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Background Some surgeons change gloves and instruments after the extirpative phase of cancer surgery with the intent of reducing the risk of local and wound recurrence. Although this practice is conceptually appealing, the evidence that gloves or instruments act as vectors of cancer-cell seeding in the clinical setting is weak. To determine the potential effect of further investigation of this question, we surveyed the practices and beliefs of a broad spectrum of surgeons who operate on cancer patients. Methods Using a modified Dillman approach, a survey was mailed to all 945 general surgeons listed in the College of Physicians and Surgeons of Ontario public registry. The survey consisted of multiple-choice and free-text response questions. Responses were tabulated and grouped into themes, including specific intraoperative events and surgeon training. Predictive variables were analyzed by chi-square test. Results Of 459 surveys returned (adjusted response rate: 46%), 351 met the inclusion criteria for retention. Of those respondents, 52% reported that they change gloves during cancer resections with the intent of decreasing the risk of tumour seeding, and 40%, that they change instruments for that purpose. The proportion of respondents indicating that they take measures to protect the wound was 73% for laparoscopic cancer resections and 31% for open resections. Training and years in practice predicted some of the foregoing behaviours. The most commonly cited basis for adopting specific strategies to prevent tumour seeding was "gut feeling," followed by clinical training. Most respondents believe that it is possible or probable that surgical gloves or instruments harbour malignant cells, but that a cancer recurrence proceeding from that situation is unlikely. Conclusions There is no consensus on how gloves and instruments should be handled in cancer operations. Further investigation is warranted. [ABSTRACT FROM AUTHOR]

Abstract Background There is immunohistochemical evidence to suggest that expression of epidermal growth factor receptor (EGFR) in primary colorectal adenocarcinoma predicts its expression in recurrent disease. This study investigates whether postoperative chemotherapy affects the degree of concordance between EGFR statuses of the two tumors. Methods Thirty-three patients were identified from the files of Sunnybrook Health Sciences Center from July 1994 to June 2005. All patients had resection of their primary tumors and their distant recurrences. Eighteen patients received postoperative chemotherapy, 3 of which also received postoperative radiation therapy. Representative primary and recurrent tumor sections were stained using mouse anti-EGFR antibodies and only membranous staining of malignant cells was recorded. Results were reported as negative (no staining), 1+ (positivity in 50% of cells). Results EGFR immunostaining in the 15 patients, who received no postoperative chemotherapy, was decreased in 3 recurrences, remained the same in 10 and increased in 2. In the group of 18 patients who received postoperative chemotherapy, EGFR immunostaining was decreased in 6 recurrences, remained the same in 9 and increased in 3 (p = 0.6598). In patients who received postoperative chemotherapy, the odds ratio for a recurrence to show lower levels of EGFR immunostaining compared to its originally resected primary was 4.75 (CI = 0.94 – 26.73). Conclusion These preliminary data suggest that recurrences following postoperative chemotherapy are likely to have lower levels of EGFR expression compared to cases who receive no chemotherapy. Although the difference of immunostaining profiles between the two groups was not statistically significant, this observation might impact the management of these patients by targeted biologic therapies and its practical implications need further validation in larger series.

Purpose: Retroperitoneal sarcomas (RPS) are rare, heterogeneous tumours. Treatment recommendations are mainly derived from cohorts treated at reference centres. The applicability of data from cancer registries (CR) is controversial. This work compares CR and TARPSWG (Transatlantic Australasian Retroperitoneal Sarcoma Working Group) data to assess the representativeness of the TARPSWG and the applicability of the CR data., Methods: TARPSWG cohort has previously been described. The CR Baden-Württemberg cohort includes patients with primary RPS M0 (years 2016-2021, ICD-10 C.49.4/5, C48.x) who underwent surgery within 12 months. Only patients with sarcoma-typical histology codes as used for the German Cancer Society certification system were included. Patient, tumour and therapy factors as well as survival times were compared with Chi 2 -test, Kaplan Meier curves, and adjusted models., Results: 1000 (TARPSWG) and 364 (CR) patients were included. CR patients were older (median: 64 years vs. 58 years), had more high-grade tumours (FNCLCC 3 48.1% vs. 27.4%, p < 0.0001) and the 5-year survival rate was significantly lower (56.3% vs. 67.9%, p = 0.0015). The proportions of dedifferentiated liposarcoma (CR 37.1% vs. 37.0%) and leiomyosarcoma (CR 20.1% vs. 19.2%), and patterns of recurrence in these most frequent RPS subtypes were similar., Conclusion: ICD-O/ICD 10 based filters appear to be a valid tool for extracting RPS cases from CR. The similar distribution and biological behavior of distinct RPS subtypes suggests that TARPS-WG are representative, and CR data may be used to verify recommendations derived from reference centre cohorts. Complementary use of data from different sources warrants further investigation in rare cancers., Competing Interests: Declarations. Conflict of interest: The authors declare that they do not have any conflict of interest., (© 2024. The Author(s).)

