Extracellular Vesicle - MDM2-DNA as a Potential Liquid Biopsy Biomarker for Disease Identification in Retroperitoneal Liposarcoma.

OBJECTIVE: We aimed to assess the levels of MDM2-DNA within extracellular vesicles (EVs) isolated from the serum of retroperitoneal liposarcoma (RLS) patients versus healthy donors, as well as within the same patients at the time of surgery versus post-operative surveillance visits. To determine whether EV-MDM2 may serve as a possible first-ever biomarker of liposarcoma recurrence. BACKGROUND: A hallmark of well-differentiated and de-differentiated (WD/DD) retroperitoneal liposarcoma is elevated MDM2 due to genome amplification, with recurrence rates of >50% even after complete resection. Imaging technologies frequently cannot resolve recurrent WD/DD-RLS versus postoperative scarring. Early detection of recurrent lesions, for which biomarkers are lacking, would guide surveillance and treatment decisions. METHODS: WD/DD-RLS serum samples were collected both at the time of surgery and during follow-up visits from 42 patients, along with sera from healthy donors (n=14). EVs were isolated, DNA purified and MDM2-DNA levels determined through q-PCR analysis. Non-parametric tests were employed to compare EV-MDM2 DNA levels from patients versus control group, as well as the time of surgery versus post-surgery conditions. RESULTS: EV-MDM2 levels were significantly higher in WD/DD-RLS than controls (P= 0.00085). Moreover, EV-MDM2 levels were remarkably decreased in WD/DD-RLS patients after resection (P=0.00036), reaching values comparable to control group (P=0.124). During post-operative surveillance, significant increases of EV-MDM2 was observed in some patients, correlating with CT scan evidence of recurrent or persistent post-resection disease. CONCLUSIONS: Serum EV-MDM2 may serve as a potential biomarker of early recurrent or post-operatively persistent WD/DD-RLS, a disease currently lacking such determinants.

Radiation therapy for retroperitoneal sarcoma: practice patterns in North America.

BACKGROUND: The addition of radiation therapy (RT) to surgery in retroperitoneal sarcoma (RPS) remains controversial. We examined practice patterns in the use of RT for patients with RPS over time in a large, national cohort. METHODS: Patients in the National Cancer Database (2004-2017) who underwent resection of RPS were included. Trends over time for proportions were calculated using contingency tables with Cochran-Armitage Trend test. RESULTS: Of 7,485 patients who underwent resection, 1,821 (24.3%) received RT (adjuvant: 59.9%, neoadjuvant: 40.1%). The use of RT decreased annually by < 1% (p = 0.0178). There was an average annual increase of neoadjuvant RT by 13% compared to an average annual decrease of adjuvant RT by 6% (p < 0.0001). Treatment at high-volume centers (OR 14.795, p < 0.0001) and tumor > 10 cm (OR 2.009, p = 0.001) were associated with neoadjuvant RT. In contrast liposarcomas (OR 0.574, p = 0.001) were associated with adjuvant RT. There was no statistically significant difference in overall survival between patients treated with surgery alone versus surgery and RT (p = 0.07). CONCLUSION: In the United States, the use of RT for RPS has decreased over time, with a shift towards neoadjuvant RT. However, a large percentage of patients are still receiving adjuvant RT and this mostly occurs at low-volume hospitals.

Disparities in Survival and NCCN Guideline-Concordant Care in Patients With Extremity Soft Tissue Sarcoma.

BACKGROUND: Based on the NCCN Guidelines for Soft Tissue Sarcoma (STS), treatment of extremity STS (ESTS) includes radiation therapy (RT) and surgical resection for tumors that are high-grade and >5 cm. ​​The aim of this study was to describe the association between neighborhood socioeconomic status (nSES), concordance with NCCN Guidelines recommendations, and outcomes in patients with ESTS. METHODS: Patients with ESTS diagnosed from 2006 through 2018 were identified in SEER registries. The analytic cohort was restricted to patients with high-grade tumors >5 cm without nodal or distant metastases who received limb-sparing surgery. Patient demographics and tumor characteristics associated with receipt of RT were analyzed using adjusted regression analyses. Kaplan-Meier curves and adjusted accelerated failure time models were used to examine disparities in cancer-specific survival. RESULTS: Of 2,249 patients, 29.0% (n=648) received neoadjuvant RT, 49.7% (n=1,111) received adjuvant or intraoperative RT, and 21.3% (n=476) did not receive RT. In adjusted analyses, lower nSES was associated with lower likelihood of receiving RT (odds ratio, 0.70 [95% CI, 0.57-0.87]; P<.001). Low nSES was associated with worse cancer-specific survival (hazard ratio, 1.19 [95% CI, 1.01-1.40]; P=.04). Race and ethnicity were not significant predictors of receipt of RT or cancer-specific survival in the fully adjusted models. CONCLUSIONS: Patients from lower nSES areas were less likely to receive NCCN Guideline-recommended RT for their ESTS and had worse cancer-specific survival. Efforts to better define and resolve disparities in the treatment and survival of patients with ESTS are warranted.

