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Matteo Petrini,1,2 Wouter JM Lokerse,1 Agnieszka Mach,1 Martin Hossann,3 Olivia M Merkel,2 Lars H Lindner1 1Department of Internal Medicine III, University Hospital, Ludwig Maximilian University, Munich, Germany; 2Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, Ludwig Maximilian University, Munich, Germany; 3Thermosome GmbH, Planegg, GermanyCorrespondence: Lars H LindnerLudwig Maximilian University, Department of Internal Medicine III, Klinikum Grosshadern, Marchioninistr. 15, Munich, 81377, GermanyTel +49-89-7095-4768Fax +49-89-7095-4776Email lars.lindner@med.uni-muenchen.dePurpose: Previous studies demonstrated the possibility of targeting tumor-angiogenic endothelial cells with positively charged nanocarriers, such as cationic liposomes. We investigated the active targeting potential of positively charged nanoparticles in combination with the heat-induced drug release function of thermosensitive liposomes (TSL). This novel dual-targeted approach via cationic TSL (CTSL) was thoroughly explored using either a novel synthetic phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG2) or a conventional polyethylene glycol (PEG) surface modification. Anionic particles containing either DPPG2 or PEG were also included in the study to highlight difference in tumor enrichment driven by surface charge. With this study, we aim to provide a deep insight into the main differences between DPPG2- and PEG-functionalized liposomes, focusing on the delivery of a well-known cytotoxic drug (doxorubicin; DOX) in combination with local hyperthermia (HT, 41– 43°C).Materials and Methods: DPPG2- and PEG-based cationic TSLs (PG2-CTSL/PEG-CTSL) were thoroughly analyzed for size, surface charge, and heat-triggered DOX release. Cancer cell targeting and DOX delivery was evaluated by FACS, fluorescence imaging, and HPLC. In vivo particle behavior was analyzed by assessing DOX biodistribution with local HT application in tumor-bearing animals.Results: The absence of PEG in PG2-CTSL promoted more efficient liposome–cell interactions, resulting in a higher DOX delivery and cancer cell toxicity compared with PEG-CTSL. By exploiting the dual-targeting function of CTSLs, we were able to selectively trigger DOX release in the intracellular compartment by HT. When tested in vivo, local HT promoted an increase in intratumoral DOX levels for all (C)TSLs tested, with DOX enrichment factors ranging from 3 to 14-fold depending on the type of formulation.Conclusion: Cationic particles showed lower hemocompatibility than their anionic counterparts, which was partially mitigated when PEG was grafted on the liposome surface. DPPG2-based anionic TSL showed optimal local drug delivery compared to all other formulations tested, demonstrating the potential advantages of using DPPG2 lipid in designing liposomes for tumor-targeted applications.Keywords: thermosensitive liposomes, mild hyperthermia, cationic liposomes, dual tumor targeting, drug delivery, liposome functionalization

F Johannes P van Valenberg,1,* Iris SG Brummelhuis,1,* Lars H Lindner,2 Felix Kuhnle,2 Barbara Wedmann,2 Pascal Schweizer,3 Martin Hossann,3 J Alfred Witjes,1 Egbert Oosterwijk1 1Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands; 2Department of Medicine III, University Hospital LMU Munich, Munich, Germany; 3Thermosome GmbH, Munich, Germany*These authors contributed equally to this workCorrespondence: Iris SG BrummelhuisDepartment of Urology, Radboud University Medical Center, Geert Grooteplein Zuid 10 (610), PO Box 9101, Nijmegen 6500 HB, the NetherlandsTel +31 24 3619515Fax +31 24 3635121Email iris.brummelhuis@radboudumc.nlPurpose: Current treatment options for muscle-invasive bladder cancer (MIBC) are associated with substantial morbidity. Local release of doxorubicin (DOX) from phosphatidyldiglycerol-based thermosensitive liposomes (DPPG2-TSL-DOX) potentiated by hyperthermia (HT) in the bladder wall may result in bladder sparing without toxicity of systemic chemotherapy. We investigated whether this approach, compared to conventional DOX application, increases DOX concentrations in the bladder wall while limiting DOX in essential organs.Materials and Methods: Twenty-one pigs were anaesthetized, and a urinary catheter equipped with a radiofrequency-emitting antenna for HT (60 minutes) was placed. Experimental groups consisted of iv low or full dose (20 or 60 mg/m2) DPPG2-TSL-DOX with/without HT, iv low dose (20 mg/m2) free DOX with HT, and full dose (50 mg/50 mL) intravesical DOX with/without HT. After the procedure, animals were immediately sacrificed. HPLC was used to measure DOX levels in the bladder, essential