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Background Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. Methods To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1 , BRCA2 , ATM , BARD1 , BRIP1 , CHEK1 , CHEK2 , FANCA , FANCB , FANCC , FANCD2 , FANCE , FANCF , FANCG , FANCI , FANCL , FANCM , NBN , PALB2 , RAD51C , RAD51D , RAD50 , and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. Clinical Report and Results We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n  = 193) displayed 9 of all 31 BRCA2 alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2 alt (4.66%; q  < 0.001). All of 9 BRCA2 alt were represented by homDel, which related to a high fraction of genome altered. Conclusion uLMS displays a significant frequency of somatic BRCA2 alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations. [ABSTRACT FROM AUTHOR]

Background: Bone and soft-tissue sarcoma are rare tumors. Complementary and alternative medicine (CAM) is often used in cancer patients however limited data are available in sarcoma patients. The aim of the present study is to explore the use of CAM in patients with bone and soft-tissue sarcoma.Methods: Patients in follow-up visit for high grade bone or soft-tissue sarcoma at the Rizzoli outpatient clinic from September 1, 2014, to December 31, 2015, were asked, after written consent, to fill out a questionnaire with items pertaining to sociodemographic factors and their use of CAM before, during, or after chemotherapy.Results: Four hundred and sixty-nine participated to the survey: 409 were adults and 60 were <18 years old. The percentage of use of CAM in adults was 44.7% and in minors 38.3%. The most common type of CAM was vitamins and minerals, followed by phytotherapy and homeopathy. The majority of patients used CAM after the sarcoma diagnosis. None used CAM alone instead of conventional chemotherapy. Benefits from use of CAM were reported by 75% of patients (some benefit in 53% plus high benefit in others 22%) and side effects in 6.7%. A significant correlation was found with CAM use and female gender, young age (18-44) and higher education. Disclosure to the oncologist was 56% and 69% to their family doctors.Conclusions: This study shows that CAM use is frequent among adults and pediatric patients with bone and soft tissue sarcoma as in other cancer patients. Moreover, the profile of these Italian CAM consumers in sarcoma patients is similar to other studies. Patients disclosure to their oncologist or physician about the use of CAM was similar to other Italian studies, but higher compared to other international studies. [ABSTRACT FROM AUTHOR]

Systemic treatments for advanced soft tissue sarcoma are limited. Eribulin showed activity in metastatic soft tissue sarcoma, particularly liposarcomas. Data from six patients with advanced liposarcoma that received eribulin as third- or fourth-line therapy are presented herein. Eribulin treatment was well tolerated; no grade 3–4 toxicity or therapy delay was observed. Two patients had a partial response; four had a prolonged stable disease. The first case, with pre-existing chronic renal dysfunction, achieved a 6-month stable disease with dose-reduced eribulin. The second case became resectable after eribulin treatment, with a 6-month complete surgical remission. The third case obtained a 7-month stable disease with eribulin and stereotactic body radiotherapy. The last three cases were ≥65 years old, and two of them had objective response with eribulin. [ABSTRACT FROM AUTHOR]

Introduction: The heterogeneity of soft tissue sarcomas (STS) presents a formidable management challenge. Consequently, one of the main research goals is to define specific tailored therapy for each histological subtype and to develop a more personalised approach to treatment. The standard first line chemotherapy for advanced STS is doxorubicin, with or without ifosfamide, however, a number of different drugs are emerging as active therapies beyond first-line. Areas covered: Eribulin has recently been approved for advanced liposarcoma, after an anthracycline-containing regimen, demonstrating an overall survival (OS) advantage in liposarcoma and leiomyosarcoma in a randomised Phase III clinical trial. In this manuscript, an overview of the efficacy and safety of eribulin in STS is presented, highlighting different clinical outcomes between histological subtypes and comparing data with other effective drugs used in the treatment of sarcomas. The potential mechanisms of action of eribulin are also described, including its activity as potent microtubule-destabilizing anticancer agent, which has other antitumor biological effects. Expert commentary: Eribulin is highly effective in some STS populations and also has an acceptable toxicity profile. Further studies are required to better understand the precise mechanism of action of this agent and potential role in combination schedules. [ABSTRACT FROM AUTHOR]