Background: Peritumoral edema on staging magnetic resonance imaging (MRI) is associated with higher local recurrence in soft tissue sarcoma (STS). This may relate to the presence of satellite malignant cells that are difficult to distinguish from benign atypia, leading to over- or undertreatment. This study evaluated a novel targeted molecular approach to identify malignancy in STS peritumoral planes as a means to improve personalized care., Methods: In the targeted molecular approach, whole-exome sequencing was employed to identify tumor-specific variants (TSVs), and peritumoral planes were assayed for malignancy, defined as two or more TSVs/plane, using droplet digital polymerase chain reaction (PCR). Feasibility was evaluated using a retrospective cohort (n = 8) in which planes with cellular atypia were tested. A prospective cohort (n = 8) then assayed all peritumoral planes with radiologic edema., Results: The targeted molecular approach identified malignancy in three of eight cases with cellular atypia of unknown significance (37.5%) and five of eight cases with peritumoral edema on staging MRI (62.5%). Peritumoral regions were heterogeneous; in none of the malignant cases did all sampled planes have evidence of tumor. Malignancy was also identified in regions without cellular atypia. Both cases with a local recurrence had molecular evidence of malignancy outside the main mass despite R0 margins., Conclusion: This study describes a novel personalized approach to detect malignancy in peritumoral regions in STS and is the first to identify molecular evidence of tumor outside the main mass. While development of a clinical tool is underway, these findings support the current approach of treating all peritumoral edema as malignant., Competing Interests: Disclosure Miguel Alfonso V. Principe, Nalan Gokgoz, Patrick Prochazka, Victoria S. Coward, Sidharth Saini, Sonya MacParland, Rebecca Gladdy, Peter Ferguson, Jay S. Wunder, Irene L. Andrulis, Peter Chung, Anthony M. Griffin, Lawrence M. White, Brendan C. Dickson, and Kim M. Tsoi have no potential conflicts of interest to declare that may be relevant to the contents of this study., (© 2024. Society of Surgical Oncology.)

Background: Radiation-induced sarcomas (RIS) tend to have aggressive behaviour and because of their rarity, the most appropriate management for these malignancies is uncertain., Objectives: Using the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) database, a national sarcoma registry, we aimed to investigate prognostic factors and outcomes for RIS., Design: Retrospective study of RIS patients treated from 1996 to 2021 at three Canadian centres., Methods: RIS was defined as a sarcoma arising in a previously irradiated field following a 3+ year latency period, whose histology was distinct from the initially irradiated tumour. Clinicopathologic and treatment-related information was extracted from the CanSaRCC database. Overall survival (OS) was defined as the time from RIS diagnosis to death from any cause. Response rate (RR) to neoadjuvant chemotherapy (NACT) was based on physician assessment. Time-to-event analyses were estimated using the Kaplan-Meier method, with Cox regression for multivariate analysis. We considered a two-tailed p -value of <0.05 as statistically significant., Results: One hundred seven tumours met the criteria for RIS and were divided into three subgroups: breast angiosarcoma (BAS, n  = 54), osteosarcoma (OST, n  = 16), and other soft-tissue sarcomas (STS, n  = 37). Patients were mostly female ( n  = 85, 79%), treated initially for breast carcinomas ( n  = 54, 50.5%), and diagnosed with high-grade tumours ( n  = 61/71, 86%). None had evidence of synchronous metastasis. Patients with OST were younger (median age: 48 years, p  < 0.001), and BAS had the shortest latency interval (8 versus 18 years for OST/STS, p  < 0.001). Most patients underwent surgery, 76% ( n  = 76/100) R0; 24% ( n  = 26) received radiation therapy, mostly ( n  = 15, 57.7%) neoadjuvant. Among those receiving chemotherapy, 30 (75%) underwent NACT; among patients with documented response assessment, the RR was 68% ( n  = 17/25), being even higher in the BAS population (89.5%, n  = 13/17). Median OS was 53 months (95% CI 34-101), with a 5-year OS of 47.6%; larger tumour size, high histologic grade and older age were independent prognostic factors for worse OS., Conclusion: Surgery is standard, and NACT might be useful to downsize large lesions, especially in BAS patients. Raising RIS awareness is fundamental to promoting appropriate management and fostering research through multi-institutional collaborations., (© The Author(s), 2023.)

Mesenchymal breast tumors are a rare and diverse group of tumors that present some of the most challenging cases for multidisciplinary breast cancer teams. As a result of overlapping morphologies and a lack of large-scale studies on these tumors, practices are often heterogeneous and slow to evolve. Herein, we present a non-systematic review that focuses on progress, or lack thereof, in the field of mesenchymal breast tumors. We focus on tumors originating from fibroblastic/myofibroblastic cells and tumors originating from less common cellular origins (smooth muscle, neural tissue, adipose tissue, vascular tissue, etc.).

Among mesenchymal tumors, MAML2 gene rearrangements have been described in a subset of composite hemangioendothelioma and myxoinflammatory fibroblastic sarcoma (MIFS). However, we have recently encountered MAML2-related fusions in a group of seven undifferentiated malignant epithelioid neoplasms that do not fit well to any established pathologic entities. The patients included five males and two female, aged 41-71 years old (median 65 years). The tumors involved the deep soft tissue of extremities (hip, knee, arm, hand), abdominal wall, and the retroperitoneum. Microscopically, the tumors consisted of solid sheets of atypical epithelioid to histiocytoid cells with abundant cytoplasm. Prominent mitotic activity and necrosis were present in 4 cases. In 3 cases, the cells displayed hyperchromatic nuclei or conspicuous macronucleoli, and were admixed with background histiocytoid cells and a lymphoplasmacytic infiltrate. By immunohistochemistry (IHC), the neoplastic cells had a nonspecific phenotype. On targeted RNA sequencing, MAML2 was the 3' partner and fused to YAP1 (4 cases), ARHGAP42 (2 cases), and ENDOD1 (1 case). Two cases with YAP1::MAML2 harbored concurrent RAF kinase fusions (RBMS3::RAF1 and AGK::BRAF, respectively). In 2 cases with targeted DNA sequencing, mutations in TP53, RB1 and PTEN were detected in 1 case, and PDGFRB mutations, CCNE1 amplifications and CDKN2A/2B deletion were detected in another case, which showed strong and diffuse PDGFRB expression by IHC. Of the 4 cases with detailed clinical history (median follow-up period 8 months), three developed distant metastatic disease (one of which died of disease); one case remained free of disease 3 years following surgical excision. In conclusion, we describe a heterogeneous series of MAML2-rearranged undifferentiated malignant epithelioid neoplasms, a subset of which may overlap with a recently described MIFS variant with YAP1::MAML2 fusions, further expanding the clinicopathologic spectrum of mesenchymal neoplasms with recurrent MAML2 gene rearrangements., (© 2022 Wiley Periodicals LLC.)

