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OBJECTIVES: To investigate the toxicity of 4 types of resin-based dental composites with different compositions and to determine the components released from them using high-performance liquid chromatography (HPLC). METHOD AND MATERIALS: Resin composite disks (Z100, Solitaire 2, Filtek P60, and Synergy) were prepared, and cytotoxicity was tested on Balb/C 3T3 fibroblasts. In the first part of the study, cells were exposed to the composites for 72 hours (direct method), and in the second part to ethanolic extracts of the composites for 24 hours (indirect method), both at 37 degrees C. Cell viability was then determined by the MTT (3[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) method. RESULTS: The dental composites and their ethanolic extracts had adverse effects on the viability of Balb/C 3T3 fibroblasts. ANOVA revealed highly significant differences in cytotoxicity between the groups (P <.001) for both the direct and indirect methods. Follow-up comparison by Tukey test (alpha = .05) showed that Synergy was significantly less toxic than the other resin composites and Solitaire 2 was significantly more cytotoxic when the materials were tested by the direct method. However, using the indirect method, the extract of Synergy was significantly more toxic than all the other extracts. Bis-GMA, TEGDMA, UDMA, bis-EMA, and bisphenol A were detected by HPLC analysis; however, their presence and concentrations varied from one composite to another. CONCLUSIONS: The cytotoxicity level of resin-based dental composites depends on their chemical composition, leaching medium, and the amount and type of the components that can be extracted from the materials. [ABSTRACT FROM AUTHOR]

Background: In this open-label, randomized, non-comparative, multicenter phase II study (Alliance A091401) we report on three expansion cohorts treated with nivolumab (N) with and without ipilimumab (N+I) and provide a multi-omic correlative analysis of actionable biomarkers., Methods: Patients were randomized (non-comparative) to receive either N or N+I. The primary endpoint was a 6-month confirmed response rate (CRR) defined by Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included treatment-related adverse events (TRAEs), progression-free survival, and overall survival. Multi-omic correlative analyses were conducted using samples from both the primary and expansion cohorts., Results: A total of 66 patients were evaluated for the primary endpoint with disease including gastrointestinal stromal tumor (GIST, n=18), undifferentiated pleomorphic sarcoma (UPS, n=24), and dedifferentiated liposarcoma (DDLPS, n=24). Neither N nor N+I achieved a complete or partial response in the GIST expansion cohort. In DDLPS and UPS, the primary response endpoint of CRR was met with N+I (both 16.6%, 2/12) but not with N alone (both 8.3%, 1/12). In the GIST cohort, TRAE was higher with N+I treatment, halting enrollment as required per protocol. In a correlative analysis of patients for the expansion cohort and the original cohort (n=86), traditional biomarkers of immunotherapy response were not correlated with response in any histological subtype. Markers of genomic instability including the presence of gene fusions and increased subclonal mutations correlated with improved clinical outcomes., Conclusions: This expansion cohort reaffirms the outcomes of A091401. There remains a pressing need to determine the role of and predictive biomarkers for immunotherapy in sarcoma., Trial Registration Number: NCT02500797., Competing Interests: Competing interests: JLC: Foundation Medicine (personal fees), Tempus (employment); BVT: Daiichi Sankyo Inc (personal fees), Deciphera Pharmaceuticals (personal fees), Advenchen (personal fees), Putnam (personal fees), Boxer Capital LLC (personal fees), Acuta Capital Partners, LLC (personal fees), Aadi (personal fees), Race Oncology (personal fees), Hinge Bio, Inc (personal fees), Kronos Bio, Inc, (personal fees) Sonata Therapeutics, Inc. (personal fees), Total Health Conference (personal fees), Adaptimmune (other support), Boehringer Ingelheim (consulting/licensing), Accuronix Therapeutics (patent), Polaris (non-paid member of Scientific/Safety Board); DAL: AADI Bioscience (consulting), MatchTx, LLC (patents); all other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Leiomyosarcoma (LMS) is a malignancy with smooth muscle differentiation. Metastatic LMS is associated with poor prognosis and limited efficacy of systemic treatment. Novel treatment modalities are desperately needed for this entity., Case Presentation: We report the first use of pembrolizumab plus pharmacologic ascorbate in 3 patients with metastatic LMS. All cases resulted in persistent objective responses and disease control significantly better than has been reported with chemotherapy or other immunotherapeutic approaches. Three patients with metastatic LMS, one each of uterine, vascular, and soft tissue origin, were treated with pembrolizumab plus pharmacologic ascorbate. The patient with uterine LMS received combination therapy at presentation and had persistent response for 12 months, which is ongoing. The patient with metastatic LMS of the inferior vena cava received combination therapy at presentation and had persistent response for 12 months, at which time new metastases were found. The patient with soft tissue LMS had disease progression on pembrolizumab monotherapy prior to the addition of ascorbate, after which she had a 17-month response, which is ongoing. No side effects attributed to treatment were reported., Conclusion: Pembrolizumab plus pharmacologic ascorbate is a novel immunotherapeutic approach and warrants further study in LMS., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Extremity soft-tissue sarcomas (STS) are commonly treated with neoadjuvant radiation therapy followed by surgical resection. However, the pathological near-complete response rate is low (9-25%). Noninvasive imaging assessment that predicts treatment response before and during treatment is desirable to optimize treatment regimens. This pilot study aimed to investigate the application of a quantitative MRI parameter, T 2 *, in assessing neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS., Methods: This prospective cohort study included seven patients diagnosed with extremity STS and scheduled to receive neoadjuvant radiation therapy combined with pharmacological ascorbate. T 2 * maps were obtained from each patient before treatment (baseline MRI), two weeks after initiating treatment (on-treatment MRI), and before surgery (pre-surgery MRI). The T 2 * values within the tumor region were transformed into z-scores with respect to the normal- appearing tissue region. The voxel-wise z-scores within the tumor region were thresholded to generate masks representing significantly high (z-score>1.96) and low z-score (z-score<-1.96) voxels. The means of the total z-scores and within each of the significantly high and low z-score mask were computed. Their correlations with percent necrosis from pathological examination were evaluated using Spearman's rank correlation coefficient r. A correlation was considered as moderate or strong when r is higher than 0.6 and 0.8, respectively. A correlation was considered as fair or weak when r is below 0.6., Results: For the baseline and on-treatment MRIs, the means of the significantly high z-scores of the T 2 * measurements showed moderate correlations with percent necrosis (r = 0.68 and 0.6; p = 0.11 and 0.24). For the pre-surgery MRI, the means of the total and significantly high z-scores showed strong correlations with percent necrosis (r = 0.8 and 0.9; p = 0.13 and 0.08). Tumor volume and baseline MRI-based percent necrosis showed fair or weak correlations (r = 0.3-0.54; p = 0.24-0.68)., Conclusion: T 2 * measurements prior to treatment, two weeks after initiating treatment, and before surgery showed moderate to strong correlations with percent necrosis. These results support the potential for using T 2 * mapping to predict and assess response to neoadjuvant radiation therapy combined with pharmacological ascorbate in extremity STS. Level of Evidence: IV ., Competing Interests: Disclosures: The authors report no potential conflicts of interest related to this study., (Copyright © The Iowa Orthopaedic Journal 2023.)

