Atezolizumab for Advanced Alveolar Soft Part Sarcoma.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported. METHODS: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action. RESULTS: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1. CONCLUSIONS: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.).

Defining the role of neoadjuvant systemic therapy in high-risk retroperitoneal sarcoma: A multi-institutional study from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: In patients with retroperitoneal sarcoma (RPS), the incidence of recurrence after surgery remains high. Novel treatment approaches are needed. This retrospective study evaluated patients with primary, high-risk RPS who received neoadjuvant systemic therapy followed by surgery to 1) determine the frequency and potential predictors of radiologic tumor responses and 2) assess clinical outcomes. METHODS: Clinicopathologic data were collected for eligible patients treated at 13 sarcoma referral centers from 2008 to 2018. Univariable and multivariable logistic models were performed to assess the association between clinical predictors and response. Overall survival (OS) and crude cumulative incidences of local recurrence and distant metastasis were compared. RESULTS: Data on 158 patients were analyzed. A median of 3 cycles of neoadjuvant systemic therapy (interquartile range, 2-4 cycles) were given. The regimens were mostly anthracycline based; however, there was significant heterogeneity. No patients demonstrated a complete response, 37 (23%) demonstrated a partial response (PR), 88 (56%) demonstrated stable disease, and 33 (21%) demonstrated progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Only a higher number of cycles given was positively associated with PR (P = .005). All patients underwent complete resection, regardless of the tumor response. Overall, patients whose tumors demonstrated PD before surgery showed markedly worse OS (P = .005). An indication of a better clinical outcome was seen in specific regimens given for grade 3 dedifferentiated liposarcoma and leiomyosarcoma. CONCLUSIONS: In patients with high-risk RPS, the response to neoadjuvant systemic therapy is fair overall. Disease progression on therapy may be used to predict survival after surgery. Subtype-specific regimens should be further validated.

Predictors of readmission after craniotomy for meningioma resection: a nationwide readmission database analysis.

BACKGROUND: Meningiomas are the most common benign primary brain tumors. The mainstay of treatment, surgical resection, is often curative. Given the excellent prognosis of these lesions, minimizing perioperative complications is of the utmost importance. With the establishment of the National Readmissions Database (NRD), researchers are now able to identify variables associated with postoperative complications beyond the index admission. OBJECTIVE: In this study, we sought to identify the leading causes for non-elective readmission and variables associated with increased likelihood of readmission at 30 and 90 days after discharge following a craniotomy for meningioma resection. METHODS: Adult inpatients who underwent craniotomy for meningioma resection between 2010 and 2014 were queried from the NRD. All-cause readmissions following craniotomy at 30 and 90 days were identified, and a multivariable logistic regression model was used to characterize independent risk factors. RESULTS: Among 26,034 patients who received craniotomy for meningioma resection, 2825 (10.9%) were readmitted at 30 days and 3436 (16.1%) were readmitted at 90 days. Postoperative wound infection was the most common readmission diagnosis, occurring in 9.32% and 10.2% of 30- and 90-day readmissions respectively. Patient factors associated with increased likelihood of readmission included male gender, greater illness severity, non-routine discharge, index length of hospitalization, and having Medicare or Medicaid insurance. CONCLUSIONS: Readmission following craniotomy for meningioma resection occurs at a clinically significant rate. Several patient factors were identified in association with all-cause 30- and 90-day readmissions. Further studies are required to identify means for preventing complications following discharge in these vulnerable patient populations.

Bevacizumab alone or in combination with TRC105 for patients with refractory metastatic renal cell cancer.

BACKGROUND: Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab. METHODS: Eligible patients with metastatic RCC who had previously received 1 to 4 prior lines of therapy, including VEGF-targeted agents, were randomized 1:1 to receive bevacizumab 10 mg/kg intravenously every 2 weeks (arm A) or the same plus TRC105 10 mg/kg intravenously every 2 weeks (arm B). The primary endpoint was progression-free survival (PFS) at 12 and 24 weeks. Correlative studies included serum transforming growth factor ß (TGFß) and CD105 levels as well as tissue immunostaining for TGFß receptors. RESULTS: Fifty-nine patients were enrolled (28 on arm A and 31 on arm B), and 1 patient on each arm had a confirmed partial response. The median PFS for bevacizumab alone was 4.6 months compared with 2.8 for bevacizumab plus TRC105 (P = .09). Grade ≥ 3 toxicities occurred in 16 patients (57%) who received bevacizumab compared with 19 (61%) who received bevacizumab plus TRC105 (P = .9). Baseline serum TGFß levels below the median (<10.6 ng/mL) were associated with longer median PFS (5.6 vs 2.1 months; P = .014). CONCLUSIONS: TRC105 failed to improve PFS when added to bevacizumab. TGFß warrants further study as a biomarker in RCC. Cancer 2017;123:4566-4573. © 2017 American Cancer Society.