Background: Regional lymph node metastasis (RLNM) occurs infrequently in patients with soft tissue sarcoma (STS), although certain STS subtypes have a higher propensity for RLNM. The identification of RLNM has significant implications for staging and prognosis; however, the precise impact of node-positive disease on patient survival remains a topic of controversy. Although the benefits of sentinel lymph node biopsy (SLNB) are well documented in patients with melanoma and breast cancer, whether this procedure offers a benefit in STS is controversial., Methods: A systematic literature search was performed and articles reviewed to determine if SLNB in patients with extremity/truncal STS impacts disease-free or overall survival., Results: Six studies were included. Rates of sentinel lymph node positivity were heterogeneous (range 4.3-50%). The impact of SLNB on patient outcomes remains unclear. The overall quality of available evidence was low, as assessed by the Grading of Recommendations, Assessment, Development, and Evaluation system., Conclusions: The literature addressing the impact of nodal basin evaluation on the staging and management of patients with extremity/truncal STS is confounded by heterogeneous patient cohorts and clinical practices. Multicenter prospective studies are warranted to determine the true incidence of RLNM and whether SLNB could benefit patients with clinically occult RLNM at diagnosis., (© 2022. Society of Surgical Oncology.)

When decellularizing kidneys, it is important to maintain the integrity of the acellular extracellular matrix (ECM), including associated adhesion proteins and growth factors that allow recellularized cells to adhere and migrate according to ECM specificity. Kidney decellularization requires the ionic detergent sodium dodecyl sulfate (SDS); however, this results in a loss of ECM proteins important for cell adherence, migration, and growth, particularly glycosaminoglycan (GAG)-associated proteins. Here, we demonstrate that using submicellar concentrations of SDS results in a greater retention of structural proteins, GAGs, growth factors, and cytokines. When porcine kidney ECM scaffolds were recellularized using human adult primary renal epithelial cells (RECs), the ECM promoted cell survival and the uniform distribution of cells throughout the ECM. Cells maintained the expression of mature renal epithelial markers but did not organize on the ECM, indicating that mature cells are unable to migrate to specific locations on ECM scaffolds.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication., Competing Interests: Disclosure SS: Honoraria, consultancy or advisory role: Adaptimmune, Bayer, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, Immune Design, Karyopharm, MaxiVAX, Novartis, PharmaMar; Institutional financial interests: Advenchen, Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Glaxo, Hutchison MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks. AMF: Institutional financial interests: Advenchen, Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Glaxo, Hutchison MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks. AC: Advisory board: Angelini Holding S.p.A, Shionogi B.V., L. Molteni & C., Kyowa Kirin S.r.l.; invited speaker King Faisal Specialist Hospital & Research Center. JB: Uncompensated advisory board: Novartis; research funding (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis Co. Ltd, Paxman Coolers Ltd, Sun Pharma. SB: Personal fees from Bayer, Deciphera, Lilly, Daiichi Sankyo, Plexxikon, Exelixis, PharmaMar, Lilly, Roche, GlaxoSmithKline (GSK); grants from Incyte, grants and personal fees from Blueprint Medicines, Novartis; research funding (institutional) Pfizer. SB: Research support from Novartis, Incyte, Blueprint Medicines; honoraria or consultation fees from Novartis, Lilly, Pfizer, PharmaMar, Bayer. JYB: Research support and honoraria from Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Roche, Bayer, Novartis, GSK, Deciphera, OSE Pharma, AstraZeneca. Member of the supervisory board: Innate Pharma. SB: Honoraria from PharmaMar. JVMGB: Research funding from TRACON Pharmaceuticals; Royalties from UptoDate and Wolters Kluwer. KB: Advisory: Bayer; expert testimony: Bayer; invited speaker: Lilly; institutional research funding: Lilly. TB: Advisory board from Bayer; honoraria: Novartis, PharmaMar, Eli Lilly. ME: Consultant for Blueprint Medicines; advisory boards for Clinigen and Bayer. AF; Honoraria: Amgen, Lilly, Roche, MSD; research funding; MSD, Roche, Clovis, AstraZeneca. BMS; Abbvie. VF: Consulting or advisory role: BMS, MSD, Novartis; speakers' bureau: BMS, MSD, Novartis, Pierre Fabre. XGdM: Advisory boards for Ipsen, EUSA Pharma, BMS, Pfizer, Roche, PharmaMar; honoraria from Lilly, Astellas Pharma, Eisai, Pfizer. HG: Reports institutional funding from Novartis, Deciphera. FG: Honoraria from Deciphera, Amgen; stock ownership from Atlanthera; royalties from Zimmer. GG: Grants/research supports: PharmaMar, Novartis, Bayer; honoraria or consultation fees: PharmaMar, Bayer, Merck, Eisai, Novartis, Glaxo. NH: Research grants from PharmaMar, Eisai, Immix BioPharma and Novartis; honoraria and travel grants from PharmaMar; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Adaptimmune Therapeutics, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. PH: Honoraria for consultations and speaker's fees from Roche, GSK, AstraZeneca, Pfizer, PharmaMar, Lilly, Nanobiotix, Novartis, EISAI, Nektar, Sirtex and Pekkip Oncology; research funding