Purpose: (1) To describe the technique of postoperative echography to confirm the intended treatment dose to the tumor apex in patients with uveal melanoma treated with plaque brachytherapy. (2) To describe the local tumor control rate and visual outcomes with the brachytherapy strategies used at our institution., Design: Retrospective review., Subjects: Three hundred seventy-two consecutive patients with uveal melanoma (small, medium, and large) treated with plaque brachytherapy at the University of Iowa from August 2008 to February 2019., Methods: Patient demographics and tumor characteristics were recorded for each patient. Patients with posterior tumors treated with plaque brachytherapy (n = 355) underwent intraoperative ultrasound to confirm plaque placement, and additional postoperative ultrasound on day 1 to 3 postplaque insertion. In cases where intratumor/episcleral plaque edema or hemorrhage shifted the dose to the prescription point to < 85 Gray (Gy), the duration of plaque brachytherapy was increased to compensate. Statistical analysis was performed to compare variables associated with the need for plaque adjustment., Main Outcomes Measures: Variables associated with plaque dose needing to be recalculated, local tumor control, and visual acuity outcomes., Results: In 31 (8.3%) cases, postoperative echography showed that the tumor apex had shifted outside the 85 Gy isodose curve, requiring adjustment of the duration of brachytherapy (28 cases) or repositioning of the plaque (3 cases). Collaborative Ocular Melanoma Study tumor size was significantly associated with need to adjust the plaque prescription dose (P = 0.03), with large tumors having the highest rate of adjustment. Tumor thickness was larger in cases requiring plaque adjustment compared with those that were not adjusted (median 4.9 mm vs. 3.0 mm, P < 0.01). Local tumor control was 99% (95% confidence interval, 97%-100%) at 5 years and 99% (95% confidence interval, 97%-100%) at 10 years. The percentage of patients who had experienced a visual acuity decline of ≥ 3 lines of vision or had < 20/200 acuity was 14.9% at 1 year after brachytherapy, 35.3% at 3 years, and 51.6% at 5 years., Conclusions: Postoperative ultrasound performed on postoperative day 1 to 3 after plaque insertion for patients undergoing brachytherapy for uveal melanoma may result in improved local tumor control, particularly in the setting of thicker or larger tumors., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking., Patients and Methods: We performed a single-arm, multicenter clinical trial using "flip dose" ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network., Results: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%-66%] and 37% (95% CI, 19%-55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%-95%) and 68% (95% CI, 46%-83%), respectively. Median RFS was 10.3 months (95% CI, 5.7-25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities., Conclusions: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing., (©2023 American Association for Cancer Research.)