Comparing Multivisceral Resection with Tumor-only Resection of Liposarcoma Using the Win Ratio.

BACKGROUND: Multivisceral resection of retroperitoneal liposarcoma (LPS) is associated with increased morbidity and may not confer a survival benefit compared with tumor-only (TO) resection. We compared both approaches using a novel statistical method called the "win ratio" (WR). METHODS: Patients who underwent resection of LPS from 2004 to 2015 were identified from the National Cancer Database. Multivisceral resection was defined as removal of the primary site in addition to other organs. The WR was calculated based on a hierarchy of postoperative outcomes: 30-day and 90-day mortality, long-term survival, and severe complication. RESULTS: Among 958 patients (multivisceral 634, TO 324) who underwent resection, the median age was 63 years (interquartile range [IQR] 54-71) with a median follow-up of 51 months (IQR 30-86). There was no difference in the WR among patients who underwent TO versus multivisceral resection in the matched cohort (WR 0.82, 95% confidence interval [CI] 0.61-1.10). In patients aged 72-90 years, those who underwent multivisceral resection had 36% lower odds of winning compared with patients undergoing TO resection (WR 0.64, 95% CI 0.40-0.98). A subgroup analysis of patients classified as not having adjacent tumor involvement at the time of surgery revealed that those patients who underwent multivisceral resection had 33% lower odds of winning compared to TO resection (WR 0.67, 95% CI 0.45-0.99). CONCLUSIONS: Based on win-ratio assessments of a hierarchical composite endpoint, multivisceral resection in patients without adjacent tumor involvement may not confer improved outcomes. This method supports the rationale for less invasive resection of LPS in select patients, especially older patients.

Preoperative radiation therapy increases adherence in patients with high-risk extremity soft tissue sarcoma.

BACKGROUND: Surgery and radiation therapy remain the standard of care for patients with high-grade extremity soft tissue sarcoma that are >5 cm. Radiation therapy is time and labor-intensive for patients, and social determinants of health may affect adherence. The aim of this study was to define demographic, clinical, and treatment factors associated with the completion of radiation therapy and determine if preoperative radiation therapy improved adherence compared to postoperative radiation therapy. METHODS: The cohort included patients in the National Cancer Database with high-grade extremity soft tissue sarcoma >5 cm without nodal or distant metastases who received limb-sparing surgery and radiation therapy with microscopically negative R0 margins. Multivariable logistic regression analyses identified factors associated with radiation therapy sequencing and adherence (defined as completion of 50 Gy preoperative radiation therapy or at least 60 Gy postoperative radiation therapy). A multivariable Cox Proportional Hazards model assessed overall survival. RESULTS: Among 2,145 patients, 47.1% received preoperative radiation therapy (n = 1,010), and 52.9% (n = 1135) received postoperative radiation therapy. A greater proportion of patients treated with preoperative (77.2%) versus postoperative radiation therapy (64.9%, P < .0001) received the recommended dose. More patients with private insurance (49.8% vs 35.3% Medicaid vs 44.9% Medicare, P = .011) and patients treated at an academic medical center (52.6% vs 47.4%, P < .001) received preoperative radiation therapy. Patients who received preoperative radiation therapy had lower odds of receiving insufficient doses of radiation therapy (odds ratio 0.34 [95% CI 0.27-0.47]). Neither radiation therapy adherence nor sequencing were independent predictors of overall survival. CONCLUSIONS: Patients who received preoperative radiation therapy were more likely to complete therapy and receive an optimal dose than patients treated with postoperative radiation therapy. Preoperative radiation therapy improves adherence and should be widely considered in patients with high-grade extremity soft tissue sarcoma, particularly in patients at risk for not completing therapy.