Contemporary Management of Retroperitoneal Soft Tissue Sarcomas.

Management of retroperitoneal soft tissue sarcomas (RP STS) can be very challenging. In contrast to the more common extremity STS, the two predominant histologic subtypes encountered in the retroperitoneum are well-differentiated/dedifferentiated liposarcoma and leiomyosarcoma. Surgery remains the mainstay of treatment for RP STS. Preoperative planning and anticipation of the need for resection of adjacent organs/structures are critical. The extent of surgery, including the role of compartmental resection, is still controversial. Radiation therapy may be an important adjunct to surgery to provide locoregional disease control; this is currently being evaluated in the preoperative setting in the EORTC STRASS trial. Systemic therapy, tailored to the specific histologic subtype, may also be of benefit for the management of RP STS. Further investigation of novel therapies (e.g., targeted therapies, immunotherapy) is needed. Overall, multi-institutional collaboration is important moving forward, to continue to better understand and optimize management of this disease.

Contrast-Enhanced Sonography for Monitoring Neoadjuvant Chemotherapy in Soft Tissue Sarcomas.

Neoadjuvant chemotherapy is a mainstay in treating soft tissue sarcomas. Soft tissue sarcomas can show an increase in size and central necrosis, with a decrease in the viable tumor, as an initial response to neoadjuvant chemotherapy. Thus, the maximum tumor diameter may not reliably assess the response to this therapy. Contrast-enhanced sonography may address this limitation. We evaluated 4 patients with soft tissue sarcomas by contrast-enhanced sonography, performed concomitantly with conventional imaging (computed tomography, magnetic resonance imaging, or positron emission tomography). Quantitative analysis was also performed on 1 sarcoma. A viable, enhancing tumor versus tumor necrosis was nearly identical on contrast-enhanced sonography and conventional imaging. Preliminary results demonstrate potential for contrast-enhanced sonographic monitoring of soft tissue sarcomas during neoadjuvant chemotherapy.

Physician Leadership and Burnout: The Need for Agency; a Qualitative Study of an Academic Institution.

Purpose: Organizational approaches to physician burnout are limited. Training physician leaders to influence the organizational environment is a growing area of study. This study explored perceived physician leadership behaviors in response to burnout from the viewpoint of faculty physicians not in formal leadership positions. Understanding physician leadership behaviors from the viewpoint of those faculty being led can inform organizational strategy and leadership training to address physician burnout. Subjects and Methods: Interview requests were sent to 70 randomly identified faculty physicians from a roster containing all 1145 physician faculty that excluded the Pediatric Department, at an academic health care institution in Southern California. The first ten respondents were asked to participate in a 30-to-40-minute semi-structured virtual interview via Zoom. The interviewees were asked two questions pertaining to burnout and their perception of how leadership responded. The two questions were "What has leadership done to address burnout?" and "If you had five minutes to advise your leaders on burnout, what would you say?" The recorded interviews were transcribed, redacted, and then sent to two reviewers. Thematic analysis through iterative coding was completed, and categories were constructed that aligned with the two interview questions. Results: Overall, five themes were identified. These themes were organized according to the interview questions and broadly categorized as physician leadership behaviors observed that corresponded to the interview question of what leadership had done to address burnout and physician leadership behaviors desired corresponding to the second interview question of what advice should be given. Leadership behaviors observed in the context of burnout included three themes; referral to individual wellness programs, increased number of meetings and events, and a lack of agency in addressing wellness issues. The two themes of leadership behaviors desired were the obtainment of more resources and the granting of greater appreciation and recognition for work done through enhanced communication. Conclusion: This small study of faculty physician perceptions of leadership behaviors identified several themes that had been identified in previous studies of leadership and burnout; need for relationship building through communication, need for resources to address work issues, and referral to wellness programs. However, the identification of a lack of agency in addressing factors in the wellness environment has not been identified in the previous burnout and physician leadership literature. Further study into the causes of this perceived lack of agency should be explored. Understanding the root causes of physician leaders' lack of agency can further inform physician leadership education as an organizational approach to burnout.