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10 6 plaque-forming units (PFU)/mL in week 1, followed by 10 8 PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported.At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297., Competing Interests: Competing interests: JAC: research funding: Amgen, Replimune, Iovance Biotherapeutics, Bristol Myers Squibb; patents, royalties, other intellectual property: University of Louisville US Patents. IP: stock and other ownership interests: Celldex; consulting or advisory role: Amgen, Iovance Biotherapeutics, Merck, Roche, Nouscom, Seneca Therapeutics, Nektar, Oncorus. FAC: research funding: Amgen and Replimune. PS: consulting fees: Aveo, EMD Serono, Janssen, Bayer; payment or honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events: CURIO Sciences; participation on a Data Safety Monitoring Board or Advisory Board: Aveo, EMD Serono, Janssen, Bayer. MMM: consulting: Syneos, Exicure, Novartis, Immunocore, Biontech, Blueprints Medicine, Amgen, Array, Trieza. JG: funding for this trial: Amgen. OH: consultant advisor: Aduro, Akeso, Amgen, BeiGene, BioAtla, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, NextCure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Tempus, Zelluna; speaker bureau: BMS, Novartis, Pfizer, Sanofi/Regeneron; contracted research (for institution): Arcus, Aduro, Akeso, Amgen, BioAtla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck-Serono, NextCure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Torque, Zelluna. MR: honoraria: Merck and Amgen; advisory board: Merck and Amgen; research funding: Amgen and Provectus; travel funding: Merck, Amgen, Provectus, Novartis and Castle Biosciences. PF: consultant: DBV Technologies; travel to and participation on the advisory board: Castle Biosciences; stock or stock options: Gilead, Iovance. CG: personal fees: Amgen, MSD, Philogen; grants and personal fees: Novartis, NeraCare, BMS, Roche, Sanofi, outside of the submitted work. TL: funding for this trial: Amgen; grants or contracts: Abbott, Abraxis, Acceleron, Amgen, Argos, AstraZeneca, Aveo, Biovex, Bristol Myers Squibb, Eisai, Lilly, GlaxoSmithKline, Immatics, Roche, Merck, Novartis, Pfizer, Synta, Thershold, Millenium, Tracon, Cerulean, EMD Serono, Prometheus, Macrogenics, Peloton, Iovance, MedImmune, Dynavax, NiKang; consulting fees: Prometheus; payment or honoraria for lectures, presentations, speakers bureau, manuscript writing, or educational events: SITC Advances in Cancer Immunotherapy program, organizer and presented for local program in Indianapolis. Two separate programs. AH: grants and personal fees: Amgen, BMS, Eisai, Immunocore, Pfizer, MSD/Merck, Novartis Pharma, Philogen, Pierre Fabre, Regeneron, Replimune, Immunocore, Roche, Sanofi-Genzyme, Seagen, outside the submitted work. CL: Honoraria: Roche, Bristol Myers Squibb, Novartis, Amgen, MSD, Pierre Fabre, Pfizer, Incyte; consulting or advisory role: Bristol Myers Squibb, MSD, Novartis, Amgen, Roche, Merck Serono, Sanofi, Pierre Fabre; speakers bureau: Roche, Bristol Myers Squibb, Novartis, Amgen, MSD; research funding: Roche (Inst), Bristol Myers Squibb (Inst); travel, accommodations, expenses: Bristol Myers Squibb, MSD, Novartis, Sanofi, Pierre Fabre; other relationship: Avantis Medical Systems, InflaRx. HJ: employee: Parexel. WS: employee and stockholder: Amgen. JMM: stock and other ownership interests: Pfizer; honoraria: EMD Serono, Pfizer/EMD Serono; consulting or advisory role: Merck Sharp and Dohme, Celldey, Sanofi/Regeneron, Bristol Myers Squibb, Seattle Genetics, Eisai, Novartis; research funding: Amgen, AstraZeneca, Incyte, Kinnate, Macrogenics, Bristol Myers Squibb, Merck, Novartis, Regeneron; travel, accommodations, expenses: EMD Serono, Merck Sharp and Dohme, Array BioPharma, Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The treatment of sarcoma necessitates a collaborative approach, given its rarity and complex management. At a single institution, multidisciplinary teams of specialists determine and execute treatment plans involving surgical, radiation, and medical management. Treatment guidelines for systemic therapies in advanced or nonresectable soft tissue sarcoma have advanced in recent years as new immunotherapies and targeted therapies become available. Collaboration between institutions is necessary to facilitate accrual to clinical trials. Here, we describe the success of the Midwest Sarcoma Trials Partnership (MWSTP) in creating a network encompassing large academic centers and local community sites. We propose a new model utilizing online platforms to expand the reach of clinical expertise for the treatment of advanced soft tissue sarcoma.

Background: Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant and selective inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aim of the study was to determine the safety and clinical activity of olutasidenib in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation., Methods: This was an open-label, multicenter, nonrandomized, phase Ib/II clinical trial. Eligible patients (≥18 years) had histologically confirmed IDH1R132X-mutated glioma that relapsed or progressed on or following standard therapy and had measurable disease. Patients received olutasidenib, 150 mg orally twice daily (BID) in continuous 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs) (cycle 1) and safety in phase I and objective response rate using the Modified Response Assessment in Neuro-Oncology criteria in phase II., Results: Twenty-six patients were enrolled and followed for a median 15.1 months (7.3‒19.4). No DLTs were observed in the single-agent glioma cohort and the pharmacokinetic relationship supported olutasidenib 150 mg BID as the recommended phase II dose. In the response-evaluable population, disease control rate (objective response plus stable disease) was 48%. Two (8%) patients demonstrated a best response of partial response and eight (32%) had stable disease for at least 4 months. Grade 3‒4 adverse events (≥10%) included alanine aminotransferase increased and aspartate aminotransferase increased (three [12%], each)., Conclusions: Olutasidenib 150 mg BID was well tolerated in patients with relapsed/refractory gliomas harboring an IDH1R132X mutation and demonstrated preliminary evidence of clinical activity in this heavily pretreated population., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Recurrence after resection of metastatic sarcoma is common. The gangliosides GM2, GD2 and GD3 are strongly expressed across sarcoma subtypes. We hypothesised that generation of anti-ganglioside antibodies would control micrometastases and improve outcomes in sarcoma patients who were disease-free after metastasectomy., Methods: We conducted a randomised phase II trial of the immunological adjuvant OPT-821 with a KLH-conjugated ganglioside vaccine targeting GM2, GD2 and GD3, versus OPT-821 alone in patients with metastatic sarcoma following complete metastasectomy. Patients received 10 subcutaneous injections at Weeks 1, 2, 3, 8, 16, 28, 40, 52, 68 and 84 and were followed for evidence of recurrent disease. The primary end-point was relapse-free survival. Secondary end-points included overall survival and serologic response., Results: A total of 136 patients were randomised, 68 to each arm. The mean age was 51.2, 52.2% were male, 90.4% had relapsed disease, 86.8% had high-grade tumours and 14% had ≥4 metastases resected. Histologies included leiomyosarcoma (33%), spindle cell sarcoma (14%), undifferentiated pleomorphic sarcoma (13%), osteosarcoma (10%), synovial sarcoma (9%), liposarcoma (9%) and others (12%). Most adverse events were Grade ≤2 (83.8% and 70.6% in the vaccine and adjuvant arms, respectively). The most common (≥20% of patients) were injection site reaction (89.7%), fatigue (44.1%) and pyrexia (27.9%) on the vaccine arm, and injection site reaction (69.1%) on the adjuvant only arm. The 1-year relapse-free survival rate (34.5% and 34.8% in the vaccine and OPT-821 monotherapy arm, respectively) did not differ between arms (P = 0.725). One-year overall survival rates were 93.1% and 91.5% in the vaccine and OPT-821 monotherapy arm, respectively (P = 0.578). Serologic responses at week 9 were more frequent on the vaccine arm (96.5% of patients) than in the adjuvant arm (32.8%), and the difference between groups was durable., Conclusions: A sustained serologic response to vaccination was induced with the vaccine, but no difference in recurrence-free or overall survival was observed between treatment arms., Clinicaltrials: gov identifier: NCT01141491., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy., Methods: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations., Results: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1 / -2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies., Conclusions: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.