This study designs a strategy for an adoptive cellular therapy (ACT) protocol based on the ex-vivo selection of autologous peripheral blood-derived CD8-enriched T-cells, stimulated with dendritic cells (DCs) that had been pulsed with apoptotic tumor cells to generate cytotoxic T lymphocytes (CTLs) with anti-tumor activity. Seventy-eight colorectal cancer (CRC) patients were enrolled in this study. Tumor tissues and peripheral blood (PB) were obtained at surgery. Tissues were mechanically dissociated and cultured to obtain a primary tumor cell line from each patient. DCs were derived from peripheral blood mononuclear cells (PBMCs) using magnetic positive selection of CD14+ monocytes. Anti-tumor CTLs were elicited in co-/micro-cultures using DCs as antigen-presenting cells, autologous apoptotic tumor cells as a source of antigens, and CD8+ T lymphocytes as effectors. Interferon-γ (IFN-γ) secretion was assessed by ELISpot assays to evaluate the activation of the CTLs against the autologous tumor cells. Primary tumor cell lines were obtained from 20 of 78 patients (25.6%). DCs were generated from 26 patients, and of them, corresponding tumor cell lines were derived from six patients. ELISpot results showed that significant IFN-γ secretion was detected after different numbers of stimulations for two patients, whereas weak secretion was observed for three patients. Despite difficulties due to contamination of several primary tumor cell lines with gut intestinal flora, the results suggest that the generation of tumor-specific CTLs is feasible from patients with CRC, and could be useful for supporting an ACT approach in CRC. J. Cell. Physiol. 230: 1457-1465, 2015. © 2015 Wiley Periodicals, Inc., A Wiley Company [ABSTRACT FROM AUTHOR]

Summary: While surgery remains the cornerstone of treatment of bone and soft tissue sarcomas, chemotherapy has improved the 5-year overall survival in osteosarcoma and Ewing''s sarcoma from 10% to 70% in localized disease. Patients with metastases at presentation treated with surgery combined with chemotherapy have a 3-year survival of 30–50%, but cure is still rare. The role of adjuvant chemotherapy in soft tissue sarcoma has yet to be determined, but it is likely that some patients will benefit. As some bone sarcomas do not respond to chemotherapy, surgery remains the only effective treatment, and there are no effective drugs to treat relapsing patients. Radiotherapy has both a curative role in combination with chemotherapy in soft tissue and Ewing''s sarcoma and a palliative role in the other sarcomas. [Copyright &y& Elsevier]

Background: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. Methods: Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/− ifosfamide (MAP+/−I)] with measurable disease according to RECIST1.1 were eligible to ifosfamide (3 g/m2/day) continuous infusion (c.i.) days 1–5 q21d. RECIST1.1 overall response rate (ORR) (complete response (CR) + partial response (PR)), progression-free survival at 6-month (6m-PFS), duration of response (DOR), and 2-year overall survival (2y-OS) were assessed. PARP1 expression and gene mutations were tested by immunohistochemistry and next-generation sequencing. Results: 51 patients were included. ORR was 20% (1 CR + 9 PR). Median DOR was 5 months (95%CI 2–7). Median PFS, 6m-PFS, OS, and 2y-OS were 6 months (95%CI 4–9), 51%, 15 months (10–19), and 30%, respectively. A second surgical complete remission (CR2) was achieved in 26 (51%) patients. After multivariate analysis, previous use of ifosfamide (HR 2.007, p = 0.034) and CR2 (HR 0.126, p < 0.001) showed a significant correlation with PFS and OS, respectively. No significant correlation was found between outcomes and PARP1 or gene mutations. Conclusions: HD-IFO should be considered as the standard first-line treatment option in relapsed osteosarcoma and control arm of future trial in this setting. [ABSTRACT FROM AUTHOR]