Physician Burnout-Evidence That Leadership Behaviors Make a Difference: A Cross-Sectional Survey of an Academic Medical Center.

INTRODUCTION: High rates of physician burnout are well documented in the USA. Identifying beneficial leadership behaviors as an organizational approach to mitigating burnout can lead to improved wellness in the physicians that they lead; however, few studies have examined which leadership behaviors are beneficial and which may be detrimental. MATERIALS AND METHODS: This survey study of academic medical center physicians and their physician leaders assessed the correlation between burnout and leadership behaviors. Data were analyzed for the strength of correlation between scores for leadership behaviors and self-reported physician burnout with analysis of variance by sex, time from training, specialty, and age. RESULTS: Of 1,145 physicians surveyed, 305 returned surveys. Among the respondents, 45% were female, 25% were 56 years or older, and 57% self-identified as practitioners of medicine or medicine subspecialties. Two transformational leadership categories of behaviors (idealized influence behaviors and individualized consideration) and one transactional leadership behavior category (contingent reward) correlated favorably with all domains of burnout (P < .0001). Conversely, two transactional leadership categories of burnout (management by exception passive and laissez-faire) correlated unfavorably with all burnout domains. CONCLUSIONS: Organizational interventions are needed to improve burnout in physicians. Adopting favorable leadership behaviors while avoiding unfavorable leadership behaviors can improve burnout in those physicians being led. These findings could inform the conceptual basis of future physician leadership training programs as transactional leadership behaviors also have an impact on physician wellness.

Tumor lysis syndrome following ifosfamide monotherapy in metastatic osteosarcoma: a case report and review of the literature.

BACKGROUND: Tumor lysis syndrome is an oncologic emergency that involves multiple metabolic abnormalities and clinical symptoms such as acute renal failure, cardiac arrhythmias, seizures, and multiorgan failure, and may be fatal if not promptly recognized. Tumor lysis syndrome occurs most often in patients with hematologic malignancies, and relatively few cases have been described in patients with sarcoma. CASE PRESENTATION: A 64-year-old male of Asian heritage presented to his primary care physician with a right lower-extremity mass and was ultimately diagnosed with widely metastatic osteosarcoma. He was treated with one cycle of cisplatin and doxorubicin that was complicated by hypervolemia and hypoxic respiratory failure. Given concerns for volume overload, therapy was changed to single-agent, dose-reduced ifosfamide. After receiving one dose of ifosfamide 1 g/m2 (1.8 g total) intravenously over 1 hour, the patient developed renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and lactic acidosis. The patient ultimately died from severe electrolyte abnormalities associated with tumor lysis syndrome. CONCLUSION: This is the first instance of tumor lysis syndrome described in a patient with osteosarcoma undergoing ifosfamide monotherapy. Clinicians must be vigilant in identifying tumor lysis syndrome regardless of the malignancy type or chemotherapy regimen in order to prevent potentially fatal complications.

Circulating Tumor Cells and Biomarker Modulation with Olaratumab Monotherapy Followed by Olaratumab plus Doxorubicin: Phase Ib Study in Patients with Soft-Tissue Sarcoma.

This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1-2; 15 mg/kg, cycles 3-7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [n = 31 (72.1%)] and PDGFRß [n = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, n = 30 (69.8%); PDGFRß, n = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome.

Treatment of advanced, metastatic soft tissue sarcoma: latest evidence and clinical considerations.

Soft tissue sarcoma (STS) is a biologically heterogeneous malignancy with over 50 subtypes. Historically, there have been few systemic treatment options for this relatively rare disease. Traditional cytotoxic agents, such as anthracyclines, alkylating agents, and taxanes have limited clinical benefit beyond the first-line setting; across all high-grade STS subtypes, median overall survival remains approximately 12-18 months for advanced metastatic disease. The development of targeted therapies has led to recent US Food and Drug Administration approval of four new treatments for high-grade STS in the advanced metastatic setting. Among these, olaratumab is most notable for its improvement in overall survival for patients with anthracycline-naïve disease. Further progress in STS management will rely on novel trial design, subtype-specific therapies and validation of biomarkers to tailor therapy. Immunotherapy has shown promise as a new, but yet undiscovered frontier in the management of STS.