Background: Cancer cells often have altered iron metabolism relative to non-malignant cells with increased transferrin receptor and ferritin expression. Targeting iron regulatory proteins as part of a cancer therapy regimen is currently being investigated in various malignancies. Anti-cancer therapies that exploit the differences in iron metabolism between malignant and non-malignant cells (e.g. pharmacological ascorbate and iron chelation therapy) have shown promise in various cancers, including glioblastoma, lung, and pancreas cancers. Non-invasive techniques that probe tissue iron metabolism may provide valuable information for the personalization of iron-based cancer therapies. T 2 * mapping is a clinically available MRI technique that assesses tissue iron content in the heart and liver. We aimed to investigate the capacity of T 2 * mapping to detect iron stores in soft tissue sarcomas (STS)., Methods: In this study, we evaluated T 2 * relaxation times ex vivo in five STS samples from subjects enrolled on a phase Ib/IIa clinical trial combining pharmacological ascorbate with neoadjuvant radiation therapy. Iron protein expression levels (ferritin, transferrin receptor, iron response protein 2) were evaluated by Western blot analysis. Bioinformatic data relating clinical outcomes in STS patients and iron protein expression levels were evaluated using the KMplotter database., Results: There was a high level of inter-subject variability in the expression of iron protein and T 2 * relaxation times. We identified that T 2 * relaxation time is capable of accurately detecting ferritin-heavy chain expression (r = -0.96) in these samples. Bioinformatic data acquired from the KMplot database revealed that transferrin receptor and iron-responsive protein 2 may be negative prognostic markers while ferritin expression may be a positive prognostic marker in the management of STS., Conclusion: These data suggest that targeting iron regulatory proteins may provide a therapeutic approach to enhance STS management. Additionally, T 2 * mapping has the potential to be used a clinically accessible, non-invasive marker of STS iron regulatory protein expression and influence cancer therapy decisions that warrants further investigation. Level of Evidence: IV ., (Copyright © The Iowa Orthopaedic Journal 2022.)

While urothelial carcinoma is the most common histologic type of bladder cancer in the United States, leiomyosarcoma is a rare and aggressive variant. The rarity of bladder leiomyosarcoma results in uncertainty regarding the optimal treatment pathway. We report on a patient with a giant non-metastatic bladder leiomyosarcoma effectively managed with primary surgical intervention without chemoradiation., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (© 2022 The Authors. Published by Elsevier Inc.)

We describe the case of a 69-year-old woman who presented with a decline in vision in the left eye and was found to have a choroidal lesion with clinical and echographic features concerning for primary uveal melanoma. Systemic imaging identified numerous metastases to the liver, kidneys, paratracheal lymph nodes, lung, and brain. The hepatic lesion was biopsied, and genetic analysis identified a Val600Glu (c.1799T>A) BRAF mutation, consistent with a cutaneous primary malignancy, although no primary tumor was identified. This case highlights that metastasis to the choroid is a rare presentation of nonuveal melanoma that can mimic primary uveal melanoma. Genetic analysis of tumor tissue can identify the origin of the melanoma and guide treatment options. Systemic imaging should be performed prior to intervention for choroidal neoplasms., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by The Author(s). Published by S. Karger AG, Basel.)

Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10., Significance: In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response. See related commentary by Sullivan, p. 2960. This article is highlighted in the In This Issue feature, p. 2945., (©2021 The Authors; Published by the American Association for Cancer Research.)

Immunotherapies have an established role in the management of several advanced malignancies. Their responses are largely dependent on the presence of PD-L1, microsatellite instability (MSI), and high tumor mutation burden. Sarcomas are heterogenous tumors which comprise over 100 subtypes. They are broadly considered immunologically inert or "cold". Immunotherapy as monotherapy has shown interesting responses in a certain handful of subtypes, such as undifferentiated pleomorphic sarcoma, dedifferentiated and pleomorphic liposarcoma, and alveolar soft part sarcoma. However, the mechanisms of action of immunotherapy agents in several sarcoma subtypes remains unknown. Several sarcoma types such as leiomyosarcoma have been shown to have an immunosuppressive microenvironment. Early clinical studies suggest the emergence of B cell infiltration in sarcoma tumor tissues as well as the role of PD-1 and PD-L1 as biomarkers of response. Immunotherapy combinations with conventional chemotherapies, radiation therapies, tyrosine kinase inhibitors and oncolytic viruses are showing promise in turning these "cold" tumors "hot". Several novel agents as well as repurposing therapies with the potential to enhance immunotherapy responses are undergoing pre-clinical and clinical studies in other tumor types. Herein we review current clinical studies which have explored the use of immunotherapeutic agents in the management of sarcomas and discuss the challenges and future directions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-6041). The series “Cancer Immunotherapy: Recent Advances and Challenges” was commissioned by the editorial office without any funding or sponsorship. MMM reports research funding from Amgen, Novartis, Merck, Pfizer, ER Squibb & Sons, and Prometheus, honoraria from Blueprint Medicine, Immunocore, Amgen, and Trieza, and serves in a consulting or advisory role for Blueprint Medicine, Amgen, Immunocore, and Trieza. VM serves in a consulting or advisory role for Forma therapeutics and reports research funding and travel expenses from Deciphera and GSK and research funding from Amgen. The authors have no other conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2-4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45-0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32-0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.