organs and serum, and fluorescence microscopy to evaluate DOX distribution in the bladder wall.Results: Iv DPPG2-TSL-DOX with HT resulted in a significantly higher bladder wall DOX concentration which was more homogeneous distributed, than iv and intravesical free DOX administration with HT. Specifically in the detrusor, DPPG2-TSL-DOX with HT led to a > 7- and 44-fold higher DOX concentration, compared to iv free DOX with HT and intravesical DOX, respectively. Organ DOX concentrations were significantly lower in heart and kidneys, and similar in liver, spleen and lungs, following iv DPPG2-TSL-DOX with HT, compared to iv free DOX. Intravesical DOX led to the lowest organ DOX concentrations.Conclusion: Iv DPPG2-TSL-DOX combined with HT achieved higher DOX concentrations in the bladder wall including the detrusor, compared to conventional iv and intravesical DOX application. In combination with lower DOX accumulation in heart and kidneys, compared to iv free chemotherapy, DPPG2-TSL-DOX with HT has great potential to attain a role as a bladder-sparing treatment for MIBC.Keywords: MIBC, drug delivery system, therapy, chemotherapeutic, local release, porcine model

Barbara Kneidl,1,2 Michael Peller,3 Gerhard Winter,2 Lars H Lindner,1 Martin Hossann11Department of Internal Medicine III, University Hospital Munich, 2Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics, 3Institute for Clinical Radiology, University Hospital Munich, Ludwig-Maximilians University, Munich, GermanyAbstract: Thermosensitive liposomes are a promising tool for external targeting of drugs to solid tumors when used in combination with local hyperthermia or high intensity focused ultrasound. In vivo results have demonstrated strong evidence that external targeting is superior over passive targeting achieved by highly stable long-circulating drug formulations like PEGylated liposomal doxorubicin. Up to March 2014, the Web of Science listed 371 original papers in this field, with 45 in 2013 alone. Several formulations have been developed since 1978, with lysolipid-containing, low temperature-sensitive liposomes currently under clinical investigation. This review summarizes the historical development and effects of particular phospholipids and surfactants on the biophysical properties and in vivo efficacy of thermosensitive liposome formulations. Further, treatment strategies for solid tumors are discussed. Here we focus on temperature-triggered intravascular and interstitial drug release. Drug delivery guided by magnetic resonance imaging further adds the possibility of performing online monitoring of a heating focus to calculate locally released drug concentrations and to externally control drug release by steering the heating volume and power. The combination of external targeting with thermosensitive liposomes and magnetic resonance-guided drug delivery will be the unique characteristic of this nanotechnology approach in medicine.Keywords: thermosensitive liposomes, phosphatidyloligoglycerol, hyperthermia, high intensity focused ultrasound, drug delivery, drug targeting

Background: Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice.Methods: NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity.Results: Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (<10%) in a dose dependent manner. Subcutaneous injections of high-dose Erufosine caused local reactions at the injection site. Therefore, this regimen at 40 mg/kg body weight Erufosine was stopped after 14 days. No gross changes were observed in organ weight, clinical chemistry and white blood cell count in treated compared to untreated controls except for a moderate increase in lactate dehydrogenase and aspartate-aminotransferase after intensive treatment. Repeated Erufosine injections resulted in drug-accumulation in different organs with maximum concentrations of about 1000 nmol/g in spleen, kidney and lungs.Conclusion: Erufosine was well tolerated and organ-concentrations surpassed the cytotoxic drug concentrations in vitro. Our investigations establish the basis for a future efficacy testing of Erufosine in xenograft tumor models in nude mice alone and in combination with chemo- or radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Dacarbazine is currently considered the better combination partner for doxorubicin compared to ifosfamide for the treatment of leiomyosarcoma (LMS). Regional hyperthermia (RHT) combined with neoadjuvant chemotherapy has been shown to improve survival in patients with locally advanced high-risk STS. We sought to evaluate the role of doxorubicin and dacarbazine (AD) versus doxorubicin and ifosfamide (AI) in combination with RHT in patients with