and educational grants from Novartis, Siemens, Boehringer, Merck, BLUMedicine and Springer; trial support to my institution by Novartis and Siemens. PH: Advisory roles for Sarcoma UK and National Leiomyosarcoma Foundation; research grants from Sarcoma UK, Desmoid Tumor Research Foundation, Children's Cancer and Leukemia Group and Cancer Research UK, funding from EHE Rare Cancer Charity (UK). HJ: Chair of the Orion Pharma Scientific Advisory Board, chair of Neutron Therapeutics Advisory Board; he has been employed by Orion Pharma, and owns stocks of Orion Pharma and Sartar Therapeutics. RJ: Advisory board Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immune Design, Lilly, Merck, PharmaMar, SpringWorks, TRACON, UptoDate; honoraria: BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi. CJ: Travel grants from PharmaMar, Ipsen. BK: Reports advisory board Bayer, Blueprint, Boehringer Ingelheim, GSK, PharmaMar, SpringWorks; research funding (institutional) PharmaMar, SpringWorks. AK: Advisory board Otsuka; invited speaker for Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Taiho. ALC: Advisory boards with Lilly, PharmaMar, Deciphera, Blueprint. AL: Reports institutional financial interest, and educational grant from Alphamed, ImplanTec, Johnson & Johnson, Medacta. JMB: Research grants from PharmaMar, Eisai, Immix BioPharma and Novartis; honoraria from PharmaMar, Lilly, Bayer, Eisai, Daichii. Travel grants from PharmaMar; advisory board: Roche, Lilly, PharmaMar; research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Adaptimmune Therapeutics, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen, Celgene, Pfizer, BMS, and Daiichi Sankyo. OMe: Consultation fees from MSD, AstraZeneca, Takeda, Megapharm, Medison, Progenetics; supported lecture: MSD, AstraZeneca, Roche, BMS. OMi: Consultancy for Amgen, AstraZeneca, Bayer, BMS, Eli Lilly, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor Pharma; Speakers bureau: Eli Lilly, Roche, Servier; Stock ownership: Amplitude Surgical, Ipsen, Transgene. EP: Advisory boards for Amgen, Daiichi Sankyo, Lilly, Deciphera, EUSA Pharma, and SynOx Therapeutics; research support from BMS, Pfizer, PharmaMar, Daiichi Sankyo, Incyte; travel support from Lilly, PharmaMar and Takeda. MAP: Advisory board Lilly, Pfizer, Roche. SP: Consultant: Deciphera, Daichi Sankyo, Dova, Epizyme, MaxiVAX; Research/Grant Support: Blueprint Medicines, Hutchison MediPharma. SPN: Advisory board for Immunocore. AR: Consulting role with Lilly, Merck, Boehringer Ingelheim; research funding from CASI Pharmaceuticals, Boehringer Ingelheim, Lilly, Novartis, Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, Boston Biomedical, BMS, MedImmune, Amgen, GSK, Blueprint Medicines, Merck, AbbVie, Adaptimmune. PRe: Advisory roles for Bayer, Clinigen, Roche, MSD, Deciphera, PharmaMar, Mundibiopharma, and speaker's honoraria from Lilly, PharmaMar. BPR: Reports advisory board from Deciphera. PRu: Advisory board MSD, BMS, Merck, Sanofi, Pierre Fabre, Blueprint Medicines; honoraria from BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi. MS: Travel grant from PharmaMar. SJS: Advisory boards for Lilly and GSK. WDT: Reports fees from Eli Lilly, EMD Serono, Eisai, Mundipharma, C4 Therapeutics, Daiichi Sankyo, Blueprint, GSK, Agios Pharmaceuticals, NanoCarrier, Deciphera; patent Companion Diagnostic for CDK4 inhibitors - 14/854 329 pending to MSKCC/SKI, and patent Enigma and CDH18 as companion Diagnostics for CDK4 inhibition – SKI2016-021-03 pending to MSKCC/SKI and Scientific Advisory Board - Certis Oncology Solutions, Stock Ownership Üo-Founder - Atropos Therapeutics; Stock Ownership/scientific advisory board Innova Therapeutics. WTAWDG: Reports consultancy from SpringWorks to her institute; research grant support from Novartis and Lilly to her institute; advisory for Bayer to her institute. AJW: Consulting: Daiichi Sankyo, Deciphera, Epizyme, Mundipharma; research support to my Institution: Aadi Bioscience, Daiichi Sankyo, Deciphera, Eli Lilly, Karyopharm, Plexxikon. PGC: Honoraria, consultancy or advisory role: Bayer, Deciphera, Eisai, Eli Lilly, Pfizer. Institutional financial interest: Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme, Glaxo, Hutchinson MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar. APDT: Honoraria: Roche, Bayer, Pharmamar, MSD. AG: Compensations for Advisory boards from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, Nanobiotix; honoraria from Lilly and PharmaMar; institutional research grants from PharmaMar. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Desmoid-type fibromatosis represents a challenge in the landscape of surgical oncology, for several reasons. The tumors can be infiltrative and locally aggressive, surgery may be morbid, and patients are usually young, and thus treatment sequelae must be managed for decades. Desmoids do not have metastatic potential, therefore management strategies for desmoids have evolved to employ frontline treatments that are largely non-operative. In fact, with unpredictable and benign behavior, we now recognize that desmoids can also stabilize and regress, making active observation an option for many patients. Moreover, many medical therapies are active in the disease. We reviewed landmark studies describing contemporary issues that affect treatment recommendations for desmoid patients: prognostic factors, indication to active surveillance, role of surgical margins, postoperative radiotherapy, and the most recent expert consensus papers.