Adjuvant Palbociclib May be Associated with Delayed Recurrence in Completely Resected Retroperitoneal Liposarcoma: Results of a Single-Institution Retrospective Cohort Study.

BACKGROUND: Retroperitoneal liposarcomas are locally aggressive and frequently recur following complete surgical resection. Palbociclib, a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor, is effective in the treatment of metastatic or unresectable liposarcoma. OBJECTIVE: The purpose of this study was to describe our initial experience using adjuvant palbociclib to delay recurrence. METHODS: Patients with resected RPS were identified from a prospectively maintained institutional database. In 2017, we began offering adjuvant palbociclib to patients following complete gross resection. Treatment interval, defined as the time between surgical resection and re-resection or change in systemic therapy, was compared between patients selected for adjuvant palbociclib or observation. RESULTS: Between 2017 and 2020, 12 patients underwent a total of 14 operations (14 patient cases) and were selected for adjuvant palbociclib for recurrence prevention. These patients were compared with 14 patients who, since 2010, underwent a total of 20 operations (20 patient cases) and were selected for observation. Histology was primarily dedifferentiated liposarcoma for both groups (observation: 70% [14/20]; adjuvant palbociclib: 64% [9/14]). All patients underwent complete gross resection. Neither age, number of previous surgeries, histologic grade, or Eastern Cooperative Oncology Group (ECOG) performance status differed between groups (p > 0.05 for all). Patients selected for adjuvant palbociclib experienced a longer treatment interval than those selected for observation, although it did not reach statistical significance (20.5 months vs. 13.1 months, p = 0.08, log rank). CONCLUSION: Adjuvant palbociclib may be associated with a prolonged interval between liposarcoma resection and the need for re-resection or other systemic therapy. Palbociclib may be effective in delaying liposarcoma recurrence, and its use for this indication warrants prospective study.

Association between surgical delay and outcomes among patients with invasive cutaneous melanoma.

BACKGROUND: The relationship between surgical delay and outcomes for patients with cutaneous melanoma is understudied. The objectives of this study were to determine the impact of surgical delay on regional nodal involvement and mortality in patients with cutaneous melanoma. METHODS: Retrospective study of patients diagnosed with clinically node-negative invasive cutaneous melanoma from 2004 to 2018. Outcomes included regional lymph node disease and overall survival. Multivariable logistic regression and Cox proportional-hazards models were constructed to adjust for pertinent clinical factors. RESULTS: Of 423,001 patients, 21.8% experienced a surgical delay (≥45 days). These patients were more likely to have nodal involvement (OR1.09; P â€‹= â€‹0.01). Surgical delay (HR1.14; P â€‹< â€‹0.001), Black race (HR1.34; P â€‹= â€‹0.002), and Medicaid (HR1.92; P â€‹< â€‹0.001) were associated with lower survival. Patients treated at academic/research (HR0.87; P â€‹< â€‹0.001) or integrated network cancer programs (HR0.89; P â€‹= â€‹0.001) had improve survival. CONCLUSIONS: Surgical delay was frequent and resulted in higher rates of lymph node involvement and decreased overall survival.

Prognostic factors in patients receiving surgery and radiation therapy for retroperitoneal sarcoma: A machine-learning analysis.

