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Background: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma., Methods: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 10 9 -10·0 × 10 9 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3., Findings: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred., Interpretation: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies., Funding: Adaptimmune., Competing Interests: Declaration of interests EC reports participation in an advisory board for Adaptimmune; and research support paid to their institution for clinical trial activities from Adaptimmune, Novartis, Tracon, Boehringer Ingelheim, Merck, Bayer, Amgen, and Mirati. J-YB reports grants paid to institution from Netsarc+ and Euracan; and research support and honoraria from Adaptimmune and GSK. FT reports research support paid to institution for clinical trial activities from Adaptimmune, Achilles Therapeutics, T-knife Therapeutics, GSK, Immunocore, and Instil Bio; consulting fees from T-knife Therapeutics; speaker fees from Kite and Royal Marsden Hospital Cell Therapy Preceptorship; travel or meeting support from Kite; advisory board fees from Immatics, Bristol Myers Squibb (BMS), GSK, Janssen, Leucid, and Scenic Biotech; institutional advisory board fees from Pfizer; and is an unpaid panel member with Sarcoma UK, Cancer Research UK New Agents Committee, and the Medical Research Council Developmental pathway funding scheme. MA reports institutional support from Exelixis; consulting fees from Boehringer Ingelheim and Aadi; and honoraria from Regeneron, Deciphera, and Bayer. EF reports honoraria from Novartis, Alexion, Astellas, GSK, Gilead, and Sanofi; and travel or meeting support from Novartis, Alexion, Gilead, Sanofi, MSD, and Neovii. SJS reports consulting fees from Ceridwen Oncology; honoraria from Boehringer Ingelheim; travel or meeting support from Adaptimmune; and participated on advisory or data safety monitoring boards for GSK and Inhibrx. ARAR reports support from Adaptimmune, AbbVie, Amgen, Blueprint Medicines, BMS, Daiichi Sankyo, Deciphera Pharmaceuticals, GSK, Iterion Therapeutics, Karyopharm Therpaeutics, MedImmune, Merck, Neoleuki Therapeutics, Pfizer, Rain Therapeutics, Roche/Genentech, and Symphogen; honoraria from Medison; and participated on advisory or data safety monitoring boards for Adaptimmune, Bayer, GSK, Inhibrx, and Medison. SMS reports institutional support from Adaptimmune, Boehringer Ingelheim, GSK, Rain Oncology, Shanghai Pharma, and TRACON; royalties or licenses from UpToDate; participated on an advisory or data safety monitoring board for Bioatla; and is an unpaid National Comprehensive Cancer Network Soft Tissue Sarcoma committee member. CMVM reports institutional support from Adaptimmune; consulting fees from Deciphera; honoraria from Bayer; travel or meeting support from PharmaMar; and participation on advisory or data safety monitoring boards for PharmaMar, Bayer, and Boehringer Ingelheim. MJW reports consulting fees from Adaptimmune, Deciphera, Aadi, Epizyme, and PharmaEssentia. JG reports support from Adaptimmune for this study. VM reports consulting fees from Roche, Bayer, Pieris, BMS, Janssen, Basilea, Regeneron/Sanofi, and Nanobiotix; and institutional support from AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca, Bayer, Beigene, BioInvent International, BMS, Boehringer Ingelheim, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Therapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millenium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, Pricipia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, and Upsher-Smith. LH, TW, JB, AS, LF, EVW, EN, DW, RW, J-MN, SR, and EE are employees of, and have stock options in, Adaptimmune. SB, CM, and CL were employees of Adaptimmune at the time of the study. VLK reports institutional support from Adaptimmune, Deciphera, Plexxikon, Advenchen, Boehringer Ingelheim, and TRACON; consulting fees from Epizyme; and honoraria from Deciphera. WDT reports institutional support from Adaptimmune; consulting and travel fees from Eli Lilly; consulting fees from C4 Therapeutics, Daiichi Sankyo, Deciphera, Adcendo, Ayala Pharmaceuticals, Kowa, Servier, Bayer Pharmaceuticals, Epizyme, Cogent, Medpacto, Foghorn Therapeutics, Amgen, AmMax Bio, Boehringer Ingelheim, BioAtla, Inhibrx, PharmaEssentia, Avacta, Ipsen, Sonata, Curadev, Nuvation Bio, and Abbisko; has patents pending for companion diagnostics with Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center (New York, NY, USA); is on advisory boards of Innova Therapeutics and the Osteosarcoma Institute; is on the advisory board and holds stock in Certis Oncology Solutions; and is a co-founder and has stock in Atropos Therapeutics. JAC reports consulting fees from Adaptimmune and Deciphera; and honoraria from Adaptimmune. BAVT reports a research grant from Polaris; royalties or licenses from Accuronix Therapeutics; consulting fees from Bayer, Deciphera, GIST Expert Interview Project, Daiichi Sankyo, EcoR1, Advenchen, Putnam, Salarius Pharmaceuticals, Boxer Capital, Acuta Capital Partners, Aadi, Race Oncology, Hinge Bio, Kronos Bio, and Sonata