Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

A Pilot Study of Pembrolizumab Combined With Stereotactic Ablative Radiotherapy for Patients With Advanced or Metastatic Sarcoma.

OBJECTIVES: Immunotherapy with immune checkpoint inhibitors has shown only limited success in the management of metastatic soft tissue sarcoma. Overall response rates (ORR) with single agent pembrolizumab were 18% and median PFS was 18 weeks on the clinical trial SARC028. One strategy to improve the responses to immunotherapy is with stereotactic body radiation therapy (SBRT), which can enhance the antitumor CD8 T cell response through the release of tumor-specific antigens, potentially priming a more diverse class of T cell receptors. METHODS: This is a phase 0, pilot prospective study taking place at a single center with 2 arms. In Arm A, patients are treated with pembrolizumab 400 mg IV infusion on day 1 of a 42-day cycle. Stereotactic body radiation therapy (SBRT) is delivered in 1-5 fractions starting on C1D15-28 and given every other day. In Arm B, patients who have started an immune checkpoint inhibitor within 60 days are treated with SBRT in addition to the current therapy. RESULTS: In this study we outline testing the feasibility of adding SBRT to pembrolizumab. CONCLUSION: The ultimate goal of combination therapy is improved overall response, including tumors not treated with SBRT. This trial can be found registered online: NCT05488366.

The cure from within? a review of the microbiome and diet in melanoma.

Therapy for cutaneous melanoma, the deadliest of the skin cancers, is inextricably linked to the immune system. Once thought impossible, cures for metastatic melanoma with immune checkpoint inhibitors have been developed within the last decade and now occur regularly in the clinic. Unfortunately, half of tumors do not respond to checkpoint inhibitors and efforts to further exploit the immune system are needed. Tantalizing associations with immune health and gut microbiome composition suggest we can improve the success rate of immunotherapy. The gut contains over half of the immune cells in our bodies and increasingly, evidence is linking the immune system within our gut to melanoma development and treatment. In this review, we discuss the importance the skin and gut microbiome may play in the development of melanoma. We examine the differences in the microbial populations which inhabit the gut of those who develop melanoma and subsequently respond to immunotherapeutics. We discuss the role of dietary intake on the development and treatment of melanoma. And finally, we review the landscape of published and registered clinical trials therapeutically targeting the microbiome in melanoma through dietary supplements, fecal microbiota transplant, and microbial supplementation.

Single protein encapsulated SN38 for tumor-targeting treatment.

BACKGROUND: The alkaloid camptothecin analog SN38 is a potent antineoplastic agent, but cannot be used directly for clinical application due to its poor water solubility. Currently, the prodrug approach on SN38 has resulted in 3 FDA-approved cancer therapeutics, irinotecan, ONIVYDE, and Trodelvy. However, only 2-8% of irinotecan can be transformed enzymatically in vivo into the active metabolite SN38, which severely limits the drug's efficacy. While numerous drug delivery systems have been attempted to achieve effective SN38 delivery, none have produced drug products with antitumor efficacy better than irinotecan in clinical trials. Therefore, novel approaches are urgently needed for effectively delivering SN38 to cancer cells with better efficacy and lower toxicity. METHODS: Based on the unique properties of human serum albumin (HSA), we have developed a novel single protein encapsulation (SPE) technology to formulate cancer therapeutics for improving their pharmacokinetics (PK) and antitumor efficacy and reducing their side effects. Previous application of SPE technology to doxorubicin (DOX) formulation has led to a promising drug candidate SPEDOX-6 (FDA IND #, 152154), which will undergo a human phase I clinical trial. Using the same SPE platform on SN38, we have now produced two SPESN38 complexes, SPESN38-5 and SPESN38-8. We conducted their pharmacological evaluations with respect to maximum tolerated dose, PK, and in vivo efficacy against colorectal cancer (CRC) and soft tissue sarcoma (STS) in mouse models. RESULTS: The lyophilized SPESN38 complexes can dissolve in aqueous media to form clear and stable solutions. Maximum tolerated dose (MTD) of SPESN38-5 is 250 mg/kg by oral route (PO) and 55 mg/kg by intravenous route (IV) in CD-1 mice. SPESN38-8 has the MTD of 45 mg/kg by IV in the same mouse model. PK of SPESN38-5 by PO at 250 mg/kg gave mouse plasma AUC0-∞ of 0.05 and 4.5 nmol × h/mL for SN38 and SN38 glucuronidate (SN38G), respectively, with a surprisingly high molar ratio of SN38G:SN38 = 90:1. However, PK of SPESN38-5 by IV at 55 mg/kg yielded much higher mouse plasma AUC0-∞ of 19 and 28 nmol × h/mL for SN38 and SN38G, producing a much lower molar ratio of SN38G:SN38 = 1.5:1. Antitumor efficacy of SPESN38-5 and irinotecan (control) was evaluated against HCT-116 CRC xenograft tumors. The data indicates that SPESN38-5 by IV at 55 mg/kg is more effective in suppressing HCT-116 tumor growth with lower systemic toxicity compared to irinotecan at 50 mg/kg. Additionally, SPESN38-8 and DOX (control) by IV were evaluated in the SK-LMS-1 STS mouse model. The results show that SPESN38-8 at 33 mg/kg is highly effective for inhibiting SK-LMS-1 tumor growth with low toxicity, in contrast to DOX's insensitivity to SK-LMS-1 with high toxicity. CONCLUSION: SPESN38 complexes provide a water soluble SN38 formulation. SPESN38-5 and SPESN38-8 demonstrate better PK values, lower toxicity, and superior antitumor efficacy in mouse models, compared with irinotecan and DOX.