BACKGROUND: The addition of radiation therapy to surgery for retroperitoneal sarcoma remains controversial. Improved patient selection may help identify optimal candidates for multimodality treatment. The aim of this analysis was to define prognostic factors among patients who receive radiation therapy and surgery to aid in patient selection for multimodal therapy. METHODS: Patients who received radiation therapy and underwent curative-intent resection for retroperitoneal sarcoma between 2004 and 2016 were identified from a national cohort in the United States (National Cancer Database). A machine-based classification and regression tree model was used to generate similar groups of patients relative to overall survival based on preoperative factors. RESULTS: A total of 1,443 patients received radiation therapy in addition to surgery. Median age was 61 years old and 55.0% were female. Most patients (66%) received care at an academic or integrated network cancer program. With a median follow-up of 84 months, receipt of radiation therapy was not associated with improved overall survival (P = .81). Classification and regression tree analysis revealed a significant association between overall survival and American Joint Committee on Cancer stage group, age, tumor histology, and Charlson comorbidity score. Application of these parameters via machine learning stratified patients into 5 cohorts with distinct survival outcomes. In the most favorable cohort (Cohort 1: American Joint Committee on Cancer stage group ≤II, age ≤61, histology including fibrosarcoma, well differentiated liposarcoma, myxoid liposarcoma, and leiomyosarcoma), the 5-year overall survival was 81.7% and median overall survival was not reached; in the least favorable cohort (Cohort 6: American Joint Committee on Cancer stage group >II, age >68) where the 5-year survival was 41.3% and median overall survival was 45.2 months (P < .001 versus Cohort 1). CONCLUSION: In the absence of a defined survival benefit, patients with advanced American Joint Committee on Cancer stage group, older age, and medical comorbidities have relatively unfavorable overall survival after combined modality therapy and therefore stand the least to gain from the addition of radiation therapy to surgery. In contrast, younger patients with good performance status and retroperitoneal sarcoma histologies with a higher propensity for local recurrence may have the greatest opportunity to benefit from radiation therapy.

Outcomes of plastic surgical reconstruction in extremity and truncal soft tissue sarcoma: Results from the US Sarcoma Collaborative.

BACKGROUND: This study aimed to define how utilization of plastic surgical reconstruction (PSR) affects perioperative outcomes, locoregional recurrence-free survival (LRRFS), and overall survival (OS) after radical resection of extremity and truncal soft tissue sarcoma (ETSTS). The secondary aim was to determine factors associated with PSR. METHODS: Patients who underwent resection of ETSTS between 2000 and 2016 were identified from a multi-institutional database. PSR was defined as complex primary closure requiring a plastic surgeon, skin graft, or tissue-flap reconstruction. Outcomes included PSR utilization, postoperative complications, LRRFS, and OS. RESULTS: Of 2750 distinct operations, 1060 (38.55%) involved PSR. Tissue-flaps (854, 80.57%) were most commonly utilized. PSR was associated with a higher proportion of R0 resections (83.38% vs. 74.42%, p < 0.001). Tissue-flap PSR was associated with local wound complications (odds ratio: 1.81, confidence interval: 1.21-2.72, p = 0.004). Neither PSR nor postoperative complications were independently associated with LRRFS or OS. High-grade tumors (1.60, 1.13-2.26, p = 0.008) and neoadjuvant radiation (1.66, 1.20-2.30, p = 0.002) were associated with the need for PSR. CONCLUSION: Patients with ETSTS undergoing resection with PSR experienced acceptable rates of complications and a higher rate of negative margins, which were associated with improved LRRFS and OS. High tumor grade and neoadjuvant radiation were associated with requirement of PSR.

The Implications of an Unplanned Sarcoma Excision (the "Whoops" Operation).

In this review, the risk factors of an unplanned excision of soft-tissue sarcoma and the implications of non-oncologic resection are discussed. Although soft-tissue sarcoma remains a rare disease, many studies have shown the deleterious effects of unplanned excision, including decreased recurrence-free survival and increased morbidity. Once discovered, sarcomas should be referred to expert centers for further management, which often entails re-excision, radiation, and/or chemotherapy treatment. Although much still needs to be learned about this complex disease, a multidisciplinary approach including surgeons, medical oncologists, radiologists, and pathologists is paramount to its successful treatment.

Extraskeletal myxoid chondrosarcoma: Clinicopathological features and outcomes from the United States sarcoma collaborative database.