Therapeutics; honoraria from Total Health Conference and Iterion Therapeutics; travel or meeting support from Adaptimmune, Kronos Bio, Advenchen Laboratories, and Polaris; has a patent with Accuronix Therapeutics; participated in advisory boards for Apexigen, Daiichi Sankyo, Epizyme, Bayer, PTC Therapeutics, Aadi Biosciences, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Exp, Advenchen, EcoR1 Capital, Curis, and Inhibrx; and is a board member for Polaris. GDD reports institutional support from Adaptimmune, Bayer, Novartis, PharmaMar, and Daiichi-Sankyo; is a co-founder and scientific advisory board member with minor equity holding in IDRx; is a consultant or scientific advisory board member with minor equity holding in G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, RELAY Therapeutics, Bessor Pharmaceuticals, CellCarta, Ikena Oncology, Kojin Therapeutics, Aadi Biosciences, Acrivon Therapeutics, Blueprint Medicines, Tessellate Bio, and Boundless Bio; and is a scientific consultant for EMD-Serono/Merck KGaA, WCG/Arsenal Capital, Rain Therapeutics, and Minghui Pharmaceuticals. SPD'A reports institutional support from Adaptimmune for this study; grants, contracts, consulting fees, and honoraria from EMD Serono, Amgen, Nektar, Immune Design, GlaxoSmithKline, Incyte, Merck, Adaptimmune, Immunocore, Pfizer, Servier, Rain Therapeutics, GI Innovations, and Aadi Biosciences; travel support from Adaptimmune, EMD Serono, and Nektar; participation on advisory boards for GlaxoSmithKline, Nektar, Adaptimmune, and Merck; and a leadership or fiduciary role at the Connective Tissue Oncology Society in 2023–24. SA reports institutional support from Adaptimmune for this study; and institutional support from TRACON Pharma, Ayala Pharmaceuticals, Cogent Biosciences, InhibRx, Rain Therapeutics, Trillium Therapeutics, Boehringer Ingelheim, Salarius Pharmaceuticals, Theseus Pharmaceuticals, Monopar Therapeutics, C4 Therapeutics, Noxopharm, Jazz Pharmaceuticals, Shanghai Pharma, and PharmaMar. KNG reports participation in advisory boards for Adaptimmune, Daiichi Sankyo, Boehringer Ingelheim, and Deciphera. MD reports consultancy fees and advisory board fees from Deciphera, Aadi Bioscience, and Daiichi Sankyo. BAW reports consultancy fees from Springworks, Deciphera, Epizyme, Adcendo, Polaris, Boehringer Ingelheim, and AADi, research funding from Exelixis, and travel support from Agenus. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501., (© 2024. The Author(s).)

Purpose: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL)., Patients and Methods: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up., Results: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days)., Conclusion: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Attia reports institutional research funding from AB Science, Adaptimmune, Advenchen Laboratories, Ayala Pharmaceuticals, Bavarian Nordic, Bayer, Blueprint Medicines, Boehringer Ingelheim, BTG, C4 Therapeutics, CBA Pharma, Deciphera Pharmaceuticals, Eli Lilly & Co, Epizyme, FORMA Therapeutics, Genmab, GlaxoSmithKline, Gradalis, Incyte, InhibRx, Karyopharm Therapeutics, Merck, Monopar Therapeutics, Novartis, Noxopharm, Philogen, PTC Therapeutics, Rain Therapeutics, Salarius Pharmaceuticals, Springworks, Takeda, Theseus Pharmaceuticals, TRACON Pharmaceuticals and Trillium Therapeutics; and personal research funding from the Desmoid Tumour Research Foundation. Dr. Bauer reports honoraria from Novartis; advisory board fees from Roche; consulting fees from Adcendo, Bayer, Blueprint Medicines, Boehringer Ingelheim, Cogent Biosciences, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly & Co, Exelixis, GlaxoSmithKline, Incyte, Nanobiotix, Novartis and PharmaMar; institutional research funding from Novartis; and travel support from PharmaMar. Dr. Becker has no financial interests to disclose. Dr. Blay reports leadership at Innate Pharma; honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera Pharmaceuticals, Ignyta, Merck, PharmaMar and Roche; consulting fees from Bayer, Blueprint Medicines, Deciphera Pharmaceuticals, Karyopharm Therapeutics, PharmaMar and Roche; institutional research funding from AstraZeneca, Bristol Myers Squibb, Bayer, Deciphera Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, OSE Pharma, PharmaMar and Roche; and travel support from Roche. Dr. Boye reports honoraria from Eli Lilly & Co and Novartis; consulting fees from Bayer and GlaxoSmithKline; and institutional research funding from Eli Lillly & Co and Merck. Dr. Chi reports consulting fees from Deciphera Pharmaceuticals, Exelixis, NewBay, Novartis and Zai Lab; institutional research funding from Deciphera Pharmaceuticals and Pfizer/Array; and is a shareholder of Oric Pharma.Dr. Druta reports consulting fees from Eisai and Eli Lilly & Co; and speaker’s bureau fees from Eisai and Eli Lilly & Co. Dr. Gelderblom reports institutional research funding from Daiichi Sankyo, Deciphera Pharmaceuticals, Ipsen and Novartis. Dr. George reports consulting fees from Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera Pharmaceuticals, Eli Lilly & Co, Kayothera, Immunicum, MORE Health, Research to Practice