LMS., Methods: Patients with locally advanced high-grade LMS, including limited metastases, eligible for RHT and first-line treatment with either AI + RHT or AD + RHT between 2014 and 2022 were retrospectively evaluated. Endpoints were progression-free survival (PFS) and overall survival (OS). Patients were matched using propensity scores, which were estimated with a logistic regression model accounting for tumor site, presence of metastasis, surgery, and radiotherapy., Results: A total of 105 patients were included in this study, of which 101 were included in the propensity score-matched cohort. In the matched cohort, treatment with AD + RHT was associated with a significantly improved PFS (HR 0.32, 95% CI 0.13-0.74, p = 0.0081). Multivariable analysis revealed several significant predictors of PFS, including treatment with AD + RHT (HR 0.42, 95% CI 0.19-0.92, p = 0.031)., Conclusion: Treatment with AD + RHT showed improved PFS and better treatment tolerability compared to AI + RHT. Our results support the use of AD instead of AI for the treatment of patients with LMS in combination with RHT., (© 2025 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The prognosis of patients with advanced soft tissue sarcoma (STS) remains dismal. Trofosfamide (TRO) has been proposed as a well-tolerated oral maintenance therapy. This retrospective analysis aims to determine the value of this therapy., Methods: Fifty-nine patients with advanced STS who received TRO maintenance therapy between 2016 and 2022 were reviewed and analysed regarding clinical parameters and outcomes., Results: The median age was 48 years; the most common histological subtype was synovial sarcoma (n = 22, 37%), and 71% of patients (n = 42) presented with metastatic disease. No radiological evidence of disease (NED) before the start of maintenance was reported in 36% of patients (n = 21). The median follow-up was 38.2 months with a median maintenance duration of 9.0 months. The median event-free survival (EFS) and overall survival (OS) were 9.5 and 33.2 months, respectively. In metastatic patients achieving NED before the initiation of TRO, the median EFS was 29.4 months, while the median OS was not reached. In metastatic patients with anthracycline + ifosfamide (AI) as first-line induction therapy without prior metastasis-directed local therapy, the median EFS and OS from the start of AI were 13.9 and 26.8 months, respectively. Multivariate analysis of the overall cohort demonstrated that NED before the start of maintenance was significantly associated with a prolonged EFS (p = 0.024, hazard ratio [HR] = 0.26), and G2 histology correlated with longer OS (p = 0.030, HR = 0.16, reference: G3)., Interpretation: Oral maintenance therapy with TRO appears to improve outcomes in patients with advanced STS. Metastatic patients who achieve NED through prior metastasectomy may particularly benefit from TRO maintenance.

Purpose: The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers., Methods: In this cross-sectional case-based survey study, 5 anonymized patient cases with imaging data of localized STS were presented to MTBs of 21 German-speaking tertiary referral hospitals. Centers provided recommendations on treatment sequence and modalities, along with the consensus level within their MTB. Agreement percentages were calculated, and consensus levels were rated on a scale of 1 to 10., Results: Five patient cases were discussed resulting in 105 recommendations. Agreement percentages for case 1 to 5 were 14.3%, 61.9%, 33.3%, 52.4% and 9.3%, with a median agreement percentage of 33.3%. Grouping pre- and postoperative therapies as "perioperative" and including recommendations with and without regional hyperthermia raised the median agreement to 47.6%. The mean consensus level within each center across all 5 cases was 9.5., Conclusion: This first case-based analysis of inter-center agreement for STS management in German-speaking countries reveals low inter-center agreement but high intra-center consensus. Our study includes nearly all tertiary sarcoma centers in German-speaking countries, affirming its strong external validity. These findings suggest potential and clinically very relevant differences in treatment standards among sarcoma centers. Enhanced case-based exchanges and collaborative efforts are needed to reduce discrepancies and standardize the management of STS patients., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no competing interest related to the presented work. Ethics approval: The study was conducted in accordance with the Declaration of Helsinki and approved by the institutional review board (EA1/126/23)., (© 2024. The Author(s).)