BACKGROUNDS AND OBJECTIVES: This investigation described clinicopathological features and outcomes of extraskeletal myxoid chondrosarcoma (EMC) patients. METHODS: EMC patients were identified from the United States Sarcoma Collaborative database between 2000 and 2016. Overall survival (OS) and recurrence-free survival (RFS) were calculated, and prognostic factors were analyzed. RESULTS: Sixty individuals with a mean age of 55 years were included, and 65.0% (n = 39) were male. 73.3% (n = 44) had a primary tumor. A total of 41.6% (n = 25) developed tumor relapse following resection. The locoregional recurrence rate was 30.0% (n = 18/60), and mean follow-up was 42.7 months. The 5-year OS was 71.0%, while the 5-year RFS was 41.4%. On multivariate analysis for all EMC, chemotherapy (hazard ratio [HR], 6.054; 95% confidence interval [CI], 1.33-27.7; p = 0.020) and radiation (HR, 5.07, 95% CI, 1.3-20.1; p = 0.021) were independently predictive of a worse RFS. Among patients with primary EMC only, the 5-year OS was 85.3%, with a 30.0% (n = 12) locoregional recurrence rate, though no significant prognostic factors were identified. CONCLUSIONS: Long-term survival with EMC is probable, however there exists a high incidence of locoregional recurrence. While chemotherapy and radiation were associated with a worse RFS, these findings were likely confounded by recurrent disease as significance was lost in the primary EMC-only subset.

The Role of AKT in Soft Tissue Sarcoma: Review and Insights.

Soft tissue sarcomas (STS) are a biologically diverse group of mesenchymal tumors that predominantly exhibit a poor prognosis. Surgical resection is considered the mainstay of treatment and provides the only chance for long-term survival. However, some patients present with locally advanced, unresectable disease, and for those who are able to undergo resection, tumor recurrence occurs in over half of patients. In addition, the efficacy of conventional systemic therapies remains dismal. The serine/threonine kinase AKT pathway is one of the most frequently aberrantly activated signaling pathways that has been verified in many types of human cancer. Dysregulation of the AKT cascade is known to result in tumorigenesis and aggressive clinical behavior for many tumor types, including STS. EGFRs, with its downstream effectors, PI3K and protein kinase B (AKT)/mTOR, have been investigated for decades as promising targets for the treatment of STS, but significant challenges remain and the prognosis of patients with advanced STS has not improved in over two decades. In this review, we will first describe the AKT pathway and its role in STS tumor biology and then discuss the current challenges in targeting the AKT pathway to treat patients with advanced sarcoma.

All Politics Are Local: A Single Institution Investigation of the Educational Impact of Residents and Fellows Working Together.

BACKGROUND: Most general surgery residents pursue fellowship; there is limited understanding of the impact residents and fellows have on each other's education. The goal of this exploratory survey was to identify these impacts. MATERIALS AND METHODS: Surgical residents and fellows at a single academic institution were surveyed regarding areas (OR assignments, the educational focus of the team, roles and responsibilities on the team, interpersonal communication, call, "other") hypothesized to be impacted by other learners. Impact was defined as "something that persistently affects the clinical learning environment and a trainee's education or ability to perform their job". Narrative responses were reviewed until dominant themes were identified. RESULTS: Twenty-three residents (23/45, 51%) and 12 fellows (12/21, 57%) responded. Responses were well distributed among resident year (PGY-1:17% [4/23], PGY-2, 35% [8/23], PGY-3 26% [6/23], PGY-4 9% [2/23%], PGY-5 13% [3/23]). Most residents reported OR assignment (14/23, 61%) as the area of primary impact, fellows broadly reported organizational categories (Roles and responsibilities 33%, educational focus 16%, interpersonal communication 16%). Senior residents reported missing out on operations to fellows while junior residents reported positive impacts of operating directly with fellows. Residents of all levels reported that fellows positively contributed to their education. Fellows, senior residents, and junior residents reported positive experiences when residents and fellows operated together as primary surgeon and assistant. CONCLUSIONS: Residents and fellows impact one another's education both positively and negatively. Case allocation concerns senior residents, operating together may alleviate this, providing a positive experience for all trainees. Defining a unique educational role for fellows and delineating team expectations may maximize the positive impacts in this relationship.

Morbidity and Mortality after Surgery for Retroperitoneal Sarcoma.

Retroperitoneal sarcoma (RPS) is a rare disease with over 100 histologic types and accounts for 10-15% of all soft tissue sarcomas. Due to the rarity of RPS, sarcoma centers in Europe and North America have created the Transatlantic RPS Working Group (TARPSWG) to study this disease and establish best practices for its management. Current guidelines dictate complete resection of all macro and microscopic disease as the gold standard for patients with RPS. Complete extirpation often requires a multi-visceral resection. In addition, recent evidence suggests that en bloc compartmental resections are associated with reduced rates of local recurrence. However, this approach must be balanced by the potential for added morbidity. Strategies to mitigate postoperative complications include optimization of the patient through improved preoperative nutrition and pre-habilitation therapy, referral to a high-volume sarcoma center, and implementation of enhanced recovery protocols. This review will focus on the factors associated with perioperative complications following surgery for RPS and outline approaches to mitigate poor surgical outcomes in this patient population.