and UpToDate; institutional research funding from BioAtla, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, IDRX, Merck, Springworks, Theseus Pharmaceuticals and TRACON Pharma; honoraria from CStone Pharmaceuticals; patents, royalties, or other intellectual property with UpToDate; other financial relationships with Research to Practice and WCG/Ayala; and is a shareholder of Abbott Laboratories. Dr. Goldstein reports consulting fees from Deciphera Pharmaceuticals. Dr. Harrow is an employee and shareholder of Deciphera Pharmaceuticals. Dr. Heinrich reports honoraria from Novartis; consulting fees from Blueprint Medicines, Deciphera Pharmaceuticals, Novartis and Theseus Pharmaceuticals; and a patent on the treatment of GIST licensed to Novartis. Dr. Jones reports consulting fees from Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Eli Lilly & Co, Epizyme, Daiichi Sankyo, Deciphera Pharmaceuticals, Immunedesign, Immunicum, Karma Oncology, Merck, Mundipharma, PharmaMar, Springworks, SynOx, TRACON Pharmaceuticals and UpToDate. Dr. Kang reports consulting fees from ALX Oncology, Amgen, Novartis, Blueprint Medicines, Bristol Myers Squibb, Daehwa, Macrogenics, Surface Oncology and Zymeworks. Dr. Le Cesne reports honoraria from Bayer, Deciphera Pharmaceuticals, and PharmaMar. Dr. Razak reports consulting fees from Adaptimmune, Bayer, GlaxoSmithKline, Medison, Inhibrx; and research funding from AbbVie, Adaptimmune, Amgen, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Deciphera Pharmaceuticals, GlaxoSmithKline, Iterion Therapeutics, Karyopharm Therapeutics, Merck, MedImmune, Neoleukin Therapeutics, Pfizer, Roche/Genentech, Rain Therapeutics and Symphogen; and served as expert testimony for Medison. Dr. Reichmann is an employee and shareholder of Deciphera Pharmaceuticals. Dr. Ruiz-Soto is an employee of Deciphera Pharmaceuticals; a shareholder of Deciphera Pharmaceuticals and Immunogen; and is an inventor in three patents with Immunogen and pending patents at Deciphera Pharmaceuticals, the rights for which have been transferred to Immunogen and Deciphera, respectively; Dr. Ruiz-Soto has not received and will not receive royalties from these patents. Dr. Rutkowski reports honoraria from AstraZeneca, Bristol Myers Squibb, Merck, Novartis, Pierre Fabre, and Sanofi. Dr. Sanchez reports honoraria from AstraZeneca, Novartis, Pfizer and Roche; and research funding from Pfizer, Novartis and Roche. Dr. Serrano reports honoraria from Bayer and Blueprint Medicines; institutional research funding from Bayer, Deciphera Pharmaceuticals, Karyopharm Therapeutics and Pfizer; consulting fees from Blueprint Medicines, Cogent Biosciences, Deciphera Pharmaceuticals and Immunicum; and travel support from Bayer, Eli Lilly & Co, Novartis, Pfizer and PharmaMar. Dr. Siontis reports consulting fees from Deciphera Pharmaceuticals and institutional research funding from Advenchen and Deciphera Pharmaceuticals. Dr. Sherman reports employment, leadership, and stock or other ownership interests of Deciphera Pharmaceuticals and Pieris Pharmaceuticals. Dr. Somaiah reports consulting fees from Aadi Biosciences, Boehringer Ingelheim and Epizyme and research funding from Advenchen, Ascentage, AstraZeneca, Cogent, Deciphera Pharmaceuticals, GlaxoSmithKline, and Innovent. Dr. Steeghs reports consulting fees from Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma and Luszana; institutional research funding from AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Cantargia, CellCentric, Cogent, Cresecendo Biologics, Cytovation, Deciphera Pharmaceuticals, Eli Lilly & Co, Exelixis, Genentech, GlaxoSmithKline, Incyte, InteRNA, Janssen, Kinnate Biopharma, Luszana, Merck, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicine, Roche, Sanofi, Seattle Genetics, Taiho and Takeda. Dr. Trent reports consulting fees from Adcendo, AADI Bioscience, Cogent, Deciphera Pharmaceuticals, Daiichi Sankyo and Foghorn Therapeutics. Dr. von Mehren reports consulting fees from Deciphera Pharmaceuticals, GlaxoSmithKline and Moleculin; institutional research funding from ASCO, Ayala, Deciphera Pharmaceuticals, Genmab, Gradalis, Novartis, Solaris Health, Sumitomo Pharma Oncology and Theseus Pharmaceuticals; and another financial relationship with NCCN. Dr. Zalcberg reports leadership at ICON Group, Lipotek and Praxis; honoraria from Deciphera Pharmaceuticals, Halozyme, Gilead Sciences, Merck Serono, Specialised Therapeutics and Targovax; consulting fees from 1Globe Health Institute, Centre for Emerging and Neglected Diseases (CEND), Deciphera Pharmaceuticals, FivePHusion, Genor BioPharma, Halozyme, Lipotek, Merck, Merck Serono, Novotech, Revolution Medicine, Specialised Therapeutics and Targovax; institutional research funding from AstraZeneca, Bristol Myers Squibb, Eisai, Ipsen, IQVIA, Medtronic, Merck Serono, Mylan and Pfizer; stock or other ownership of Amarin Corporation, Biomarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead Sciences, Madrigal Pharmaceuticals, Moderna Therapeutics, Novavax, Opthea, Orphazyme, Twist Bioscience, UniQure and Zogenix; and travel support from AstraZeneca, Deciphera Pharmaceuticals, Merck, Merck Serono and Sanofi., (Copyright © 2023 Deciphera Pharmaceuticals LLC. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have shown modest antitumor activity in unselected advanced sarcomas. Histology driven approach to patient selection is the current standard for off-label anti-programmed cell death 1 (PD1) immunotherapy use., Methods: We retrospectively reviewed the clinical characteristics and outcomes of patients with advanced sarcoma who were treated with off label anti-PD1 immunotherapy at our center., Results: A total of 84 patients with 25 histological subtypes were included. Nineteen patients (23%) had a cutaneous primary tumor site. Eighteen patients (21%) were classified as having clinical benefit, including 1 patient with complete response, 14 with partial response, and 3 with stable disease lasting over 6 months with previously progressive disease. Cutaneous primary site location was associated with higher clinical benefit rate (58% vs. 11%, p < 0.001), longer median PFS (8.6 vs. 2.5 months, p = 0.003) and OS (19.0 vs. 9.2 months, p = 0.011), compared to non-cutaneous primary. Patients with histological subtypes that pembrolizumab is indicated per current National Comprehensive Cancer Network guidelines had modestly higher rate of clinical benefit versus other histologies, however, the difference was statistically insignificant (29% vs. 15%, p = 0.182) and no statistically significant difference in PFS or OS was observed between these groups. Immune-related adverse events were more frequently seen among patients with clinical benefit (72% vs. 35%, p = 0.007)., Conclusions: Anti-PD1-based immunotherapy is highly efficacious in advanced sarcomas of cutaneous primary site. Cutaneous primary site location is a stronger predictor of ICI response than histologic subtype and should be accounted for in treatment guidelines and clinical trial design., (© 2023. The Author(s).)

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer ( NCT03132922 ). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit-risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies., (© 2023. The Author(s).)

Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: Primary pulmonary sarcomas (PPS) and pulmonary carcinosarcomas (PCS) are rare aggressive lung malignancies. We reviewed our 21-year experience with the surgical and nonsurgical treatment of both tumors, comparing their clinical, histopathologic, and treatment results., Methods: All patients with PPS or PCS who underwent surgical and nonsurgical treatment between 1998 and 2019 at our cancer center were retrospectively reviewed. Multivariable Cox proportional hazards model was constructed., Results: In total, 100 patients were analyzed: 45 with PPS and 55 with PCS. Among patients with PPS, 31 of 45 (69%) underwent surgery with 1 (3%) operative mortality. For patients with PCS, 29 of 55 (53%) underwent surgery with no operative mortality. Patients with PPS were younger than PCS (P < .01). Fewer patients were smokers among PPS (58%) versus PCS (93%) (P < .01). For resected PPS, mean tumor size was 8.2 ± 4.1 cm (range 2.2-18.0) compared with 10.1 ± 5.0 cm (range 3.9-17.0) for unresected PPS. Tumor size for resected PCS was 6.2 ± 2.6 cm (range 2.0-10.5) versus 6.8 ± 3.5 cm (range 1.2-13.5) for unresected PCS. Of resected patients, 5 of 31 (16%) with PPS and 9 of 29 (31%) with PCS were node positive. Overall survival estimates were as follows: for PPS, median survival and 5-year overall survival for resected versus unresected cases were 39.6 months/28.7% versus 4.9 months/7.8%. For PCS, survival estimates were 23.6 months/31.0% versus 14.9 months/28.2%, respectively. In multivariable analyses (N = 100), age, smoking history, histology, and surgery were risk factors of survival., Conclusions: At initial evaluation, PPS and PCS presented with large-sized tumors and usually were not stage I. Surgery had a positive impact on survival among patients with PPS. Whenever feasible, surgical resection, even in locally advanced disease, may yield long-term survival in these aggressive lung tumors, although the level of evidence is low., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Pexidartinib is approved in the U.S. for tenosynovial giant cell tumors (TGCTs). Herein, we assessed the hepatic safety profile of pexidartinib across patients with TGCTs receiving pexidartinib., Materials, and Methods: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as (a) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (b) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82) in 140 patients with TGCTs across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288., Results: In total, 95% of patients with TGCTs (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76]), experienced a hepatic AR. A total of 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases., Conclusion: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGTs, a locally aggressive but typically nonmetastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury., Implications for Practice: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with tenosynovial giant cell tumors associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper use for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Adrenal crisis is a life-threatening complication of adrenal insufficiency which is triggered by physiological stressors such as injury, infection or a surgical procedure when the plasma concentration of adrenal corticosteroids is insufficient for physiological requirements. It is associated with a high mortality rate unless early diagnosis and treatment is initiated. We report a case of a patient with metastatic sarcoma and adrenal insufficiency who underwent right hepatic artery chemoembolization to control his intrahepatic metastases. He did not receive stress dose glucocorticoid and his glucocorticoid supplement medication was accidentally discontinued after embolization. He died due to an unrecognized adrenal crisis 2 days after embolization. This case suggests that embolization should be recognized as a stressor to prompt the need to continue chronic replacement of corticosteroids and to consider supplemental stress-dose corticosteroids. There is a growing population of patients on chronic corticosteroids for various conditions who may require tumor embolization. Therefore, it is important to consider adrenal crisis in post-embolization settings since the symptoms are non-specific and mortality can be avoided only if the diagnosis of adrenal crisis is considered and parenteral glucocorticoids administered., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Preclinical data suggest that a "prime-boost" vaccine regimen using a target-expressing lentiviral vector for priming, followed by a recombinant protein boost, may be effective against cancer; however, this strategy has not been evaluated in a clinical setting. CMB305 is a prime-boost vaccine designed to induce a broad anti-NY-ESO-1 immune response. It is composed of LV305, which is an NY-ESO-1 expressing lentiviral vector, and G305, a recombinant adjuvanted NY-ESO-1 protein. This multicenter phase 1b, first-in-human trial evaluated CMB305 in patients with NY-ESO-1 expressing solid tumors. Safety was examined in a 3 + 3 dose-escalation design, followed by an expansion with CMB305 alone or in a combination with either oral metronomic cyclophosphamide or intratumoral injections of a toll-like receptor agonist (glucopyranosyl lipid A). Of the 79 patients who enrolled, 81.0% had sarcomas, 86.1% had metastatic disease, and 57.0% had progressive disease at study entry. The most common adverse events were fatigue (34.2%), nausea (26.6%), and injection-site pain (24.1%). In patients with soft tissue sarcomas, a disease control rate of 61.9% and an overall survival of 26.2 months (95% CI, 22.1-NA) were observed. CMB305 induced anti-NY-ESO-1 antibody and T-cell responses in 62.9% and 47.4% of patients, respectively. This is the first trial to test a prime-boost vaccine regimen in patients with advanced cancer. This approach is feasible, can be delivered safely, and with evidence of immune response as well as suggestion of clinical benefit., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Purpose: The purpose of this study was to determine the safety and efficacy of liver-directed therapies in patients with unresectable metastatic leiomyosarcoma to the liver. Liver-directed therapies included in this study were transarterial chemoembolization with doxorubicin eluting beads (DEB-TACE), yttrium-90 (Y90) radioembolization, and percutaneous microwave ablation., Methods: This is a single institution retrospective study of unresectable metastatic leiomyosarcoma to the liver treated with DEB-TACE, radioembolization, or microwave ablation. DEB-TACE was performed using 70-150 or 100-300 µ doxorubicin-loaded drug-eluting LC beads. Radioembolization was performed using Y90 glass microspheres. Electronic medical records were retrospectively reviewed to evaluate clinical and biochemical toxicities, tumor response on imaging, overall survival (OS), and liver progression-free survival (PFS)., Results: A total of 24 patients with metastatic leiomyosarcoma to the liver who underwent liver-directed treatment were identified (8 males, 16 females; average age, 62.8±11.4 years). Of these patients, 13 underwent DEB-TACE, 6 underwent Y90, and 5 underwent ablation. Three patients received a combination of treatments: one received Y90 followed by DEB-TACE, one received ablation followed by DEB-TACE, and one received ablation followed by Y90. Of the 24 patients, 19 received prior chemotherapy. At 3-month follow-up, grade 1 or 2 lab toxicities were found in 20 patients; 3 patients had grade 3 toxicities. A grade 3 clinical toxicity was reported in one patient. MELD score was 7.5±1.89 at baseline and 8.8±4.2 at 3 months. Median OS was 59 months (95% CI, 39.8-78.2) from diagnosis, 27 months (95% CI, 22.9-31.0) from development of liver metastasis, and 9 months (95% CI, 0-21.4) from first liver-directed treatment. Median liver PFS was 9 months (95% CI, 1.4-16.6)., Conclusion: Treatment with liver-directed therapies for patients with unresectable metastatic leiomyosarcoma to the liver is safe and can improve overall survival, with OS after liver-directed therapy being similar to patients who underwent surgical resection.

