated with postoperative chylothorax. Chylothorax after TAAA repair can often be managed nonoperatively. Development of postoperative chylothorax may lead to significant morbidity, longer hospitalization, and increased likelihood of graft infection.

New Concepts in the Treatment of Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is a highly aggressive and generally incurable cancer. Current anti-MPM chemotherapy-based treatments are only marginally effective, and long-term survival remains an unmet goal. Nonetheless, in selected cases, personalized surgery-based multimodality treatments (MMT) have been shown to significantly extend survival. The design of MMT and selection of patients are challenging, and optimal results require accurate presurgical diagnosis, staging, and risk stratification. Further, meticulous surgical techniques and advanced radiation protocols must be applied. We review key principles and evolving concepts in the care of MPM patients with a focus on the expanding role of MMT in MPM.

Soluble Mesothelin-Related Peptides to Monitor Recurrence After Resection of Pleural Mesothelioma.

BACKGROUND: Most patients undergoing surgical resection of malignant pleural mesothelioma (MPM) will experience recurrence, and radiographic diagnosis of recurrence can be difficult in the postoperative chest. Our objective was to determine the utility of the serum biomarker soluble mesothelin-related peptide (SMRP; or mesothelin) in monitoring of the postoperative MPM patient. METHODS: We retrospectively evaluated a prospectively maintained single institution clinical database. SMRP levels were evaluated preoperatively and postoperatively in patients undergoing surgical resection of MPM. RESULTS: One hundred two patients underwent pleurectomy/decortication (58%), extrapleural pneumonectomy (20%), chest wall resection (2%), or exploratory thoracotomy (20%) for MPM of 81% epithelial histology. Sixty percent received heated intraoperative chemotherapy and 57% received perioperative systemic chemotherapy. Patients with epithelial histology had substantially greater mean (± SD) preoperative SMRP levels (4.5 ± 7.3 nmol/L) than did patients with biphasic (1.9 ± 2.5 nmol/L) or sarcomatoid (1.2 ± 1.0 nmol/L) histology. Radiologic 3-dimensional tumor volume and tumor mesothelin gene (MSLN) expression correlated with preoperative SMRP. In patients with epithelial histology undergoing complete resection (n = 66), preoperative SMRP (3.4 ± 4.9 nmol/L) dramatically decreased immediately after operation (0.8 ± 0.5 nmol/L), and preoperative SMRP was independently associated with poor disease-free survival. Percentage of change in serial postoperative SMRP values at the best statistical cutoff at 48% revealed high predictive capability of disease recurrence with 90% sensitivity and 93% specificity (area under the curve = 0.96, p < 0.001). CONCLUSIONS: SMRP is a promising serum biomarker for the detection of recurrence after resection of epithelial MPM that may have value in clinical practice and should be studied in a prospective cohort.

Intraoperative adjuncts for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rapidly fatal disease. Multimodality surgically based therapies may extend survival in select patients, however, local relapse after resection is common. Novel intraoperative adjunctive therapies including heated intraoperative chemotherapy (HIOC), heated intraoperative povidone-iodine (PVP-I), and photodynamic therapy (PDT) target micrometastatic disease and aim to improve local control. This review details the most recent studies and trials of HIOC, heated intraoperative PVP-I, and PDT, this aims to provide an update on some of the most promising intraoperative adjuncts for patients with MPM.

Alternative conduits for esophageal replacement.

Replacement of the native esophagus after esophagectomy is a problem that has challenged surgeons for over a century. Not only must the conduit be long enough to bridge the distance between the cervical esophagus and the abdomen, it must also have a reliable vascular supply and be sufficiently functional to allow for deglutition. The stomach, jejunum, and colon (right, left or transverse) have all been proposed as potential solutions. The stomach has gained favor for its length, reliable vascular supply and need for only a single anastomosis. However, there are times when the stomach is unavailable for use as a conduit. It is in these instances that an esophageal surgeon must have an alternative conduit in their armamentarium. In this paper, we will briefly discuss the technical aspects of jejunal and colonic interposition. We will review the recent literature with a focus on early and late outcomes. The advantages and disadvantages of both options will be reviewed.

Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features.

Purpose: To reconcile the heterogeneity of thymic epithelial tumors (TET) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors.Experimental Design: Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts.Results: Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild-type tumors and represented TETs enriched in expression of genes associated with T-cell signaling (TS group; 33%). The remaining two groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup.Conclusions: Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging and in the discovery and development of rational treatment options for patients with TETs. Clin Cancer Res; 23(16); 4855-64. ©2017 AACR.

The seven attributes of the academic surgeon: Critical aspects of the archetype and contributions to the surgical community.

BACKGROUND: "Academic surgeon" describes a member of a medical school department of surgery, but this term does not fully define the important role of such physician-scientists in advancing surgical science through translational research and innovation. METHODS: The curriculum vitae and self-descriptive vignettes of the records of achievement of seven surgeons possessing documented records of academic leadership, innovation, and dissemination of knowledge were reviewed. RESULTS: Out analysis yielded seven attributes of the archetypal academic surgeon: 1) identifies complex clinical problems ignored or thought unsolvable by others, 2) becomes an expert, 3) innovates to advance treatment, 4) observes outcomes to further improve and innovate, 5) disseminates knowledge and expertise, 6) asks important questions to further improve care, and 7) trains the next generation of surgeons and scientists. CONCLUSION: Although alternative pathways to innovation and academic contribution also exist, the academic surgeon typically devotes years of careful observation, analysis, and iterative investigation to identify and solve challenging or unexplored clinical problems, ideally leverages resources available in academic medical centers to support these endeavors.