Background: Therapeutic options for patients with advanced soft-tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS., Methods: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline-based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m 2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m 2 on days 1 and 8 and docetaxel at a dose of 100 mg/m 2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression-free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent-to-treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events)., Results: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P = .3, log-rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively)., Conclusions: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS., (© 2020 American Cancer Society.)

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins-but also increases wound healing complications when compared to adjuvant radiotherapy. This review elaborates on the current neoadjuvant/adjuvant RT approaches, wound healing complications in STS, and the potential application of novel radioprotective agents to minimize radiation-induced normal tissue toxicity.

Patients diagnosed with metastatic sarcoma have limited options for achieving both local and distant tumor control. While SBRT can achieve local control, distant response rates remain low. There is limited evidence demonstrating the safety and efficacy for combining SBRT with concurrent PD-1 checkpoint blockade in metastatic sarcoma. In this prospective case-series, we examined five patients with metastatic sarcoma on pembrolizumab treated concurrently with SBRT from July 1, 2016-October 30, 2018. Acute and chronic toxicity were recorded using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). SBRT-treated tumor control was assessed using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). With median follow-up of 14.9 months, three patients with undifferentiated pleomorphic sarcoma, one with intimal, and one with chondroblastic osteosarcoma received SBRT with concurrent pembrolizumab to 10 sites of metastatic disease. No grade 5 toxicities were observed. There was a single incidence of transient grade 4 lymphopenia which resolved without intervention. Grade 3 toxicities included anemia, thrombocytopenia, lymphopenia and colitis. One tumor demonstrated local progression after SBRT, and all others remained stable or with response. In conclusion, combining SBRT with PD-1 inhibition appeared to be safe in this patient population. Expected high rates of treated-tumor local control after SBRT were observed. Two of five patients demonstrated either enhanced local tumor regression, or possible abscopal effect., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Currently, several targeted therapy regimens are approved as first-line treatment in V600E/K-mutant advanced and metastatic melanoma. Patients with the third most common pathologic variant in the BRAF gene, V600R, were not included in BRAF/MEK inhibitors clinical trials, so there is lack of information about the clinical characteristics and predictive value of this mutation in systemic therapy of unresectable disease. We retrospectively reviewed clinical BRAF mutation testing results and the records of melanoma patients at the University of Iowa Hospitals and Clinics from 2011 to 2017. DNA from formalin-fixed, paraffin-embedded tumor specimens were sequenced using a next-generation sequencing panel or dye terminator sequencing covering exon 15 of the BRAF gene. The study protocol was approved by the University of Iowa Institutional Review Board. Nine patients (5.3% of 168 cases with BRAF mutation) were found to have the V600R mutation. We report our experience in treatment of seven patients with V600R-mutant melanoma, whose clinical records were available for review. Four patients in our cohort received BRAF inhibitors. Three patients demonstrated partial objective response to BRAF/MEK targeted therapy. V600R-mutant melanoma accounts for a significant number of cases even in single-institution practices. We believe that testing for BRAF-mutation status should include rare variants of this mutation. From our experience, the high rate of ulceration, male predominance and advanced age at diagnosis are features of melanoma with V600R mutation, which are similar to those reported for V600K mutation. We observed objective response to BRAF/MEK inhibitors in three cases with V600R variant.

Talimogene laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB-IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors.Trial Registration NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).

Purpose: There are no known effective medical treatments for refractory MPNST. Inactivation of the NF1 tumor suppressor in MPNST results in upregulation of mTOR (mammalian target of rapamycin) signaling and angiogenesis, which contributes to disease progression. We conducted a phase II study for patients (pts) with refractory MPNST combining everolimus (10 mg PO once daily) with bevacizumab (10 mg/kg IV every 2 weeks) to determine the clinical benefit rate (CBR) (complete response, partial response (PR), or stable disease (SD) ≥ 4 months)., Patients and Methods: Patients ≥18 years old with chemotherapy refractory sporadic or NF1 MPNST were eligible. Tumor response was assessed after every 2 cycles (the WHO criteria). A two-stage design targeting a 25% CBR was used: if ≥ 1/15 pts in stage 1 responded, enrollment would be expanded by 10 pts, and if ≥ 4/25 patients had clinical benefit, the combination would be considered active., Results: Twenty-five pts, 17 with NF1 and 8 with sporadic MPNST, enrolled. One of 15 pts in stage 1 had clinical benefit. Of 10 additional pts enrolled, 2 had clinical benefit. The median number of completed cycles was 3 (range 1-16). Adverse events were similar to those known for this combination., Conclusion: With a CBR of 12% (3/25), the combination of everolimus and bevacizumab did not reach the study's target response rate and is not considered active in refractory MPNST., Competing Interests: D. Reinke reports grant from the Department of Defense and other support from Novartis and Genentech. G. M. Cote reports personal fees from Agios Pharmaceuticals and other from Otsuka, Amgen, Epizyme, Eisai, MacroGenics, Boston Biomedical, PharmaMar, Plexxikon, Merck KGaA, EMD Serono, CBA Inc, and Bavarian-Nordic outside the submitted work. R. Chugh reports grants from AADi, Novartis, Lilly, Medivation, Plexxikon, Pfizer, Advenchen, Morphotek, and MabVax; grants and personal fees from Epizyme and Janssen; and personal fees from Immune Design outside the submitted work. K. Cichowski is an advisor to Genentech. No potential conflicts of interest were disclosed by the other authors.