Introduction: Pembrolizumab is an immune checkpoint inhibitor targeting the programmed death receptor with clinical effect on multiple malignancies including sarcoma. Associated cardio-toxicities include myocarditis, cardiomyopathy, heart failure, and arrhythmias. Although in most cases of immune checkpoint inhibitor cardiotoxicity the offending agent is discontinued, we report a case of successful and safe re-challenge with a checkpoint inhibitor in a patient with mild myocarditis., Case Report: We describe a 37-year-old female with alveolar soft part sarcoma, metastatic to the lungs on cycle 13 of pembrolizumab who presented with dyspnea, cough, and vague chest discomfort. Telemetry showed bigeminal bradycardia that transitioned to self-terminating torsades de pointes. Cardiac MRI showed subtle patchy T2 signal increase within the left ventricular septum without late gadolinium uptake, suggesting mild focal myocarditis.Management and outcome: The patient was started on a steroid taper without additional arrhythmias. We have re-challenged the patient who safely tolerated re-challenge with pembrolizumab despite an episode of torsades de pointes and documented myocarditis. She continues to receive pembrolizumab at seven months after the initial event without further cardiovascular events., Discussion: To the best of our knowledge, this is the first reported case of successful re-challenge of pembrolizumab after an episode of myocarditis. In patients with mild myocarditis and no evidence of left ventricular dysfunction, re-challenge may be a viable option. However, close monitoring for the development of heart failure, cardiomyopathy, or serious arrhythmias is necessary to ensure patient safety.

Background: Soft tissue sarcomas (STS) are rare and heterogeneous tumors making chemotherapy use controversial. Our goal was to identify a subset of patients with primary STS that benefit with the addition of chemotherapy., Methods: A retrospective chart review included intermediate to high-grade localized primary STS of the extremity/trunk, and tumor size > 5 cm. The effect of chemotherapy was evaluated for local control (LC), distant control (DC), progression free survival (PFS), and overall survival (OS)., Results: In this cohort (n = 273), patients were treated with surgery (98%), radiation (81%), and chemotherapy (24.5%). With a median follow-up of 51 months, the entire cohort's 5-year LC, DC, PFS, and OS are 79.1%, 59.9%, 43.8%, and 68.7%, respectively. The addition of chemotherapy did not provide a DC benefit (p = 0.238) for the entire cohort. High-grade disease (n = 210) experienced a 5-year benefit in DC (68% vs. 54.4%, p = 0.04), which was more pronounced with MAI (Mesna, Adriamycin, Ifosfamide) based regimens (74.2%, p = 0.016), and a 5-year PFS (50.8% vs 45%, p = 0.025) and OS benefit (76.2% vs 70%, p = 0.067) vs. no chemotherapy. On multivariate analysis of the high-grade subset, chemotherapy independently predicted for a DC benefit (HR 0.48 95% CI 0.26-89, p = 0.019). The benefit of chemotherapy was more pronounced with MAI, showing a significant benefit in DC (HR 0.333 95% CI 0.145-0.767, p = 0.01) and PFS (HR 0.52 95% CI 0.28-0.99, p = 0.047)., Conclusion: In patients with localized STS > 5 cm, the high-grade subset had a distant control benefit with the addition of chemotherapy, leading to improved progression free survival. This is more pronounced with the use of MAI and should be considered in patients eligible for this regimen., Competing Interests: Competing interestsNot applicable., (© The Author(s) 2020.)

Background: Outcomes data regarding advanced synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are limited, consisting primarily of retrospective series and post hoc analyses of clinical trials., Methods: In this multi-center retrospective study, data were abstracted from the medical records of 350 patients from nine sarcoma centers throughout the United States and combined into a registry. Patients with advanced/unresectable or metastatic SS (n = 249) or MRCL (n = 101) who received first-line systemic anticancer therapy and had records of tumor imaging were included. Overall survival (OS), time to next treatment, time to distant metastasis, and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox regression., Results: At start of first-line systemic anticancer therapy, 92.4% of patients with SS and 91.1% of patients with MRCL had metastatic lesions. However, 74.7% of patients with SS and 72.3% of patients with MRCL had ≥2 lines of systemic therapy. Median OS and median PFS from first-line therapy for SS was 24.7 months (95% CI, 20.9-29.4) and 7.5 months, respectively (95% CI, 6.4-8.4). Median OS and median PFS from start of first-line therapy for MRCL was 29.9 months (95% CI, 27-44.6) and 8.9 months (95% CI 4.5-12.0)., Conclusions: To the best of our knowledge, this is the largest retrospective study of patients with SS and MRCL. It provides an analysis of real-world clinical outcomes among patients treated at major sarcoma cancer centers and could inform treatment decisions and design of clinical trials. In general, the survival outcomes for this selected population appear more favorable than in published literature., (© 2020 The Authors and Merck Sharp & Dohme Corp. Cancer Medicine published by John Wiley & Sons Ltd.)