Vascular Surgery In-Training Examination performance following implementation of the Vascular Surgical Council on Resident Education curriculum.

OBJECTIVE: The Vascular Surgery Surgical Council on Resident Education (VSCORE) program is a standardized curriculum intended to prepare Vascular Surgery trainees for the annual Vascular Surgery In-Training Examination (VSITE). This study evaluated the performance of 0+5 and 5+2 Vascular Surgery trainees on the VSITE prior to and following implementation of the VSCORE curriculum. METHODS: VSITE scores, measured as percentage of questions correct, were collected for Vascular Surgery trainees at a United States academic medical center between 2015 and 2022. The VSITE scores were compared for the periods prior to (2015-2021) and following (2022) implementation of the VSCORE curriculum. RESULTS: Fifty-seven VSITE scores were evaluated, including 46 examinations completed prior to and 11 after the implementation of the VSCORE curriculum. The mean VSITE score across all training levels (post-graduate year [PGY] 1-7) increased significantly from 68.4% ± 1.5% prior to implementation of VSCORE curriculum to 76.5% ± 3.1% following implementation (P = .03). Two-way analysis of variance identified pre- and post-VSCORE implementation as a statistically significant categorical variable when residents were stratified into junior (PGY 1-2), senior (PGY 3-5), and fellow (PGY 6-7) training levels (P < .001). The mean change in score between consecutive years also increased following VSCORE implementation (14.1% ± 2.3%) compared with the pre-VSCORE era (5.7% ± 1.7%; P = .002) CONCLUSIONS: The implementation of the VSCORE curriculum at an academic medical center improved VSITE scores across vascular surgery trainees at all levels.

Systemic Therapy for Chondrosarcoma.

OPINION STATEMENT: Clinical trial enrollment should be actively encouraged in all patients diagnosed with advanced, surgically unresectable chondrosarcoma (CS) due to the lack of consensus treatment recommendations. In the absence of an appropriate clinical trial, treatments are determined based on histologic subtype of CS with consideration given to targetable mutations (i.e., IDH1). Conventional CS is inherently resistant to cytotoxic chemotherapy and patients may benefit from antiangiogenic therapy including off-label use of pazopanib. Individuals harboring an IDH1 mutation may derive clinical benefit from ivosidenib, an IDH1 inhibitor. Upon progression and with functional status permitting, alternative options include mTOR inhibitors (sirolimus, temsirolimus) or other tyrosine kinase inhibitors (dasatinib), though no clear sequencing data exists. For dedifferentiated CS, conventional chemotherapies with osteosarcoma-like regimens are upfront options although prospective data is limited with minimal overall benefit. Alternative treatment options include immunotherapy with pembrolizumab or ivosidenib in IDH1-mutant, dedifferentiated CS, but questionable efficacy was observed in small sample sizes with either approach. In mesenchymal CS, treatment with Ewing sarcoma-like chemotherapy regimens may be considered, although data supporting its use is even more limited given its rarity.

Cause-specific mortality of type B aortic dissection and assessment of competing risks of mortality.