Background: 13-Deoxy, 5-iminodoxorubicin (GPX-150) is a doxorubicin (DOX) analog synthesized to reduce the formation of reactive oxygen species and the cardiotoxic metabolite, doxorubiciniol, the two pathways that are linked to the irreversible, cumulative dose-dependent cardiotoxicity of DOX. In a preclinical chronic models and a phase I clinical study of GPX-150, no irreversible, cumulative dose-dependent cardiotoxicity was demonstrated. Recent studies suggest that DOX cardiotoxicity may be mediated, at least in part, by the poisoning of topoisomerase IIβ., Patients and Methods: An open-label, single-arm phase II clinical study in metastatic and unresectable soft tissue sarcoma (STS) patients was initiated to further evaluate the efficacy and safety of GPX-150, including cardiac function, specifically left ventricular ejection fraction (LVEF)., Results: GPX-150 was administered at 265 mg/m 2 every 3 weeks for up to 16 doses with prophylactic G-CSF until progression, death, or patient withdrawal from the study. GPX-150 exhibited efficacy assessed as progression-free survival (PFS) rates of 38% and 12% at 6 and 12 months and an overall survival rate of 74% and 45% at 6 and 12 months. GPX-150-treated patients did not develop any evidence of irreversible, cumulative dose-dependent chronic cardiotoxicity. Toxicities included grade 3 anemia, neutropenia, and one grade 4 leukopenia. Correlative analysis demonstrated that GPX-150 was more selective than DOX for the inhibition of topoisomerase IIα over IIβ in vitro., Conclusion: These results suggest future studies are warranted to further evaluate the clinical efficacy of GPX-150 in STS, perhaps at doses higher than 265 mg/m 2 ., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care., Methods: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated., Results: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%)., Conclusions: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10 6 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10 8 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Background and Objectives: The purpose of this investigation was to determine the effect of hospital volume on treatment decisions, treatment results, and overall patient survival in extremity soft tissue sarcoma., Methods: The National Cancer Database was used to identify patients ≥18 years of age with non-metastatic soft tissue sarcoma of the extremity treated with surgery. Patients in high- and low-volume centers were matched by propensity score and placed into two equal comparative groups of 2437 patients each., Results: Chemotherapy was used at a higher rate in high-volume centers (22% vs 17%, P < 0.001) and external beam radiation usage was similar (55% vs 52%, P = 0.108). There was a lower incidence of positive margins in high-volume centers (12% vs 17%, P < 0.001). There was no significant difference in the rates of limb salvage surgery or readmissions at high-volume hospitals compared to low-volume. In a multivariate Cox proportional hazards model, low-volume facilities demonstrated diminished overall survival at all time points (hazard ratio at 5 years = 1.24, 95%CI 1.10-1.39)., Conclusions: Treatment at high-volume hospitals was associated with fewer positive margins and increased overall survival at 2, 5, and 10 years. Continued efforts should focus on optimizing the balance between patient access to specialty care and experience of the treating center., (© 2018 Wiley Periodicals, Inc.)

Adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome is rarely caused by a pheochromocytoma. We present a case of a 46-year-old woman who developed severe hypertension, hypokalemia, and typical Cushingoid features. Investigations revealed extremely high metanephrine, cortisol, and ACTH levels. Imaging showed a 3.8-cm left adrenal mass. Preoperative control of hypertension and hypokalemia was very challenging. The patient was cured after surgical removal of the adrenal mass. We followed this by a review of the literature using the databases Google Scholar and PubMed. A total of 58 cases have been reported to date. In summary, ACTH-producing pheochromocytoma is a rare condition that poses a clinical challenge in the perioperative period. It is important that physicians be aware of such a condition because early recognition and treatment are crucial to decrease morbidity and mortality.

It has been highlighted that in the original manuscript [1] Table S3 'An example of the predictive computational modeling process. Specific details on an annexure section of the PD-L1 pathway show the step-by-step reactions, mechanisms, and reaction equations that occur. Such reactions also occurred in all of the other pathways' was omitted and did not appear in the Additional files and that the Additional files were miss-numbered thereafter. This Correction shows the correct and incorrect Additional files. The original article has been updated.

Background: Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma., Methods: We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0-1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797., Findings: Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1-16] of 38 patients) in the nivolumab group and six (16% [7-30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths., Interpretation: Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted., Funding: Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Programmed Death Ligand 1 (PD-L1) is a co-stimulatory and immune checkpoint protein. PD-L1 expression in non-small cell lung cancers (NSCLC) is a hallmark of adaptive resistance and its expression is often used to predict the outcome of Programmed Death 1 (PD-1) and PD-L1 immunotherapy treatments. However, clinical benefits do not occur in all patients and new approaches are needed to assist in selecting patients for PD-1 or PD-L1 immunotherapies. Here, we hypothesized that patient tumor cell genomics influenced cell signaling and expression of PD-L1, chemokines, and immunosuppressive molecules and these profiles could be used to predict patient clinical responses., Methods: We used a recent dataset from NSCLC patients treated with pembrolizumab. Deleterious gene mutational profiles in patient exomes were identified and annotated into a cancer network to create NSCLC patient-specific predictive computational simulation models. Validation checks were performed on the cancer network, simulation model predictions, and PD-1 match rates between patient-specific predicted and clinical responses., Results: Expression profiles of these 24 chemokines and immunosuppressive molecules were used to identify patients who would or would not respond to PD-1 immunotherapy. PD-L1 expression alone was not sufficient to predict which patients would or would not respond to PD-1 immunotherapy. Adding chemokine and immunosuppressive molecule expression profiles allowed patient models to achieve a greater than 85.0% predictive correlation among predicted and reported patient clinical responses., Conclusions: Our results suggested that chemokine and immunosuppressive molecule expression profiles can be used to accurately predict clinical responses thus differentiating among patients who would and would not benefit from PD-1 or PD-L1 immunotherapies.