Background: Primary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function., Objectives: To determine the overall survival (OS) and recurrence-free survival (RFS) for patients undergoing primary resection for mesenteric STS., Methods: The Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019., Results: Fifty-six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher-grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery., Conclusion: Primary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging., (© 2020 Wiley Periodicals LLC.)

The coronavirus disease-2019 (COVID-19) pandemic is deeply impacting the accessibility of cancer patients to surgery. In resource-limited conditions, the standard of care might not be deliverable, but evidence to support alternative management strategies often exists. By revisiting available treatment options, this review provides surgical oncologists with an evidence-based framework for treating patients with gastrointestinal stromal tumor, extremity/truncal soft tissue sarcoma, and retroperitoneal sarcoma to rapidly adapt their decision-making to the constant evolution of the COVID-19 pandemic., (© 2020 Wiley Periodicals LLC.)

Objective: Clinical experience suggests a high prevalence of emotional distress in patients with desmoid tumor (DT). We examine longitudinal Distress Assessment and Response Tool (DART) scores to estimate prevalence and persistence of distress, and compare cross-sectional data between DT and malignant sarcoma cohorts, to identify predictors of distress., Methods: Patients with DT completed DART at: T1-diagnosis, T2-during, T3-<6 months, and T4-≥6 months, post-treatment. DART includes patient-reported outcome measures of physical symptoms (ESAS-r), depression (PHQ-9), anxiety (GAD-7), and social difficulties (SDI-21). Descriptive prevalence and persistence of anxiety, depression, and wellbeing are reported, and mixed model regression analyses determine predictors of distress., Results: Between 2012 and 2018, a total of 152 DART screens from 94 patients with DT were completed (T1: n = 44, T2: n = 31, T3: n = 22, T4: n = 55). Patients had a mean age 40 years, 78% were female and DT locations were abdominal wall (48%), extremity (30%), and mesentery (22%). Moderate to severe ESAS-r scores (≥4) persisted at T4 for anxiety (20%), depression (13%), and poor wellbeing (31%). Compared to 402 patients with malignant sarcoma, patients with abdominal wall sited DT reported severe PHQ-9 and GAD-7 scores twice as frequently. Abdominal wall location, female sex, history of mood problems, and psychosocial concerns were significant predictors of anxiety, depression, and poor wellbeing in DT., Conclusions: Adults with DT experience persistently high emotional distress compared to patients with malignant sarcoma. Women with abdominal wall DT, prior mood, and current psychosocial concerns need early attention within multidisciplinary treatment settings to reduce persistent distress., (© 2019 John Wiley & Sons, Ltd.)

Background: The current study investigated the role of radiotherapy (RT) in patients with primary nonmetastatic retroperitoneal liposarcomas., Methods: A total of 607 patients with localized retroperitoneal well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS) underwent surgical resection with or without RT at 8 high-volume sarcoma centers (234 patients with WDLPS, 242 patients with grade 1 to 2 DDLPS, and 131 patients with grade 3 DDLPS; grading was performed according to the National Federation of Centers for the Fight Against Cancer [Federation Nationale des Centres de Lutte Contre le Cancer; FNCLCC]). RT was administered in 19.7%, 34.7%, and 35.1%, respectively, of these 3 cohorts. Overall survival (OS) was estimated using the Kaplan-Meier method, and the incidences of local recurrence and distant metastasis (DM) were estimated in a competing risk framework. To account for bias consistent with nonrandom RT assignment, propensity scores were estimated. Cox univariable analysis of the association between RT and oncological endpoints was performed by applying inverse probability of treatment weighting (IPTW) using propensity scores., Results: Age, tumor size, and the administration of chemotherapy were found to be significantly imbalanced between patients who did and did not undergo RT in all cohorts. IPTW largely removed imbalances in key prognostic variables. Although the 8-year local recurrence incidences in patients treated with surgery plus RT versus surgery only were 11.8% and 39.2%, respectively, for patients with WDLPS (P = .011;); 29.0% and 56.7%, respectively, for patients with grade 1 to 2 DDLPS (P = .008); and 29.8% and 43.7%, respectively, for patients with grade 3 DDLPS (P = .025), this significant benefit was lost after IPTW analyses. There were no significant differences noted with regard to DM and OS between irradiated and unirradiated patients across all 3 cohorts., Conclusions: Perioperative RT was found to be associated with better local control in univariable unadjusted analysis in all 3 cohorts, but not after accounting for imbalances in prognostic variables. RT did not impact on DM or OS. The appropriate selection of RT in this disease remains challenging. The results of the European Organization for Research and Treatment of Cancer (EORTC)-Soft Tissue and Bone Sarcoma Group (STBSG) 62092-22092 prospective randomized trial are awaited., (© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Terminal differentiation opposes proliferation in the vast majority of tissue types. As a result, loss of lineage differentiation is a hallmark of aggressive cancers, including soft tissue sarcomas (STS). Consistent with these observations, undifferentiated pleomorphic sarcoma (UPS), an STS subtype devoid of lineage markers, is among the most lethal sarcomas in adults. Though tissue-specific features are lost in these mesenchymal tumors they are most commonly diagnosed in skeletal muscle, and are thought to develop from transformed muscle progenitor cells. We have found that a combination of HDAC (Vorinostat) and BET bromodomain (JQ1) inhibition partially restores differentiation to skeletal muscle UPS cells and tissues, enforcing a myoblast-like identity. Importantly, differentiation is partially contingent upon downregulation of the Hippo pathway transcriptional effector Yes-associated protein 1 (YAP1) and nuclear factor (NF)-κB. Previously, we observed that Vorinostat/JQ1 inactivates YAP1 and restores oscillation of NF-κB in differentiating myoblasts. These effects correlate with reduced tumorigenesis, and enhanced differentiation. However, the mechanisms by which the Hippo/NF-κB axis impact differentiation remained unknown. Here, we report that YAP1 and NF-κB activity suppress circadian clock function, inhibiting differentiation and promoting proliferation. In most tissues, clock activation is antagonized by the unfolded protein response (UPR). However, skeletal muscle differentiation requires both Clock and UPR activity, suggesting the molecular link between them is unique in muscle. In skeletal muscle-derived UPS, we observed that YAP1 suppresses PERK and ATF6-mediated UPR target expression as well as clock genes. These pathways govern metabolic processes, including autophagy, and their disruption shifts metabolism toward cancer cell-associated glycolysis and hyper-proliferation. Treatment with Vorinostat/JQ1 inhibited glycolysis/MTOR signaling, activated the clock, and upregulated the UPR and autophagy via inhibition of YAP1/NF-κB. These findings support the use of epigenetic modulators to treat human UPS. In addition, we identify specific autophagy, UPR, and muscle differentiation-associated genes as potential biomarkers of treatment efficacy and differentiation.