OBJECTIVE: Natural history studies of type B aortic dissection (TBAD) commonly report all-cause mortality. Our aim was to determine cause-specific mortality in TBAD and to evaluate the clinical characteristics associated with aorta-related and nonaorta-related mortality. METHODS: Clinical and administrative records were reviewed for patients with acute TBAD between 1995 and 2017. Demographics, comorbidities, presentation, and initial imaging findings were abstracted. Cause of death was ascertained through a multimodality approach using electronic health records, obituaries, social media, Social Security Death Index, and state mortality records. Causes of death were classified as aorta related, nonaorta related, or unknown. A Fine-Gray multivariate competing risk regression model for subdistribution hazard ratio was employed to analyze the association of clinical characteristics with aorta-related and nonaorta-related mortality. RESULTS: A total of 275 individuals met inclusion criteria (61.1 ± 13.7 years, 70.9% male, 68% white). Mean survival after discharge was 6.3 ± 4.7 years. Completeness of follow-up Clark C index was 0.87. All-cause mortality was 50.2% (n = 138; mean age, 70.1 ± 14.6 years) including an in-hospital mortality of 8.4%. Cause-specific mortality was aorta related, nonaorta related, and unknown in 51%, 43%, and 6%, respectively. Compared with patients with nonaorta-related mortality, patients with aorta-related mortality were younger at acute TBAD (69.5 ± 11.2 years vs 61.6 ± 15.5 years; P = .001), underwent more descending thoracic aortic repairs (19.4% vs 45.8%; P = .002), and had a shorter survival duration (5.7 ± 3.9 vs 3.4 ± 4.5 years; P = .002). There was clear variation in cause of death by each decade of life, with higher aorta-related mortality among those younger than 50 years and older than 70 years and a stepwise increase in nonaorta-related mortality with each increasing decade (P < .001). All-cause mortality at 1 year, 3 years, and 10 years was 15%, 24%, and 57%, respectively. After accounting for competing risks, the cumulative incidence of aorta-related mortality at 1 year, 3 years, and 10 years was 8.9%, 16.5%, and 27.2%, respectively, and that of nonaorta-related mortality was 2.7%, 7.2%, and 29%, respectively. A maximum descending thoracic aortic diameter >4 cm was associated with an increase in hazard of aorta-related mortality by 84% (subdistribution hazard ratio, 1.84; 95% confidence interval, 1.03-3.28) on multivariate competing risk regression analysis. CONCLUSIONS: TBAD is associated with high 10-year mortality. Those at risk for aorta-related mortality have a clinical phenotype different from that of individuals at risk for nonaorta-related mortality. This information is important for building risk prediction models that account for competing mortality risks and to direct optimal and individualized surgical and medical management of TBAD.

Meta-analysis of redo stenting versus endarterectomy for in-stent stenosis after carotid artery stenting.

OBJECTIVE: The development of in-stent restenosis (ISR) hinders the long-term patency of carotid artery stenting (CAS), yet no optimal treatment has been established. In the present study, we compared the outcomes of redo CAS (rCAS) and carotid endarterectomy (CEA) for ISR. METHODS: A systematic search using the terms "in-stent restenosis," "carotid endarterectomy," and "carotid artery stenting" was conducted in the PubMed, Embase, and Cochrane databases. Studies reporting perioperative stroke, death, and other important complications of rCAS or CEA for ISR after previous CAS with four or more patients were included. Pooled and sensitivity analyses were conducted to synthesize and compare estimates of the outcomes. RESULTS: A total of 11 studies with 1057 patients who had undergone rCAS (n = 894) or CEA (n = 163) met the inclusion criteria. The CEA group had a significantly greater proportion of symptomatic patients (rCAS vs CEA, 30.4% vs 42.1%; P < .01). The duration from primary CAS to reintervention was relatively longer in the CEA group (rCAS vs CEA, median, 8.8 months [range, 3-26 months] vs 19.9 months [range, 0-54 months]). In the rCAS group, a greater proportion of patients had hypertension, hypercholesterolemia, and coronary artery disease and had received antiplatelet therapy before reintervention. Because of insufficient data or a low incidence, the only complications feasible for further analysis were restenosis, myocardial infarction, cranial nerve injury, and neck hematoma. No significant differences were found in the primary end point of mortality/stroke event-free rate (rCAS vs CEA, 99% vs 98%; P > .05) or other secondary end points (event-free restenosis, 100% vs 100%; event-free myocardial infarction, 100% vs 98%; event-free cranial nerve injury, 100% vs 98%; event-free neck hematoma, 100% vs 100% for rCAS vs CEA; P > .05 for all). CONCLUSIONS: rCAS is commonly used to treat patients with severe and/or symptomatic ISR after primary CAS. Although the endovascular approach is less invasive, both rCAS and CEA can be performed safely with similar short- and midterm outcomes of stroke, death, and surgery-related complications.

Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma.

BACKGROUND: This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. METHODS: Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). RESULTS: Forty-seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%-58%), which was superior to the null hypothesis rate of 30%, but the 2-sided P value (exact test) was .09 (1-sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3-35.0 months), and the median progression-free survival was 7.9 months (95% CI, 3.7-12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. CONCLUSIONS: This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Regorafenib Versus Placebo in Advanced/Metastatic, Treatment-Refractory Liposarcoma: Results from the SARC024 Study.

LESSONS LEARNED: The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. BACKGROUND: Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. METHODS: Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. RESULTS: Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. CONCLUSION: Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

Recurrent secondary genomic alterations in desmoplastic small round cell tumors.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive, translocation-associated soft-tissue sarcoma that primarily affects children, adolescents, and young adults, with a striking male predominance. It is characterized by t(11;22) generating a novel EWSR1-WT1 fusion gene. Secondary genomic alterations are rarely described. METHODS: Tumor tissue from 83 DSRCT patients was assayed by hybrid-capture based comprehensive genomic profiling, FoundationOne® Heme next generation sequencing analysis of 406 genes and RNA sequencing of 265 genes. Tumor mutation burden was calculated from a minimum of 1.4 Mb sequenced DNA. Microsatellite instability status was determined by a novel algorithm analyzing 114 specific loci. RESULTS: Comprehensive genomic profiling identified several genomically-defined DSRCT subgroups. Recurrent genomic alterations were most frequently detected in FGFR4, ARID1A, TP53, MSH3, and MLL3 genes. With the exception of FGFR4, where the genomic alterations predicted activation, most of the alterations in the remaining genes predicted gene inactivation. No DSRCT were TMB or MSI high. CONCLUSIONS: In summary, recurrent secondary somatic alterations in FGFR4, ARID1A, TP53, MSH3, and MLL3 were detected in 82% of DSRCT, which is significantly greater than previously reported. These alterations may have both prognostic and therapeutic implications.

Fenestrated endovascular aneurysm repair is financially viable at a high-volume medical center with positive hospital contribution margins and physician payment.

OBJECTIVE: To examine hospital finances and physician payment associated with fenestrated endovascular aneurysm repair (FEVAR) for complex aortic disease at a high-volume center and to compare the costs and reimbursements for FEVAR with open repair, and their trends over time. METHODS: Clinical and financial data were collected retrospectively from electronic medical and administrative records. Data for each patient included inpatient and outpatient encounters 3 months before and 12 months after the primary aneurysm operation. RESULTS: Between 2007 and 2017, 157 and 71 patients were treated with physician-modified endograft (PMEG) and Cook Zenith Fenestrated (ZFEN) repair, respectively. Twenty-one patients who were evaluated for FEVAR underwent open repair instead. The 228 FEVAR patients provided a total positive contribution margin (reimbursements minus direct costs) of $2.65 million. The index encounter (the primary aneurysm operation and hospitalization) accounted for the majority (90.6%) of the total contribution margin. The largest component (50.3%) of direct cost for FEVAR from the index encounter was implant/graft expenses. The average direct costs for FEVAR and for open repair from the index encounter were $34,688 and $35,020, respectively. The average contribution margins for FEVAR and for open repair were approximately $10,548 and $21,349, respectively, attributable to differences in reimbursement. The average direct cost for FEVAR trended down over time as cumulative experience increased. Average reimbursement for FEVAR increased after Centers for Medicare and Medicaid Services approved payments with the Investigational Device Exemption (IDE) trial for PMEG in 2011, and a new technology add-on payment for ZFEN in 2012. These factors transitioned the average contribution margin from negative to positive in 2012. The average physician payments for PMEG increased from $128 to $5848 after the start of the IDE trial. The average physician payments for ZFEN and for open repair between 2011 and 2017 were $7597 and $7781, respectively. CONCLUSIONS: FEVAR can be performed at a high-volume medical center with positive contribution margins and with comparable physician payments to open repair. At this institution, hospital reimbursement and physician payments improved for PMEG with participation in an IDE trial, while hospital direct costs decreased for both PMEG and ZFEN with accumulated experience.

Outcome Comparison of TEVAR with and without Left Subclavian Artery Revascularization from Analysis of Nationwide Inpatient Sample Database.