Molecular diagnostics of sarcoma subtypes commonly involve the identification of characteristic oncogenic fusions. EWSR1-PATZ1 is a rare fusion partnering in sarcoma, with few cases reported in the literature. In the current study, a series of 11 cases of EWSR1-PATZ1 fusion positive malignancies are described. EWSR1-PATZ1-related sarcomas occur across a wide age range and have a strong predilection for chest wall primary site. Secondary driver mutations in cell-cycle genes, and in particular CDKN2A (71%), are common in EWSR1-PATZ1 sarcomas in this series. In a subset of cases, an extended clinical and histopathological review was performed, as was confirmation and characterization of the fusion breakpoint revealing a novel intronic pseudoexon sequence insertion. Unified by a shared gene fusion, EWSR1-PATZ1 sarcomas otherwise appear to exhibit divergent morphology, a polyphenotypic immunoprofile, and variable clinical behavior posing challenges for precise classification.

Background: Gene-modified autologous T cells expressing NY-ESO-1 c259 , an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells., Methods: Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay., Results: Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163 + tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients., Conclusions: Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy., Trial Registration: ClinicalTrials.gov, NCT01343043 , Registered 27 April 2011.

Purpose: Sarcomas are a diverse group of malignant tumors that arise from soft tissues or bone. For most advanced cases, there is a substantial need for improved therapeutic options and, therefore, a desire to more precisely tailor therapy in individual cases. In this study, we review our institutional experience with next-generation sequencing (NGS)-based molecular profiling for non-GI stromal tumors sarcomas, with a focus on the clinical utility of the results., Patients and Methods: We retrospectively analyzed results of NGS performed on tumors from 114 patients with a diagnosis of sarcoma. A chart review was conducted to review the clinical impact of NGS findings., Results: A median of three putatively oncogenic gene alterations were identified per tumor sample (range, 0 to 19) and at least one mutation was detected in 96.7% of tumors. Fifty-six patients (49.1%) harbored a finding that was felt to be actionable after review by a molecular tumor board. Five patients (4.4%) had a diagnosis change as a result of NGS findings. In 15 patients (13.2%), therapeutic selection was influenced by NGS findings. Four of 15 (26.7%) of the NGS-influenced systemic therapies resulted in clinical benefit., Conclusion: Putatively oncogenic mutations are readily detected in the majority of sarcomas. Genetic profiling affected the diagnosis and/or treatment approach in a sizeable minority of patients with sarcoma treated at our center. Additional study is required to determine if genetic profiling leads to improved clinical outcomes.

Background: Retroperitoneal sarcoma is rare. Using initial specimens on biopsy, a definitive diagnosis of histological subtypes is ideal but not always achievable., Methods: A retrospective institutional review was performed for all cases of adult retroperitoneal sarcoma from 1996 to 2015. A review of the literature was also performed related to the distribution of retroperitoneal sarcoma subtypes. A meta-analysis was performed., Results: Liposarcoma is the most common subtype (45%), followed by leiomyosarcoma (21%), not otherwise specified (8%), and undifferentiated pleomorphic sarcoma (6%) by literature review. Data from Moffitt Cancer Center demonstrate the same general distribution for subtypes of retroperitoneal sarcoma. A pathology-based algorithm for the diagnosis of retroperitoneal sarcoma is illustrated, and common pitfalls in the pathology of retroperitoneal sarcoma are discussed., Conclusions: An informative diagnosis of retroperitoneal sarcoma via specimens on biopsy is achievable and meaningful to guide effective therapy. A practical and multidisciplinary algorithm focused on the histopathology is helpful for the management of retroperitoneal sarcoma.

Background: Pulmonary metastasectomy (PM) for metastatic sarcoma can result in long-term survival. The purpose of this study was to describe factors associated with survival in a series of patients undergoing PM for metastatic sarcoma., Methods: We reviewed all patients undergoing PM for metastatic sarcoma over a 12-year period (2000-2012). Multivariate analyses were used to identify factors associated with outcomes. Survival was calculated with Kaplan-Meier and Cox proportional hazard models., Results: A total of 120 patients underwent PM with a median follow-up was 48 months. Among 81 (85%) patients who presented with local disease, the median disease free interval (DFI) was 13 months and median overall survival (OS) was 48 months. Fourteen patients (15%) had synchronous metastasis with a median OS of 21 months. On multivariate analysis, synchronous metastasis (P = 0.005), older age (P = 0.02), and number of lung lesions (P = 0.003) were associated with poor survival. The median OS of patients with a DFI ≥12 versus <12 months following primary resection was 93 and 43 months (P = 0.004)., Conclusion: While patients with a DFI >12 months have the best OS following PM, patients with a DFI <12 months also have excellent outcomes as compared to systemic therapy and should be considered for PM., (© 2015 Wiley Periodicals, Inc.)

