Development and implementation of a clinical pathway approach to simulation-based training for foregut surgery.

INTRODUCTION: Contemporary demands on resident education call for integration of simulation. We designed and implemented a simulation-based curriculum for Post Graduate Year 1 surgery residents to teach technical and nontechnical skills within a clinical pathway approach for a foregut surgery patient, from outpatient visit through surgery and postoperative follow-up. METHODS: The 3-day curriculum for groups of 6 residents comprises a combination of standardized patient encounters, didactic sessions, and hands-on training. The curriculum is underpinned by a summative simulation pathway repeated on days 1 and 3. The pathway is a series of simulated preoperative, intraoperative, and postoperative encounters in following up a single patient through a disease process. The resident sees a standardized patient in the clinic presenting with distal gastric cancer and then enters an operating room to perform a gastrojejunostomy on a porcine tissue model. Finally, the resident engages in a simulated postoperative visit. All encounters are rated by faculty members and the residents themselves, using standardized assessment forms endorsed by the American Board of Surgery. RESULTS: A total of 18 first-year residents underwent this curriculum. Faculty ratings of overall operative performance significantly improved following the 3-day module. Ratings of preoperative and postoperative performance were not significantly changed in 3 days. Resident self-ratings significantly improved for all encounters assessed, as did reported confidence in meeting the defined learning objectives. CONCLUSIONS: Conventional surgical simulation training focuses on technical skills in isolation. Our novel pathway curriculum targets an important gap in training methodologies by placing both technical and nontechnical skills in their clinical context as part of managing a surgical patient. Results indicate consistent improvements in assessments of performance as well as confidence and support its continued usage to educate surgery residents in foregut surgery

Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma

SummaryAlthough BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it

Active surveillance of patients who have sentinel node positive melanoma:An international, multi-institution evaluation of adoption and early outcomes after the Multicenter Selective Lymphadenectomy trial II (MSLT-2)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168248/1/cncr33483.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168248/2/cncr33483_am.pd

A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma

Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups

Neoadjuvant therapy for gastric cancer: current evidence and future directions

Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies

Prognostic Modeling in Desmoplastic Melanoma Using Different Cutpoints for the Proportion of Desmoplasia

Currently, desmoplastic melanomas are commonly divided into “pure” desmoplastic melanoma (at least 90% desmoplasia histologically) and “mixed” (<90%), with pure having a better prognosis, but our understanding of the relationship between percent desmoplasia and prognosis is incomplete. We sought to determine whether a more refined grading system that examined extent of desmoplasia by percent in 10% increments would be a better prognostic model. We also sought to determine the optimal cutpoint for percent desmoplasia if a single cutpoint were used.We analyzed 103 patients with desmoplastic melanoma confined to the skin at diagnosis and who were followed for at least 6 months. Desmoplasia proportions ranged from 10% to 100%, with forty patients (38.4%) having 100% desmoplasia. Overall, eighteen patients (17.5%) eventually developed metastases. Those with 100% desmoplasia had a statistically significantly decreased likelihood of metastasis compared to those with <100% desmoplasia (OR=0.15, p=0.017). However, there was no trend towards decreased likelihood of metastasis with decreasing percentages below 100% (p=0.658), implying a graduated system did not appear to be a better model than a single cutpoint. We also found that a model for predicting metastasis that incorporated Breslow thickness and the presence or absence of 100% desmoplasia (Akaike information criterion (AIC) = 84.64) was better than a model using 90% desmoplasia as the cutpoint (AIC = 89.35). We determined that a single cutpoint is sufficient in modeling prognosis for desmoplastic melanoma, and that 100% desmoplasia is a better cutpoint than the 90% cutpoint found in the “pure/mixed” model currently in use

Prognostic Modeling in Desmoplastic Melanoma Using Different Cutpoints for the Proportion of Desmoplasia

Currently, desmoplastic melanomas are commonly divided into “pure” desmoplastic melanoma (at least 90% desmoplasia histologically) and “mixed” (<90%), with pure having a better prognosis, but our understanding of the relationship between percent desmoplasia and prognosis is incomplete. We sought to determine whether a more refined grading system that examined extent of desmoplasia by percent in 10% increments would be a better prognostic model. We also sought to determine the optimal cutpoint for percent desmoplasia if a single cutpoint were used.We analyzed 103 patients with desmoplastic melanoma confined to the skin at diagnosis and who were followed for at least 6 months. Desmoplasia proportions ranged from 10% to 100%, with forty patients (38.4%) having 100% desmoplasia. Overall, eighteen patients (17.5%) eventually developed metastases. Those with 100% desmoplasia had a statistically significantly decreased likelihood of metastasis compared to those with <100% desmoplasia (OR=0.15, p=0.017). However, there was no trend towards decreased likelihood of metastasis with decreasing percentages below 100% (p=0.658), implying a graduated system did not appear to be a better model than a single cutpoint. We also found that a model for predicting metastasis that incorporated Breslow thickness and the presence or absence of 100% desmoplasia (Akaike information criterion (AIC) = 84.64) was better than a model using 90% desmoplasia as the cutpoint (AIC = 89.35). We determined that a single cutpoint is sufficient in modeling prognosis for desmoplastic melanoma, and that 100% desmoplasia is a better cutpoint than the 90% cutpoint found in the “pure/mixed” model currently in use