Background: Local ablative therapies (LAT) are increasingly used in patients with metastatic soft tissue sarcoma (STS), yet evidence-based standards are lacking. This study aimed to assess the impact of LAT on survival of metastatic STS patients and to identify prognostic factors., Methods: In this retrospective multicenter study, 246 STS patients with metastatic disease who underwent LAT on tumor board recommendation between 2017 and 2021 were analyzed. A mixed effects model was applied to evaluate multiple survival events per patient., Results: Median overall survival (OS) after first metastasis was 5.4 years with 1-, 2- and 5-year survival rates of 93.7, 81.7, and 53.1 %, respectively. A treatment-free interval ≥12 months and treatment of liver metastases were positively correlated with progression-free survival (PFS) after LAT (HR = 0.61, p = 0.00032 and HR = 0.52, p = 0.0081, respectively). A treatment-free interval ≥12 months and treatment of metastatic lesions in a single organ site other than lung and liver were positive prognostic factors for OS after first LAT (HR = 0.50, p = 0.028 and HR = 0.40, p = 0.026, respectively) while rare histotypes and LAT other than surgery and radiotherapy were negatively associated with OS after first LAT (HR = 2.56, p = 0.020 and HR = 3.87, p = 0.025). Additional systemic therapy was independently associated with a PFS benefit in patients ≤60 years with ≥4 metastatic lesions (for max. diameter of treated lesions ≤2 cm: HR = 0.32, p = 0.02 and >2 cm: HR = 0.20, p = 0.0011, respectively)., Conclusion: This multicenter study conducted at six German university hospitals underlines the value of LAT in metastatic STS. The exceptionally high survival rates are likely to be associated with patient selection and treatment in specialized sarcoma centers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: While available systemic treatments have modest long term efficacy in advanced angiosarcoma, immunotherapy represents an interesting new therapeutic opportunity. To establish its benefit, it is required to conduct a clinical trial assessing its efficacy and toxicity compared to standard treatments., Material and Methods: This is a literature review from PubMed search., Results: Several systemic treatments (chemotherapy and TKI) are currently used in advanced angiosarcoma with ORR ranging from 12.5 to 68 % and PFS from 2 to 7 months. However, few randomized trials, mainly phase II, has been conducted to compare these treatments. While most centers propose doxorubicin containing regimens or paclitaxel in 1st or 2nd line, a high heterogeneity of regimens administered in this setting is observed even across sarcoma specialized centers with no consensual standard treatment. Encouraging signals of immunotherapy activity have been reported in angiosarcoma from several retrospective and phase II studies assessing anti-PD1 either alone or in combination with anti CTLA4 or TKI. Although cutaneous and head and neck location seems to benefit more from immunotherapy, response may be observed in any angiosarcoma subtype. In sarcoma in general and AS in particular, no biomarker has been clearly established to predict the efficacy of immunotherapy: high tumor mutational burden and presence of tertiary lymphoid structures are under assessment., Discussion: Even essential, developing a randomized clinical trial in AS struggles with the heterogeneity of the disease, the lack of consensual standard regimen, the uncertainty on optimal immunotherapy administration and the absence of established predictive biomarkers., Conclusion: International collaboration is essential to run randomized trial in advanced AS and asses the efficacy of immune therapy in this rare and heterogeneous disease., Competing Interests: Declaration of Competing Interest Armelle Dufresne, Jana Striefler, Bernd Kasper, Saskia Litiere, Sandrine Marreaud: these authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with ruptured gastrointestinal stromal tumour (GIST) have poor prognosis. Little information is available about how adjuvant imatinib influences survival., Methods: We explored recurrence-free survival (RFS) and overall survival (OS) of patients with ruptured GIST who participated in a randomised trial (SSG XVIII/AIO), where 400 patients with high-risk GIST were allocated to adjuvant imatinib for either 1 year or 3 years after surgery. Of the 358 patients with confirmed localised GIST, 73 (20%) had rupture reported. The ruptures were classified retrospectively using the Oslo criteria., Results: Most ruptures were major, four reported ruptures were reclassified unruptured. The 69 patients with rupture had inferior RFS and OS compared with 289 patients with unruptured GIST (10-year RFS 21% vs. 55%, OS 59% vs. 78%, respectively). Three-year adjuvant imatinib did not significantly improve RFS or OS of the patients with rupture compared with 1-year treatment, but in the largest mutational subset with KIT exon 11 deletion/indel mutation OS was higher in the 3-year group than in the 1-year group (10-year OS 94% vs. 54%)., Conclusions: About one-fifth of ruptured GISTs treated with adjuvant imatinib did not recur during the first decade of follow-up. Relatively high OS rates were achieved despite rupture., Clinical Trial Registration: NCT00116935., (© 2024. The Author(s).)