Resection Status Does Not Impact Recurrence in Well-Differentiated Liposarcoma of the Extremity.

BACKGROUND: Well-differentiated liposarcoma (WDLPS) is a low-grade soft tissue sarcoma with a propensity for local recurrence. The necessity of obtaining microscopically free surgical margins (R0) to minimize local recurrence is not clear. This study evaluates recurrence-free survival (RFS) of extremity WDLPS in relation to resection margin status. METHODS: A retrospective review of adult patients with primary extremity WDLPS at seven US institutions from 2000 to 2016 was performed. Patients with recurrent tumors or incomplete resection (R2) were excluded. Clinicopathologic factors were analyzed to assess impact on local RFS. RESULTS: 97 patients with primary extremity WDLPS were identified. The majority of patients had deep, lower extremity tumors. Mean tumor size was 18.2±8.9cm. Patients were treated with either radical (76.3%) or excisional (23.7%) resections; 64% had R0 and 36% had microscopically positive (R1) resection margins. Ten patients received radiation therapy with no difference in receipt of radiation between R0 vs R1 groups. Thirteen patients (13%) developed a local recurrence with no difference in RFS between R0 vs R1 resection. Five-year RFS was 59.5% for R0 vs 85.2% for R1. Only one patient died of disease after developing dedifferentiation and distant metastasis despite originally having an R0 resection. DISCUSSION: In this large multi-institutional study of surgical resection of extremity WDLPS, microscopically positive margins were not associated with an increased risk of recurrence. Positive microscopic margin resection for extremity WDLPS may yield similar rates of local control while avoiding a radical approach to obtain microscopically negative margins.

Nerve transfers to restore femoral nerve function following oncologic nerve resection.

INTRODUCTION: Advances in the care of soft-tissue tumors, including imaging capabilities and adjuvant radiation therapy, have broadened the indications and opportunities to pursue surgical limb salvage. However, peripheral nerve involvement and femoral nerve resection can still result in devastating functional outcomes. Nerve transfers offer a versatile solution to restore nerve function following tumor resection. METHODS: Two cases were identified by retrospective review. Patient and disease characteristics were gathered. Preoperative and postoperative motor function were assessed using the Medical Research Council Muscle Scale. Patient-reported pain levels were assessed using the numeric rating scale. RESULTS: Nerve transfers from the obturator and sciatic nerve were employed to restore knee extension. Follow up for Case 1 was 24 months, 8 months for Case 2. In both patients, knee extension and stabilization of gait without bracing was restored. Patient also demonstrated 0/10 pain (an average improvement of 5 points) with decreased neuromodulator and pain medication use. CONCLUSION: Nerve transfers can restore function and provide pain control benefits and ideally are performed at the time of tumor extirpation. This collaboration between oncologic and nerve surgeons will ultimately result in improved functional recovery and patient outcomes.

Letters of recommendation for surgical fellowships - Does gender make a difference?

BACKGROUND: Females comprise 1/3 of general surgery residents, 1/4 of surgical faculty and 10% of full professors. Inadequate sponsorship is one proposed mechanism for this decline. This study evaluated letters of recommendation (LOR) among applicants applying to a complex general surgical oncology (CGSO) fellowship. METHODS: Linguistic analysis of LOR for CGSO applicants was conducted. Demographics of authors and features of the LOR were extracted. Differences by gender of the applicant were analyzed. RESULTS: Among 340 letters, 67% were written for male and 33% written for female applicants. Males authored 84% of letters reviewed. Female authors used more grindstone adjectives than males (3.61 v 2.90). However, this difference was seen only among letters written for male applicants (3.82 v. 2.73). All other linguistic features were similar, aside from mention of physical appearance which was significantly more common in letters written about female applicants (4% v. 1%). CONCLUSIONS: Female authors write substantively different letters than males. Physical appearance is a small but important difference in letters for female applicants.