Objective: Components of metabolic syndrome (MS) have been individually linked to colorectal cancer risk and prognosis; however, an understanding of the dominant mechanisms is lacking., Materials and Methods: Twenty-one patients (10 MS; 11 non-MS) with resectable colorectal cancer were prospectively enrolled. Patients were classified for MS by the World Health Organization criteria and tested for circulating vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), fasting insulin, and tumor expression of IGF-1 receptor (IGF-1R), insulin-receptor (IR) and receptor for advanced glycation end-products (RAGE). Circulating markers were re-tested 6 months after surgery., Results: The MS group had significantly higher baseline and post-operative fasting insulin levels (p < 0.001 and 0.003). No differences were observed in circulating IL-6, VEGF, IGF-1 and free IGF-1. By immunohistochemistry (IHC), IGF-1R expression was significantly higher in tumor vs. normal tissues (p < 0.001) while IR expression showed no difference. Interestingly, 64% of tumors demonstrated high IR positivity in the vessels within or surrounding the tumor stroma, but not in the vessels away from the tumor. By reverse transcription polymerase chain reaction (RT-PCR), tumor IGF-1R over-expression (80%) was confirmed, but there was no difference between MS and non-MS patients. Tumor RAGE over-expression was found in 67% of patients and was equally distributed between the two groups., Conclusions: Hyperinsulinemia was the only significant factor distinguishing patients with colorectal cancer who have MS. The preferential over-expression of IR in the peri-tumoral microvessels suggests that hyperinsulinemia might contribute to colorectal cancer growth by enhancing angiogenesis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Pancreatectomy for ductal adenocarcinoma has been performed with increasing frequency since the late 1980s as postoperative mortality decreased and long-term survival became more common. However, the belief persists among some clinicians that pancreatectomy offers little survival benefit. This report reviews our institutional experience with pancreatectomy for pancreatic adenocarcinoma and provides a critical overview of the controversies regarding the benefits of surgical intervention for patients who are candidates for curative resection., Methods: We determined the survival of 142 patients who underwent pancreatectomy for ductal adenocarcinoma with curative intent (stage IA-IIB) at Moffitt Cancer Center during the last two decades by using data obtained from review of the medical record, the Moffitt Cancer Registry, and the Social Security Death Index. Histologic diagnosis was confirmed by expert review of stained sections cut from fixed surgical specimens., Results: In the 137 patients who survived at least 30 days after surgery, the median survival was 21.2 months after resection, with Kaplan-Meier 3- and 5-year disease-specific survival rates of 36% and 32%, respectively. One patient has survived without evidence of recurrent disease for more than 15 years after pancreatectomy. Survival for patients greater than 75 year of age did not differ from that of younger patients. The postoperative mortality rate was 1.5% during the most recent years of highest operative volume (2003 to 2006) and 3.5% for the entire patient cohort., Conclusions: Review of our 20-year experience with resection of pancreatic adenocarcinoma indicates that pancreatectomy with curative intent offers a real chance of long-term survival to patients with this highly lethal disease for which there is no other curative modality.

Purpose: The Moffitt Quality Practice Initiative (MQPI) is a practice-based system of quality self-assessment, the ultimate goal of which is to improve the quality of cancer care at a statewide level. The initial phase of this project focused on developing procedures, determining feasibility, and evaluating utility for assessing quality of care for colorectal cancer within an existing affiliate network., Patients and Methods: Representatives from four oncology groups selected quality measures consistent with evidence-, consensus-, and safety-based guidelines that could be abstracted from medical records. Trained abstractors then reviewed records of all eligible colorectal patients seen by each practice in 2004. Frequencies of responses for each indicator were tabulated for overall and practice-specific level of adherence and were compared among practices., Results: Adherence was uniformly high for several indicators, including confirmatory pathology report, staging information, and chemotherapy discussion or recommendation. Lower adherence was evident across practices for performance of carcinoembryonic tests and complete colonoscopic evaluations. Significant variation among practices was evident only for consent for chemotherapy., Conclusion: The initial phase of MQPI demonstrated the feasibility and utility of assessing quality indicators for colorectal cancer among members of an existing affiliate network. Findings identified areas where adherence to care was uniformly high, but also identified areas where both overall and practice-specific adherence were less than optimal. These efforts lay the groundwork for expanding MQPI in several directions that have in common the potential to improve the quality of cancer care on a statewide basis.