Background: In soft tissue sarcomas, unplanned resections, or so-called Whoops procedures, do occur quite frequently, thus primarily owing to the abundant presence of benign lesions. Whether re-resection reduces local recurrence or improves overall survival remains a topic of ongoing debate. The principle objective of this study was to analyze the outcomes of patients with soft tissue sarcomas of the extremities or trunk wall after an incidental marginal resection by comparing re-resections to individuals who declined the procedure., Methods: A total of 185 patients who underwent unplanned resection were included. These patients were stratified into two groups: Group A (n = 156) underwent re-excision, while Group B (n = 29) was treated conservatively. Depending on the clinical scenario, radio- or chemotherapy was either administered in a neoadjuvant or an adjuvant setting. The presence of residual tumor and metastatic disease was documented. Clinical outcomes, specifically local recurrence (LR), local recurrence-free survival (LRFS) and overall survival (OS), were utilized for evaluation., Results: Group B exhibited significantly larger tumors ( p < 0.0001) and a higher mean age than Group A. Among the patients in Group A, 11 (5.9%) had contaminated resection margins (R1), and residual disease (RD) was observed in 93 (59.6%) of the resected specimens. In group B, 10 patients received adjuvant radiotherapy alone, 5 received chemotherapy alone, and 13 underwent a combined approach consisting of both radio- and chemotherapy. In Group A, 8% (n = 12) of the patients developed local recurrence (LR) during the observation period. Conversely, in Group B, this amount was 14% (n = 4) (n.s.). Of the 12 LR in Group A, 10 were found in the subgroup with residual disease. Overall survival and local recurrence-free survival were not significantly different between the groups. A total of 15% (n = 24) of the patients in Group A developed metastatic disease, while 10% (n = 3) in Group B developed metastatic disease (n.s.)., Conclusions: Following the reresection of unplanned resected STS, there was no statistically significant difference observed in overall survival or LR compared to patients who did not undergo re-resection. However, within the subgroup of patients with residual disease in the re-resected specimen, the OS was compromised, and the LR rate was higher. Particularly for low-grade lesions, adopting a more conservative approach seems to be justified.

Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes (LN) in staging imaging are a frequent topic of discussion in multidisciplinary tumor boards. Predictive markers are needed to facilitate stratification and improve treatment of STS patients. In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined LN were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and imaging parameters. Patients with LNM exhibited significantly larger short axis diameter (SAD) and long axis diameter (LAD) vs. patients with benign LN (median 22.5 vs. 14 mm, p < 0.001 and median 29.5 vs. 21 mm, p = 0.003, respectively). Furthermore, the presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scans were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression over time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/L, p = 0.005 and 1.5 vs. 0.55 mg/dL, p = 0.039, respectively). This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs., (© 2024. The Author(s).)