Purpose: Retroperitoneal sarcomas (RPS) are connective tissue cancers that are often large and anatomically in close proximity to critical and radiation-sensitive normal structures and organs within the abdomen and pelvis. The management of RPS may include preoperative radiotherapy (RT) and surgery. We aimed to examine how treatment-related toxicities affect patient quality of life (QOL).  Methods and materials: Within two prospective cohort studies, 48 RPS patients who were treated with preoperative RT from 1998-2012 were recruited and assessed for QOL (EORTC-QLQ-C30) and to determine toxicities potentially related to RT and surgery (graded using CTCAE V.4). Baseline and prospective QOL was available for 11 patients. In the other 37 patients, prospective data were obtained at different time points during their follow-up. Unless stated otherwise, all scores refer to the global QOL subscale., Results: The patients' median age was 57 (38-82) and RT was administered to a median dose of 45 Gy (41.4-50.4). The median maximum tumor dimension was 16.0 cm (5.7-28) and the majority (35/48) were liposarcomas. The mean pre-RT QOL was 48.5/100. At one month post-RT, the mean QOL improved to 54.2; however, the mean diarrhea symptom scale worsened from baseline (78.3 vs. 18.2, p<0.001). Correspondingly, 54% of patients had gastrointestinal toxicities (92% G1-2 and 8% G3) by the end of RT. At 36 months post-RT, 88% of patients had chronic toxicities (19% G3). RPS patients who survived and are free of recurrence ≥ 36 months had significantly (mean: 75.0; p=0.001) better QOL than at diagnosis. The number of toxicities was significantly (p=0.001) associated with QOL. RT dose, tumor size, patient age, and patient gender were not associated with 36-month QOL.  Conclusions: Treatment toxicities seem to contribute to QOL recovery during the first 36 months. QOL at 36 months was better than at diagnosis., Competing Interests: The authors have declared financial relationships, which are detailed in the next section.

Liposarcoma is an often fatal cancer of fat cells. Mechanisms of liposarcoma development are incompletely understood. The cleavage of fatty acids from acylglycerols (lipolysis) has been implicated in cancer. We generated mice with adipose tissue deficiency of two major enzymes of lipolysis, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), encoded respectively by Pnpla2 and Lipe. Adipocytes from double adipose knockout (DAKO) mice, deficient in both ATGL and HSL, showed near-complete deficiency of lipolysis. All DAKO mice developed liposarcoma between 11 and 14 months of age. No tumors occurred in single knockout or control mice. The transcriptome of DAKO adipose tissue showed marked differences from single knockout and normal controls as early as 3 months. Gpnmb and G0s2 were among the most highly dysregulated genes in premalignant and malignant DAKO adipose tissue, suggesting a potential utility as early markers of the disease. Similar changes of GPNMB and G0S2 expression were present in a human liposarcoma database. These results show that a previously-unknown, fully penetrant epistatic interaction between Pnpla2 and Lipe can cause liposarcoma in mice. DAKO mice provide a promising model for studying early premalignant changes that lead to late-onset malignant disease.

Introduction: Desmoplastic small round cell tumor (DSRCT) is a rare mesenchymal malignancy. We describe our experience with treating DSRCT at a large sarcoma referral center., Methods: A retrospective chart review was performed on DSRCT patients referred to our institution (1998-2014). Pathology specimens were reviewed to confirm the diagnosis. Clinical and imaging were extracted and summarized with descriptive statistics. Univariate analysis was performed to evaluate the association between patient, tumor, and treatment variables and overall survival (OS)., Results: In this study cohort of 20 patients, median age at presentation was 29 y (range 18-43) and 90% were male. Fifty-five percent presented with metastasis. Patients underwent chemotherapy (n = 20), radiation therapy (n = 3), and cytoreductive surgery (CRS) (n = 5). Median OS was 22 m (interquartile range: 12-28 m). Five-year OS rate was 20%. Extra-abdominal metastasis was associated with a higher hazard ratio (HR) of mortality (HR: 3.1, 95% C.I. 1.0-9.4, p = 0.04), while CRS improved OS (HR: 0.1, 95% C.I. 0.03-0.7, p = 0.02)., Conclusions: Despite aggressive treatment, less than half of the patients were dead of DSRCT within 2 years of presentation. Although a select group of patients who underwent CRS had improved OS, novel treatments are urgently needed., (Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