Systemic treatments for advanced soft tissue sarcoma are limited. Eribulin showed activity in metastatic soft tissue sarcoma, particularly liposarcomas. Data from six patients with advanced liposarcoma that received eribulin as third- or fourth-line therapy are presented herein. Eribulin treatment was well tolerated; no grade 3-4 toxicity or therapy delay was observed. Two patients had a partial response; four had a prolonged stable disease. The first case, with pre-existing chronic renal dysfunction, achieved a 6-month stable disease with dose-reduced eribulin. The second case became resectable after eribulin treatment, with a 6-month complete surgical remission. The third case obtained a 7-month stable disease with eribulin and stereotactic body radiotherapy. The last three cases were ≥65 years old, and two of them had objective response with eribulin. [ABSTRACT FROM AUTHOR]

Background: Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors., Methods: To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, NBN, PALB2, RAD51C, RAD51D, RAD50, and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB., Clinical Report and Results: We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n = 193) displayed 9 of all 31 BRCA2alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2alt (4.66%; q < 0.001). All of 9 BRCA2alt were represented by homDel, which related to a high fraction of genome altered., Conclusion: uLMS displays a significant frequency of somatic BRCA2alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Among sarcomas, which are rare cancers with an incidence of <6 per 100.000/year cases, ultra-rare sarcomas have an incidence of approximately ≤1/1,000,000/year cases and altogether account for ~20% of all soft tissue sarcomas (STS) and bone sarcomas. The Italian Sarcoma Group has recently performed a non-interventional, retrospective TrObs study with data from 512 anthracycline-pretreated patients with advanced multiple STS histologies and treated with trabectedin (Palmerini, Cancers 2021; ClinicalTrials.gov Identifier: NCT02793050)., Methods: A post-hoc analysis of case series to evaluate the efficacy and safety of trabectedin on patients with ultra-rare and other rare translocation-related sarcomas included in TrObs study was performed. Main outcomes comprised investigator-assessed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and safety., Results: Thirty-six patients (18 women) with ultra-rare and other rare sarcoma and a median age of 53.0 years (range: 22-81) were included. Most patients had solitary fibrous tumor (SFT; n=11) followed by epithelioid sarcoma (n=5), malignant peripheral nerve sheath tumor (MPNST; n=4), extraskeletal myxoid chondrosarcoma (EMC; n=3), desmoplastic small round cell tumor (DSRCT; n=3), and alveolar soft part sarcoma (ASPS), rhabdomyosarcoma and clear cell sarcoma (n=2 each). Thirty-five patients had metastatic disease and 23 patients received trabectedin as a second-line treatment. Among 35 patients evaluable for response, two patients with SFT and ASPS had a partial response and one patient with DSRCT obtained a complete response, reaching an ORR of 8.6% (95% CI: 2.8-23.4%). Among patients with an ORR, 6-months PFS was 100% in patients with ASPS, 45.7% in patients with SFT and 33.3% in those with DSRCT. Two patients with epithelioid sarcoma and myoepithelioma had disease stabilization lasting >24 months. Nine patients had at least one grade 3/4 adverse event, mostly being bone marrow toxicity (n=6)., Conclusions: Trabectedin has some anti-tumor activity in some ultra-rare and other rare sarcomas, particularly translocation-related sarcomas, with the well-known manageable safety profile., Competing Interests: EP has served on an advisory board for Takeda, Amgen, Daiichi Sankyo, Lilly, Eusa Pharma, Deciphera, and SynOx Therapeutics and has received research support from Bristol Myers Squibb, Pfizer, PharmaMar, and Daiichi Sankyo. ABr is a consultant for Eli Lilly, Eisai, Glaxo-Smith Kline, Pharmamar and has received travel grants from PharmaMar, Takeda, and Ipsen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Palmerini, Sanfilippo, Grignani, Buonadonna, Romanini, Badalamenti, Ferraresi, Vincenzi, Comandone, Pizzolorusso, Brunello, Gelsomino, De Pas, Ibrahim, Gurrieri, Grosso, Zanelli, Pantaleo, Milesi, Ciuffreda, Ferrari, Marchesi, Quattrini, Righi, Setola, Carretta, Casali, Picci and Ferrari.)