Contemporary reappraisal of the efficacy of adjuvant chemotherapy in resected retroperitoneal sarcoma: Evidence from a nationwide clinical oncology database and review of the literature

While margin-negative resection remains the cornerstone of therapy for retroperitoneal sarcoma (RPS), the impact of adjuvant chemotherapy (AC) on overall survival (OS) remains poorly understood. The National Cancer Data Base was queried for patients undergoing curative-intent resection of primary non-metastatic RPS (2004-2013). Multivariable modeling identified factors associated with AC receipt. Cox regression identified covariates associated with OS, and AC and surgery alone (SA) cohorts were matched 1:1 by propensity scores based on these covariates. In the propensity-score matched cohort, OS was compared by Kaplan-Meier estimates. Results from this analysis were presented in the context of a review of the existing literature on the impact of AC in resected RPS. Of 3892 resected RPS patients, 90.0% and 10.0% received SA and AC, respectively. Predictors of AC receipt included younger age, non-Caucasian race, hospital location, histologic grade, adjacent organ invasion, and histologic subtype. The propensity score-matched cohort comprised 767 patients (SA n = 377; AC n = 390); at a median follow-up of 59.2 (IQR 35.0-85.3) months, median OS of the propensity-matched cohort was 53.6 (IQR 22.4-119.5) months. Utilization of AC was associated with significantly worse long-term survival (median OS: 47.8 vs. 68.9 months, p = 0.017; HR 1.30, 95% CI 1.05-1.61). AC was not associated with improved OS in margin-positive (R1/R2) resection, high-grade (G2/G3) and larger (>10 cm) tumors, or in any histologic subtype. Albeit not statistically significant, there was a trend toward improved OS with AC in spindle cell (HR 0.37, 95% CI 0.10-1.38), giant cell (HR 0.82, 95% CI 0.32-2.13), and synovial (HR 0.26, 95% CI 0.05-1.33) sarcoma. Data from a large nationwide oncology database and review of the existing literature do not support adjuvant chemotherapy regimens following curative-intent resection of RPS, even in subgroups at high risk of failure (e.g., R1/R2 resection, high-grade or large tumors). The possible benefit of conventional adjuvant regimens in spindle cell, giant cell, and synovial sarcoma should be explored in prospective studies

Trends in practice patterns and outcomes: A decade of sarcoma care in the United States

BACKGROUND: Soft tissue sarcomas (STS) represent a rare and heterogeneous group of tumors. We sought to characterize national trends in referral patterns, treatment strategies, and overall survival (OS) over the course of a decade. METHODS: Adult patients with extra-abdominal STS were identified using the National Cancer Database and categorized by diagnosis year (2005-2009 and 2010-2014). High-volume hospitals (HVH) were defined as those >90th percentile in volume of STS patients treated, and others were defined as low-volume hospitals (LVH). Standard statistical methods were used to compare treatment strategies and OS by diagnosis period. RESULTS: Of 55,212 patients, 25,469 (46.1%) were diagnosed in 2005-2009 and 29,743 (53.9%) in 2010-2014. Despite increased utilization of neoadjuvant radiation therapy (26.6% vs. 34.8%, P\u202f<\u202f0.001), the rate of R0 resections did not change (75.0% vs. 74.8%, P\u202f=\u202f0.067). Furthermore, at a national level, OS did not improve over time (HR 0.99, 95% CI 0.96-1.01). When outcomes were stratified by volume, treatment at HVH compared to LVH was associated with improved rates of R0 resection (OR 1.27, 95% CI 1.20-1.35) and OS (HR 0.92, 95% CI 0.89-0.95). Moreover, there was a modest improvement in OS at HVH (HR 0.95, 95% CI 0.91-1.00), but not at LVH (HR 1.01, 95% CI 0.97-1.04). However, referral to HVH did not change over time (40.7% vs. 40.7%, P\u202f=\u202f0.91). CONCLUSION: OS for STS did not change at a national level over the course of a decade, although it improved at HVH. Further outcome improvements will likely require more effective systemic therapies

Resection of primary leiomyosarcoma of the inferior vena cava (IVC) with reconstruction: a case series and review of the literature.

BACKGROUND: Leiomyosarcoma of the inferior vena cava (IVC) is a rare tumor which presents a unique surgical challenge. We present a series of six cases of leiomyosarcoma resection performed with IVC reconstruction. METHODS: Retrospective chart review was performed for patients undergoing initial operative resection of primary leiomyosarcoma with IVC reconstruction, at a tertiary care center. RESULTS: Between 2005-2013, six patients underwent resection with reconstruction. Half were female, and the mean age at presentation was 57 ± 15.4 years. Three patients required en bloc resection with adjacent organs. Three patients were resected on venovenous bypass, and one on cardiopulmonary bypass. Three underwent IVC patch repair (bovine pericardium, n = 2; saphenous vein, n = 1), and three had IVC reconstruction with graft (Dacron, n = 1; PTFE, n = 1; aortic homograft, n = 1). All achieved grossly negative margins. Median disease-free survival was 34 months (IQR 7-52 months), and median disease-specific survival was 51 months (IQR 20-108). Five year disease-free and disease-specific survival rates were 30% and 66.7%, respectively. CONCLUSIONS: Leiomyosarcomas of the IVC present a technical challenge to the surgeon. Careful preoperative workup and a collaborative team consisting of experienced cardiac and vascular surgeons and surgical oncologists can allow for a safe and successful operation despite extensive tumor involvement