A common and aggressive subtype of soft-tissue sarcoma, undifferentiated pleomorphic sarcoma (UPS) was examined to determine the role of micro-RNAs (miRNAs) in modulating distant metastasis. Following histopathologic review, 110 fresh frozen clinically annotated UPS samples were divided into two independent cohorts for Training (42 patients), and Validation (68 patients) analyses. Global miRNA profiling on the Training Set and functional analysis in vitro suggested that miRNA-138 and its downstream RHO-ROCK cell adhesion pathway was a convergent target of miRNAs associated with the development of metastasis. A six-miRNA signature set prognostic of distant metastasis-free survival (DMFS) was developed from Training Set miRNA expression values. Using the six-miRNA signature, patients were successfully categorized into high- and low-risk groups for DMFS in an independent Validation Set, with a hazard ratio (HR) of 2.25 (p = 0.048). After adjusting for other known prognostic variables such as age, gender, tumor grade, size, depth, and treatment with radiotherapy, the six-miRNA signature retained prognostic value with a HR of 3.46 (p < 0.001). A prognostic miRNA biomarker for clinical validation was thus identified along with a functional pathway that modulates UPS metastatic phenotype.

Metastasis causes most cancer deaths, but is incompletely understood. MicroRNAs can regulate metastasis, but it is not known whether a single miRNA can regulate metastasis in primary cancer models in vivo. We compared the expression of miRNAs in metastatic and nonmetastatic primary mouse sarcomas and found that microRNA-182 (miR-182) was markedly overexpressed in some tumors that metastasized to the lungs. By utilizing genetically engineered mice with either deletion of or overexpression of miR-182 in primary sarcomas, we discovered that deletion of miR-182 substantially decreased, while overexpression of miR-182 considerably increased, the rate of lung metastasis after amputation of the tumor-bearing limb. Additionally, deletion of miR-182 decreased circulating tumor cells (CTCs), while overexpression of miR-182 increased CTCs, suggesting that miR-182 regulates intravasation of cancer cells into the circulation. We identified 4 miR-182 targets that inhibit either the migration of tumor cells or the degradation of the extracellular matrix. Notably, restoration of any of these targets in isolation did not alter the metastatic potential of sarcoma cells injected orthotopically, but the simultaneous restoration of all 4 targets together substantially decreased the number of metastases. These results demonstrate that a single miRNA can regulate metastasis of primary tumors in vivo by coordinated regulation of multiple genes.

Purpose: To determine the positional and volumetric changes of retroperitoneal sarcomas (RPS) during pre-operative external beam radiotherapy (PreRT)., Material and Methods: After excluding 2 patients who received chemotherapy prior to PreRT and 15 RPS that were larger than the field-of-view of cone-beam CT (CBCT), the positional and volumetric changes of RPS throughout PreRT were characterized in 19 patients treated with IMRT using CBCT image guidance. Analysis was performed on 118 CBCT images representing one image per week of those acquired daily during treatment. Intra-fraction breathing motions of the gross tumor volume (GTV) and kidneys were measured in 22 RPS patients simulated using 4D-CT. Fifteen other patients were excluded whose tumors were incompletely imaged on CBCT or who received pre-RT chemotherapy., Results: A GTV volumetric increase (mean: 6.6%, p=0.035) during the first 2 weeks (CBCT1 vs. CBCT2) of treatment was followed by GTV volumetric decrease (mean: 4%, p=0.009) by completion of radiotherapy (CBCT1 vs. CBCT6). Internal margins of 8.6, 15 and 15 mm in the lateral, anterior/posterior and superior/inferior directions would be required to account for inter-fraction displacements. The extent of GTV respiratory motion was significantly (p<0.0001) correlated with more superiorly positioned tumors., Conclusion: Inter-fraction CBCT provides important volumetric and positional information of RPS which may improve PreRT quality and prompt re-planning. Planning target volume may be reduced using online soft-tissue matching to account for interfractional displacements of GTVs. Important breathing motion occurred in superiorly placed RPS supporting the utility of 4D-CT planning., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life-threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed., Methods: A panel of 20 functional candidate polymorphisms in genes involved in the opioid biotransformation pathway (CYP2D6, UGT2B7, ABCB1, OPRM1, COMT) were genotyped in these two patients using commercially available genotyping assays., Results: In case 1, the patient experienced adverse outcomes when administered codeine and morphine, but not hydromorphone. Genetic test results suggested that this differential response may be due to an inherent propensity to generate active metabolites from both codeine and morphine. These active metabolites are not generated with hydromorphone. In case 2, the patient experienced severe respiratory depression during postoperative recovery following standard doses of morphine. The patient was found to carry genetic variations that result in decreased morphine efflux transporter activity at the blood-brain barrier and increased sensitivity to opioids., Conclusions: Knowledge of the relative contribution of pharmacogenetic biomarkers and their influence on opioid response are continually evolving. Pharmacogenetic analysis, together with clinical history, has the potential to provide mechanistic insight into severe respiratory depressive events in patients who receive opioids at therapeutic doses.