Introduction: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study., Materials and Methods: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models., Results: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles., Conclusions: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.B. has reported grants from Deutsche Krebshilfe, Deutsche Forschungsgemeinschaft and the European Science Foundation and personal fees from Lilly, Bayer, Pfizer, Novartis, Isofol and Clinigen; E.P. has reported advisory roles for Amgen, Daiichi Sankyo, Eli Lilly, EUSA Pharma and Deciphera, received research support from Bristol Myers Squibb, Pfizer and PharmaMar and received travel support from Lilly, PharmaMar and Takeda; L.K. has reported honoraria from Bayer; P.R. has reported advisory roles for Exactech and Stryker; A.F. has reported honoraria from Ipsen Pharma, PharmaMar and Lilly; P.C. has reported honoraria for the speaker, consultancy or advisory role from Bayer, Deciphera, Eisai, Eli Lilly, Nektar Therapeutics and Pfizer and received research funds from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc., Glaxo, Karyopharm Pharmaceuticals, Novartis, Pfizer and PharmaMar; P.R. has reported honoraria from Bayer, Clinigen, BMS, Roche, MSD, Deciphera, Novartis, Pfizer, PharmaMar, Lilly and Amgen; I.H., S.F., K.S.H., P.P., S.H.-N., D.M.D., C.B., B.B., E.St., M.G., T.K., M.E., V.F., M.K., R.B., D.B., O.B., A.C., R.S., R.B., T.K., L.H., G.A., B.-N.H., E.Se., A.F., F.K., G.H.-W. and S.S. have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The Italian Sarcoma Group performed this retrospective analysis of patients with advanced soft tissue sarcoma, pretreated with ≥1 anthracycline-based treatment, and treated with trabectedin every three weeks. Primary endpoint was to describe real-life use of trabectedin across Italy. Secondary endpoints included objective response rate (ORR) and safety. Overall, 512 patients from 20 Italian centers were evaluated. Leiomyosarcoma (37.7%)/liposarcoma (30.3%) were the most prevalent histological types (abbreviated as L-sarcoma). Patients received a median of four trabectedin cycles (range: 1-40), mostly as a second-line treatment (~60% of patients). The ORR was 13.7% superior ( p < 0.0001) in patients with L-sarcoma compared with patients with non-L-sarcoma (16.6% vs. 9.0%). Median progression-free survival (PFS) was 5.1 months, whereas median overall survival (OS) was 21.6 months. Significantly better PFS and OS were observed in patients with L-sarcoma, those with objective responses and/or disease stabilization, treated in an early line and treated with reduced dose. Bone marrow toxicity (61.4%) and transaminase increases (21.9%) were the most common grade 3/4 adverse events. The results of this real-life study suggest that trabectedin is an active treatment, which is mostly given as a second-line treatment to patients with a good performance status and high-grade, metastatic L-sarcoma (clinical trial information: NCT02793050).