Background: This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma., Methods: Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12)., Results: Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy., Conclusions: The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Objectives: Extra-thoracic tumors send out pilot cells that attach to the pulmonary endothelium. We hypothesized that this could alter regional lung mechanics (tissue stiffening or accumulation of fluid and inflammatory cells) through interactions with host cells. We explored this with serial inspiratory computed tomography (CT) and image matching to assess regional changes in lung expansion., Materials and Methods: We retrospectively assessed 44 pairs of two serial CT scans on 21 sarcoma patients: 12 without lung metastases and 9 with lung metastases. For each subject, two or more serial inspiratory clinically-derived CT scans were retrospectively collected. Two research-derived control groups were included: 7 normal nonsmokers and 12 asymptomatic smokers with two inspiratory scans taken the same day or one year apart respectively. We performed image registration for local-to-local matching scans to baseline, and derived local expansion and density changes at an acinar scale. Welch two sample t test was used for comparison between groups. Statistical significance was determined with a p value < 0.05., Results: Lung regions of metastatic sarcoma patients (but not the normal control group) demonstrated an increased proportion of normalized lung expansion between the first and second CT. These hyper-expanded regions were associated with, but not limited to, visible metastatic lung lesions. Compared with the normal control group, the percent of increased normalized hyper-expanded lung in sarcoma subjects was significantly increased (p < 0.05). There was also evidence of increased lung "tissue" volume (non-air components) in the hyper-expanded regions of the cancer subjects relative to non-hyper-expanded regions. "Tissue" volume increase was present in the hyper-expanded regions of metastatic and non-metastatic sarcoma subjects. This putatively could represent regional inflammation related to the presence of tumor pilot cell-host related interactions., Conclusions: This new quantitative CT (QCT) method for linking serial acquired inspiratory CT images may provide a diagnostic and prognostic means to objectively characterize regional responses in the lung following oncological treatment and monitoring for lung metastases.

Sarcomas are a rare but fatal tumor type that accounts for <1% of adult solid malignancies and ~15% of childhood malignancies. Although the use of immunotherapy is being actively investigated for other solid tumors, advances in immunotherapy for sarcoma patients are lacking. To better understand the systemic immune environment in sarcoma patients, we performed a detailed multiplex analysis of serum cytokines, chemokines, and protumorigenic factors from treatment-naive subjects with localized, high-grade sarcoma. Because obesity is a major healthcare issue in the United States, we additionally examined the effects of obesity on serum protein profiles in our sarcoma subject cohort. We found that the systemic host environment is profoundly altered to favor tumor progression, with epidermal growth factor, angiopoietin-2, vascular endothelial growth factor A, IL-6, IL-8, and MIP-1β all increased relative to tumor-free controls (all p < 0.05). Surprisingly, we found that obesity did not exacerbate this protumorigenic profile, as epidermal growth factor and IL-8 decreased with increasing subject body mass index (both p < 0.05 versus normal or overweight subjects). The Th2-related cytokines IL-4, IL-5, and IL-13 were also decreased in the presence of obesity. Thus, although the systemic environment in sarcoma subjects favors tumor progression, obesity does not further aggravate the production of protumorigenic factors., Competing Interests: DISCLOSURES The authors have no financial conflicts of interest.

Purpose: Clinical trials commonly use physician-adjudicated adverse event (AE) assessment via the common terminology criteria for adverse events (CTCAE) for decision-making. Patient-reported health-related quality of life (HRQoL) data are becoming more frequent in oncology; however, the relationship between physician-adjudicated AE assessment and HRQoL is understudied., Methods: Data from a phase II trial (clinicaltrials.gov identifier: NCT01143402) where patients with metastatic uveal melanoma were randomized to receive selumetinib, an oral MEK inhibitor, or chemotherapy were analyzed. Patients reported HRQoL at baseline, after 1 month, and end of treatment (n = 118), whereas physicians adjudicated AEs via CTCAE. Mean HRQoL scores were compared between patient randomization arms, as well as between those patients who did/did not receive dose modifications., Results: Ninety-four percent had a CTCAE grade ≥1 for at least one treatment-associated AE, with 18% undergoing dose modification due to toxicity. Mean HRQoL scores did not significantly differ at each of the three time points. Patient and physician-adjudicated reports of nausea were significantly correlated at the start (r = 0.31, p < 0.01) and end of treatment (r = 0.42, p < 0.05). There were no significant correlations between need for dose modification and HRQoL scores., Conclusions: Despite the high rate of physician-adjudicated AEs and need for dose modifications with selumetinib, patient-reported HRQoL was not impacted by treatment. Since HRQoL did not differ in the subgroup of patients who received dosage reductions due to AEs, patients may be willing to tolerate select AEs without dose modification (if medically appropriate). More research is needed to determine how to best integrate HRQoL data into clinical trial conduct., Competing Interests: The Authors declare that there is no conflict of interest.

Background: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2)., Patients and Methods: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin R Observational Study to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIM SM ) beginning in 2011. Statistical analyses were performed using datasets as of September 24, 2015., Results: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2., Conclusions: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2016 American Cancer Society.)

Background: Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported., Methods: We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%)., Results: 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual., Conclusions: This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.