Chondrosarcoma is a unique type of bone cancer in that it does not respond to chemotherapy or radiation therapy, and therefore many affected patients die from metastatic disease. Metastasis has been correlated with the upregulation of the matrix metalloproteinase (MMP) family of proteases, which can degrade extracellular components. ETV5 is a transcription factor which has shown to be overexpressed in various types of invasive tumors. We hypothesized that ETV5 regulates MMP2 in human chondrosarcoma with the protease acting as a downstream effector. Gene knock-down of ETV5 in human chondrosarcoma cells reduces MMP2 mRNA expression as well as decreased protein production and significantly decreased MMP2 activity. With plasmid transfected ETV5 upregulation, MMP2 expression is similarly upregulated at the gene expression and protein levels. Data from our bone resorption studies revealed that when a matrix metalloproteinase-2 inhibitor is added to the growth media of chondrosarcoma cells, collagen released from bone chips incubated with the cells decreased by 27%. This data suggests that ETV5 has a significant role in regulating MMP2 expression and therefore matrix resorption in human chondrosarcoma, and thus may be a targetable upstream effector of the metastatic cascade in this cancer., (Copyright © 2012 Orthopaedic Research Society.)

Background: Positive peritoneal fluid cytology predicts poor outcome in patients with resected pancreatic cancer. Reverse transcription-polymerase chain reaction (RT-PCR) has been proposed as a more sensitive means of detection of peritoneal micrometastases than conventional cytology. The clinical significance of RT-PCR positivity in the absence of other evidence of peritoneal disease is unknown. The purpose of the current study was to determine the outcome RT-PCR positive/cytology-negative patients who underwent potentially curative resection., Methods: Peritoneal washings were collected prospectively from 115 patients with pancreatic cancer undergoing diagnostic laparoscopy at a single institution. Specimens were analyzed by a cytopathologist and by RT-PCR for carcinoembryonic antigen (CEA)., Results: Of the 115 patients, 62 (54%) underwent R0 resection. Eleven of the 62 patients (18%) had peritoneal washings that were negative by conventional cytology but positive for CEA by RT-PCR. Those 11 patients experienced early peritoneal and overall disease recurrence versus those who were RT-PCR negative (P = 0.001, P = 0.003, respectively) independent of nodal status., Conclusions: RT-PCR for CEA is a sensitive and specific method for the detection of clinically significant peritoneal micrometastases from pancreatic cancer and it might identify a subgroup of patients with otherwise negative findings at staging laparoscopy who might respond better to treatment other than primary surgical resection.

Background: Transplant immunosuppression regimen facilitates successful adenovirus-mediated gene transfection and retransfection in the rat lung. Herein, we investigated the effect of this strategy on circulating cytokines and antiadenoviral immunoglobin G antibody., Methods: Male Lewis rats were transfected with 1 x 10(9) pfu/mL of E1-deleted Ad5CMVLacZ vector transtracheally. Rats were randomly assigned to receive daily intraperitoneal triple immunosuppression regimen consisting of cyclosporine (15 mg/kg per day), azathioprine (6 mg/kg per day), and methylprednisolone (2.5 mg/kg per day), or normal saline solution. Retransfection was performed 35 days later to all nonimmunosuppressed animals, whereas immunosuppressed rats were further randomized to receive retransfection or phosphate-buffered saline. Animals were sacrificed on days 1, 2, 7, 35, 42, and 49 after the initial transfection. Beta-galactosidase activity was measured on lung homogenates. Interferon-gamma, tumor necrosis factor-alpha, and antiadenoviral immunoglobin G were measured from the serum., Results: Enhanced and prolonged transgene expression was observed in immunosuppressed animals, especially after retransfection. Concentrations of serum tumor necrosis factor-alpha in both groups were less than 12 pg/mL throughout the study. A significant increase in serum interferon-gamma levels was observed in nonimmunosuppressed animals after retransfection; this was not seen in the immunosuppressed animals. Serum antiadenoviral immunoglobin G titers in both groups were sharply elevated on day 1, and declined to basal levels by day 7, reflecting a preexisting level of humoral immunity to adenovirus. The titer in nonimmunosuppressed rats was significantly increased after retransfection, but remained at very low level in immunosuppressed animals., Conclusions: Inhibition of interferon-gamma and antiadenoviral immunoglobin G production by triple immunosuppressants may be part of the mechanisms that lead to enhanced and prolonged transgene expression after retransfection.

A retrospective review of 100 liver transplantations in 98 children was performed to determine the incidence of infection caused by Candida organism in these patients and to identify risk factors that may predispose to serious fungal infection. Thirty-one infections caused by Candida organisms developed during the initial 28 days posttransplantation: 19 were definite invasive infections (one deep site or one positive blood culture), 2 were probable invasive infections (three superficial sites), and 10 were urinary tract infections. Eleven of 19 patients had fungemia or a disseminated infection (two noncontiguous deep organs involved and/or positive blood cultures) and 8 of 19 had peritoneal candidiasis. Infection caused by Candida organisms was a contributing factor to mortality in 7 of 21 patients (case fatality rate of 33%) with invasive infection. Risk factors that were predictive for invasive infection by univariate analysis included the following: pretransplantation antibiotic therapy, length of transplant operation, transfusion requirement, number of days in the intensive care unit, number of days intubated, number of concurrent bacterial infections, number of antibiotics administered, number of laparotomies performed posttransplantation, retransplantation, hepatic artery thrombosis, bile leaks, and renal and respiratory failure. By logistic regression analysis, bile leak, hepatic artery thrombosis, preoperative steroid use, transfusion requirement, and the number of days intubated were identified as independent risk factors for invasive infection caused by Candida organisms. The use of prophylactic antifungal agents in high-risk patients may be important in reducing the serious morbidity and mortality associated with sepsis caused by Candida organisms in pediatric liver transplant recipients.