BACKGROUND: The purpose of this study was to compare the outcomes of thoracic endovascular aortic repair (TEVAR) without and with left subclavian artery (LSA) revascularization using the Nationwide Inpatient Sample (NIS) database. METHODS: NIS records from 2005 to 2013 were retrospectively analyzed to identify patients undergoing TEVAR without and with LSA revascularization. Perioperative outcomes were compared between the two groups. The LSA revascularization group was further subdivided to compare perioperative outcomes if the revascularization was performed pre- or post-TEVAR or if the revascularization was performed open versus endovascular. Comparisons were examined using univariable analysis and multivariable logistic regression. Multivariable models were constructed using a forward selection approach with P < 0.05 required for model entry. Odds ratios are expressed per standard deviation change for continuous covariates. Continuous variables were compared between different groups using t-test, and categorical variables were compared using the chi-squared test. All statistical analyses were performed using R (cran.r-project.org). RESULTS: 7,773 TEVAR patients were included in this study. 6,411 (82.5%) were performed without and 1,362 (17.5%) with LSA revascularization. The rate of revascularization for LSA coverage during TEVAR doubled after the Society for Vascular Surgery Guidelines recommending revascularization were published in 2009. Groups were not significantly different in age (65.5 ± 15.8 and 66.1 ± 14.4 years old, respectively), gender, or race. Multivariable analysis showed that although rates of spinal cord ischemia and upper extremity ischemia were similar, perioperative cardiac complications (OR 1.5, 95% CI [1.2, 1.9], P = 0.025), stroke (OR 2.1, 95% CI [1.6, 2.8], P = 0.001), and pulmonary complications (OR 1.9, 95% CI [1.7, 2.3], P < 0.001) were significantly higher in the patients undergoing TEVAR with LSA revascularization than those without. Of the 1,362 patients with LSA revascularization, 1,251 (91.9%) were performed pre-TEVAR and 111 (8.1%) were performed post-TEVAR. Among the 1,251 patients with pre-TEVAR LSA revascularization, 583 had open surgery and 553 had stenting. In 115 patients, LSA revascularization was coded as both open and endovascular. Compared with pre-TEVAR revascularization, post-TEVAR revascularization was associated with higher risks of pulmonary complications and spinal cord ischemia. Endovascular LSA revascularization had lower pulmonary and stroke morbidity versus open LSA revascularization. The perioperative outcomes for the LSA revascularization subgroups are summarized. CONCLUSIONS: TEVAR with LSA revascularization is associated with significantly increased rates of perioperative stroke and cardiopulmonary complications. LSA revascularization before TEVAR, compared with post-TEVAR revascularization, had lower perioperative complications. In high-risk patients, endovascular LSA revascularization may be recommended over open surgery.

Primary liver sarcomas in the modern era: Resection or transplantation?

BACKGROUND AND OBJECTIVES: Primary liver sarcomas (PLS) are rare. Published series are limited by small numbers of patients. METHODS: We reviewed the National Cancer Database (2004-2014) for patients who underwent surgical resection of PLS. RESULTS: Of 237 patients identified, the majority were female (60.8%), with median age of 52 years. Histologies were: epithelioid hemangioendothelioma (n = 67), angiosarcoma (n = 64), leiomyosarcoma (n = 33), embryonal rhabdomyosarcoma (n = 31), carcinosarcoma (n = 16), giant cell sarcoma (n = 14), spindle cell sarcoma (n = 12). Ninety-seven (40.9%) patients underwent lobectomies or extended lobectomies, 41 patients (17.3%) underwent transplantation. Surgical margins were negative in 82.9%. Tumors were well differentiated in 11.3%. Histology type correlated with outcome with the best prognosis for epithelioid hemangioendothelioma (OS: not reached, similar for resection and transplantation) and the worst for angiosarcoma (OS:16.6 mo with resection; 6 mo with transplantation; P = 0.04). Resections with microscopically negative margins were associated with improved survival (58.7 vs 11.3 mo for positive margins; P < 0.001). Chemotherapy and radiation therapy were used in a minority of patients (32.9% and 4.3% respectively) with no improvement in outcomes. CONCLUSIONS: Both hepatic resection and liver transplantation can be associated with long term survival for selected primary liver sarcomas such as epitheliod hemangioendotheliomas. Histology type and the ability to resect the tumor with negative margins correlate with outcomes and the decision to operate should be carefully weighed for subtypes with particularly dismal prognosis such as angiosarcomas.

Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor.

BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.

NCCN Guidelines Insights: Bone Cancer, Version 2.2017.