Purpose: Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma., Methods: In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety., Results: Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%., Conclusion: T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy., (© 2016 by American Society of Clinical Oncology.)

TAZ (WWTR1) and YAP are transcriptional coactivators and oncoproteins inhibited by the Hippo pathway. Herein we evaluate 159 sarcomas representing the most prevalent sarcoma types by immunohistochemistry for expression and activation (nuclear localization) of TAZ and YAP. We show that 50% of sarcomas demonstrate activation of YAP while 66% of sarcomas demonstrate activated TAZ. Differential activation of TAZ and YAP are identified in various sarcoma types. At an RNA level, expression of WWTR1 or YAP1 predicts overall survival in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. Immunohistochemistry demonstrates that TAZ and YAP expression and activation are positively correlated with grade in the well-differentiated liposarcoma to dedifferentiated liposarcoma tumor progression sequence as well as conventional chondrosarcomas. TAZ and YAP are constitutively activated oncoproteins in sarcoma cell lines. Knock-down of TAZ and YAP demonstrate differential activity for the two proteins. Verteporfin decreases colony formation in soft agar as well as CTGF expression in sarcoma cell lines harboring activated TAZ and YAP., Competing Interests: The authors do not have any conflict of interest to report.

Background: Adenoid cystic carcinomas (ACCs) are malignant salivary gland tumors noteworthy for high rates of late failure with limited salvage therapy options. We have previously shown increased Akt signaling is common in ACC and the human immunodeficiency virus (HIV) protease inhibitor nelfinavir (NFV) inhibits in vitro tumor growth by suppressing Akt signaling. This phase II trial was conducted to determine progression-free survival in response to NFV in patients with recurrent/endstage ACC who have failed standard therapies., Methods: Eligible patients had recurrent or end-stage ACC and measureable disease per Response Evaluation Criteria in Solid Tumors (RECIST) criteria. NFV was provided at 1250 mg twice daily., Results: Among 15 trial participants, median progression-free survival was 5.5 months (lower 95% bound 4.4 months). No patient achieved a RECIST partial or complete response to therapy., Conclusion: NFV monotherapy does not result in a meaningful improvement in clinical outcomes among patients with recurrent ACC., (© 2014 Wiley Periodicals, Inc.)

Metastatic melanoma is a deadly treatment-resistant form of skin cancer whose global incidence is on the rise. During melanocyte transformation and melanoma progression the expression profile of many genes changes. Among these, a gene implicated in several steps of melanocyte development, TFAP2A, is frequently silenced; however, the molecular mechanism of TFAP2A silencing in human melanoma remains unknown. In this study, we measured TFAP2A mRNA expression in primary human melanocytes compared to 11 human melanoma samples by quantitative real-time RT-PCR. In addition, we assessed CpG DNA methylation of the TFAP2A promoter in these samples using bisulfite sequencing. Compared to primary melanocytes, which showed high TFAP2A mRNA expression and no promoter methylation, human melanoma samples showed decreased TFAP2A mRNA expression and increased promoter methylation. We further show that increased CpG methylation correlates with decreased TFAP2A mRNA expression. Using The Cancer Genome Atlas, we further identified TFAP2A as a gene displaying among the most decreased expression in stage 4 melanomas vs. non-stage 4 melanomas, and whose CpG methylation was frequently associated with lack of mRNA expression. Based on our data, we conclude that TFAP2A expression in human melanomas can be silenced by aberrant CpG methylation of the TFAP2A promoter. We have identified aberrant CpG DNA methylation as an epigenetic mark associated with TFAP2A silencing in human melanoma that could have significant implications for the therapy of human melanoma using epigenetic modifying drugs.

Introduction: The pathophysiology and therapeutic options in sepsis-induced lung injury remain elusive. High-dose interleukin 2 therapy (HDIL-2) is an important protocol for advanced malignancies but is limited by systemic inflammation and pulmonary edema that is indistinguishable from sepsis. In preclinical models, IL-2 stimulates angiopoietin 2 (AngP-2) secretion, which increases endothelial permeability and causes pulmonary edema. However, these relationships have not been fully elucidated in humans. Furthermore, the relevance of plasma AngP-2 to organ function is not clear. We hypothesized that plasma AngP-2 concentrations increase during HDIL-2 and are relevant to clinical pathophysiology., Methods: We enrolled 13 subjects with metastatic melanoma or renal cell carcinoma admitted to receive HDIL-2 and collected blood and spirometry data daily. The plasma concentrations of AngP-2 and IL-6 were measured with enzyme-linked immunosorbent assay., Results: At baseline, the mean AngP-2 concentration was 2.5 (SD, 1.0) ng/mL. Angiopoietin 2 concentrations increased during treatment: the mean concentration on the penultimate day was 16.0 (SD, 4.5) ng/mL and increased further to 18.6 (SD, 4.9) ng/mL (P < 0.05 vs. penultimate) during the last day of therapy. The forced expiratory volume in 1 s decreased during treatment. Interestingly, plasma AngP-2 concentrations correlated negatively with forced expiratory volume in 1 s (Spearman r = -0.78, P < 0.0001). Plasma AngP-2 concentrations also correlated with plasma IL-6 concentrations (r = 0.61, P < 0.0001) and Sequential Organ Failure Assessment scores (r = 0.68, P < 0.0001)., Conclusions: Plasma AngP-2 concentrations increase during HDIL-2 administration and correlate with pulmonary dysfunction. High-dose IL-2 may serve as a clinical model of sepsis and acute lung injury. Further investigation is warranted.

Importance: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation., Objective: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma., Design, Setting, and Participants: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada., Interventions: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression., Main Outcomes and Measures: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013., Results: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction., Conclusions and Relevance: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events., Trial Registration: clinicaltrials.gov Identifier: NCT01143402.