Background: Palliative sedation involves the use of sedative medication to relieve refractory symptoms in patients by reducing their level of consciousness. Although it is considered an acceptable clinical practice from most ethical points of view, palliative sedation is still a widely debated procedure and merits better understanding., Methods: The relevant medical literature pertaining to palliative sedation was analyzed and reviewed from various technical, relational, and bioethical perspectives., Results: Proportionate palliative sedation is considered to be the most clinically appropriate modality for performing palliative sedation. However, guidelines must be followed to ensure that it is performed correctly. Benzodiazepines represent the first therapeutic option and careful monitoring of dosages is essential to avoid oversedation or undersedation., Conclusions: Proportionate palliative sedation is used to manage and relieve refractory symptoms in patients with cancer during their last days or hours of life. Evidence suggests that its use has no detrimental effect on survival. A different decision-making process is used to manage the withdrawal of hydration than the process used to determine whether proportionate palliative sedation is appropriate. Communication between patients, their relatives, and the health care staff is important during this medical intervention.

Background: Investigation of the relation between primary tumor and metastatic disease is necessary for the identification of predictive factors for postrecurrence survival (PRS) in patients with recurrent osteosarcoma., Methods: Cellular levels of P-glycoprotein, ErbB-2, p53, and Bcl-2 expression were evaluated in primary tumor biopsy and metachronous pulmonary metastasis specimens from 19 patients with high-grade osteosarcoma. Results were analyzed for differences between primary tumor and pulmonary metastases and for correlations between expression patterns and survival., Results: Positive staining in lung metastases was noted in 68%, 53%, 32%, and 84% of patients for P-glycoprotein, ErbB-2, p53, and Bcl-2, respectively. These percentages were higher than those observed in primary tumor specimens for all genetic markers evaluated, with a significant difference in the percentage of patients with positive staining for P-glycoprotein (68% vs. 32%; P = 0.05) and a near-significant difference in the percentage of patients with positive staining for Bcl-2 (84% vs. 53%; P = 0.08). Patients with ErbB-2 expression in the primary tumor were more likely to have multiple metastases and shorter recurrence-free intervals compared with patients in whom ErbB-2 expression was not observed, whereas differences in P-glycoprotein, p53, and Bcl-2 expression were not related to differences in metastatic pattern. PRS was influenced by p53 expression levels in pulmonary metastases, with patients who had negative staining for p53 having a significantly better PRS rate relative to patients with positive staining for p53 (3-year PRS rate: p53-negative, 64%; p53-positive, 17%; P = 0.008)., Conclusions: In the current study of patients with high-grade osteosarcoma, most patients exhibited increased cellular expression of P-glycoprotein, ErbB-2, and Bcl-2 in recurrent pulmonary metastases compared with primary tumor. Further studies aimed at investigating the relation between altered p53 expression in lung metastases and postrecurrence survival are recommended., (Copyright 2004 American Cancer Society.)

Purpose: The aim of this study was to compare the results in terms of histologic response to primary chemotherapy of two sequential studies in osteosarcoma patients preoperatively treated with methotrexate, doxorubicin, cisplatin, and ifosfamide, given at different doses., Patients and Methods: Between January 1993 and March 1995, 171 patients with osteosarcoma of the extremity were treated according to a protocol of neoadjuvant chemotherapy with preoperative methotrexate, cisplatin, doxorubicin, and ifosfamide. From April 1995 to December 1999, 196 osteosarcoma patients were preoperatively treated with the same drugs at higher doses. Postoperatively, patients received the same treatment in both studies used, but poor responders (tumor necrosis <95%) had more cycles of treatment than good responders., Results: Comparing the two chemotherapy regimens, there were no significant differences in terms of good histologic response to chemotherapy (69% vs. 62%), 5-year event-free survival (60% vs. 65%), 5-year overall survival (74% vs. 80%), and rate of local recurrence (6% vs. 4%). The 5-year event-free survival was significantly related to the serum level of alkaline phosphatase before treatment (77% for patients with normal values vs. 46% for patients with high values) and the degree of histologic response to preoperative chemotherapy (69% for good responders vs. 54% for poor responders)., Conclusions: Increasing the doses of preoperative chemotherapy does not improve the rate of good histologic response and survival in osteosarcoma of the extremity. The degree of necrosis induced by preoperative treatment probably reflects an innate sensitivity to chemotherapy, which is not altered by increasing drug doses.