The NCCN Guidelines for Bone Cancer provide interdisciplinary recommendations for treating chordoma, chondrosarcoma, giant cell tumor of bone, Ewing sarcoma, and osteosarcoma. These NCCN Guidelines Insights summarize the NCCN Bone Cancer Panel's guideline recommendations for treating Ewing sarcoma. The data underlying these treatment recommendations are also discussed.

SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma.

BACKGROUND: Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. METHODS: Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%. RESULTS: A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients. CONCLUSIONS: Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity.

A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study.

BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas. METHODS: Eligibility criteria included age ≥ 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks × 4 and every 12 weeks thereafter. RESULTS: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a ≥ 50% decrease in tumor size that lasted for <4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%). CONCLUSIONS: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted.

Phosphaturic mesenchymal tumor with de novo liver metastases: a case report and literature review.

Phosphaturic mesenchymal tumors (PMTs) are rare tumors that can cause tumor-induced osteomalacia (TIO) through overproduction of FGF23, a peptide hormone that causes renal phosphate wasting and reduced osteoblastic activity. The diagnosis of PMTs can be difficult to make as the presenting symptoms are non-specific. Although PMT is a rare entity, most cases are benign in nature, not requiring further intervention after surgery, as resection is typically curative. Here, we present a unique case of malignant PMT with de novo liver metastasis in a female patient who presented with TIO and underwent surgical resection of her primary lesion with subsequent regression of her liver metastasis. Moreover, we analyze a review of literature and discuss the importance of a timely diagnosis of this rare phenomenon. It is encouraged that providers strongly consider a diagnosis of PMT in patients with otherwise unexplained bone pain, fatigue, weakness, especially if accompanied with hypophosphatemia. Further studies are also warranted to identify prognostic factors that predict a PMT's malignant potential as they may help identify possible therapeutic targets.

Phosphaturic mesenchymal tumor with spread to the liver: A case report and literature review Phosphaturic mesenchymal tumors (PMTs) are rare tumors that can cause bone loss through the excess production of a signal named FGF23. This hormone causes the kidneys to lose phosphate and reduces the body's ability to build new bone. PMTs are incredibly rare and difficult to diagnose especially since the presenting symptoms can be seen in several different diseases. Although PMT is rare, most cases are benign, only requiring surgery. We are presenting a unique case of a patient who presented with PMT in her right thigh and had evidence that the disease spread to her liver. Our patient underwent surgical resection of her thigh lesion and subsequently had improvement of her liver lesion. In our study, we analyze a review of literature and discuss the importance of a timely diagnosis of this rare phenomenon. It is encouraged that providers strongly consider a diagnosis of PMT in patients with otherwise unexplained bone pain, fatigue, weakness, especially if accompanied by low phosphate levels. Further studies are also warranted to identify prognostic factors that predict a PMT's malignant potential as they may help identify possible therapeutic targets.

The Correlation Between Lymphocyte Nadir and Radiation Therapy for Soft Tissue Sarcoma: Defining Key Dosimetric Parameters and Outlining Clinical Significance.

Purpose: The objectives of this study were to identify key dosimetric parameters associated with postradiation therapy lymphopenia and uncover any effect on clinical outcomes. Methods and Materials: This was a retrospective review of 69 patients (between April 2010 and January 2023) who underwent radiation therapy (RT) as a part of curative intent for soft tissue sarcoma (STS) at a single academic institution. All patients with treatment plans available to review and measurable absolute lymphocyte count (ALC) nadir within a year after completion of RT were included. Results: Median follow-up was 22 months after the start of RT. A decrease in lymphocyte count was noted as early as during treatment and persisted at least 3 months after the completion of RT. On multivariable linear regression, the strongest correlations with ALC nadir were mean body dose, body V10 Gy, mean bone dose, bone V10 Gy, and bone V20 Gy. Five-year overall survival was 60% and 5-year disease-free survival was 44%. Advanced T-stage, chemotherapy use, use of intensity-modulated RT, lower ALC nadir, and the development of grade ≥2 lymphopenia at nadir were associated with worse overall survival and disease-free survival. Conclusions: Post-RT lymphopenia was associated with worse outcomes in STS. There were associations between higher body V10 Gy and bone V10 Gy and lower post-RT ALC nadir, despite the varying sites of STS presentation, which aligns with the well-known radiosensitivity of lymphocyte cell lines. These findings support efforts to reduce treatment-related hematopoietic toxicity as a way to improve oncologic outcomes. Additionally, this study supports the idea that the effect of radiation on lymphocyte progenitors in the bone marrow is more significant than that on circulating lymphocytes in treatments with limited involvement of the heart and lung.