Background: Soft tissue sarcomas (STSs) are a heterogeneous group of tumors. Wide surgical resection is standard, often combined with neoadjuvant chemotherapy, radiotherapy, or both. Studies have shown the predictive value of tumor necrosis in bone sarcoma (BS); however, the role of necrosis in STS after neoadjuvant therapies is still unclear. This study aimed to investigate the role of chemo- and radiotherapy in the formation of tumor necrosis and to evaluate the influence of tumor necrosis on overall survival and local recurrence-free survival. Data from BS patients and patients who did not receive neoadjuvant therapy were compared., Methods: A total of 779 patients with STS or BS were treated surgically. In all patients, tumor-specific factors such as type, size, or grading and the type of adjuvant therapy were documented. Local recurrence (LR), the diagnosis of metastatic disease, and survival during follow-up were evaluated., Results: A total of 565 patients with STS and 214 with BS were investigated. In STS, 24.1% G1 lesions, 34.1% G2 lesions, and 41.8% G3 lesions were observed. Two hundred twenty-four of the patients with STS and neoadjuvant therapy had either radiotherapy (RTx) (n = 80), chemotherapy (CTx) (n = 93), or both (n = 51). Three hundred forty-one had no neoadjuvant therapy at all. In STS, tumor necrosis after neoadjuvant treatment was significantly higher (53.5%) than in patients without neoadjuvant therapy (15.7%) (p < 0.001). Patients with combined neoadjuvant chemo-/radiotherapy had substantially higher tumor necrosis than those with radiotherapy alone (p = 0.032). There was no difference in tumor necrosis in patients with combined chemo-/radiotherapy and chemotherapy alone (p = 0.4). The mean overall survival for patients with STS was 34.7 months. Tumor necrosis did not influence survival in a subgroup of G2/3 patients. In STS with no neoadjuvant therapy and grading of G2/3, the correlation between necrosis and overall survival was significant (p = 0.0248). There was no significant correlation between local recurrence (LR) and necrosis., Conclusion: STS shows a broad spectrum of necrosis even without neoadjuvant chemo- or radiotherapy. After CTx or/and RTx necrosis is enhanced and is significantly pronounced with a combination of both. There is a trend toward higher necrosis with CTx than with RTx. Grading substantially influences the necrosis rate, but necrosis in soft-tissue sarcoma following neoadjuvant therapy does not correlate with better survival or a lower local recurrence rate, as in bone sarcomas., (© 2024. The Author(s).)

Soft tissue sarcomas account for less than 1% of tumors in adults. With more than 80 different subtypes and often dismal prognosis, treatment of patients with soft tissue sarcomas is diagnostically and therapeutically complex. In patients with localized disease, surgery remains the mainstay of therapy. A multimodal approach consisting of neoadjuvant chemotherapy +/- regional hyperthermia may be suitable in patients with high-risk disease to maximize tumor shrinkage before surgery and to treat micrometastases. In patients with oligometastatic disease, local treatment options should be discussed within a specialized tumor board. In patients with disseminated metastatic disease, chemotherapy with anthracyclines remains the backbone of therapy. Immune checkpoint inhibitors have proven to be effective for patients with alveolar soft part sarcoma and targeted therapies with NTRK-inhibitors should be evaluated in patients with NTRK-fusions. This article focuses on current standards and developments in the treatment of soft tissue sarcomas., Competing Interests: L. Lindner erhielt Forschungs- und Reiseunterstützungen von Dr. Sennewald Medizintechnik; Reiseunterstutzung und Honorare von PharmaMar, Bayer, Roche, Boehringer Ingelheim Pharma und ELMedconsult., (Thieme. All rights reserved.)

Background: In soft tissue or bone sarcomas, multimodal therapeutic concepts represent the standard of care. Some patients reject the therapeutic recommendations due to several reasons. The aim of this study was to assess the impact of that rejection on both prognosis and local recurrence., Methods: Between 2012 and 2019, a total of 828 sarcoma patients were surgically treated. Chemotherapy was scheduled as a neoadjuvant, and adjuvant multi-agent therapy was performed following recommendations from an interdisciplinary tumor board. Radiotherapy, if deemed appropriate, was administered either in a neoadjuvant or an adjuvant manner. The recommended type of therapy, patient compliance, and the reasons for refusal were documented. Follow-ups included local recurrences, diagnosis of metastatic disease, and patient mortality., Results: Radiotherapy was recommended in 407 (49%) patients. A total of 40 (10%) individuals did not receive radiation. A reduction in overall survival and local recurrence-free survival was evident in those patients who declined radiotherapy. Chemotherapy was advised for 334 (40%) patients, 250 (75%) of whom did receive all recommended cycles. A total of 25 (7%) individuals did receive a partial course while 59 (18%) did not receive any recommended chemotherapy. Overall survival and local recurrence-free survival were reduced in patients refusing chemotherapy. Overall survival was worst for the group of patients who received no chemotherapy due to medical reasons. Refusing chemotherapy for non-medical reasons was seen in 8.8% of patients, and refusal of radiotherapy for non-medical reasons was seen in 4.7% of patients., Conclusions: Divergence from the advised treatment modalities significantly impacted overall survival and local recurrence-free survival across both treatment modalities. There is an imperative need for enhanced physician-patient communication. Reducing treatment times, as achieved with hypofractionated radiotherapy and with therapy in a high-volume sarcoma center, might also have a positive effect on complying with the treatment recommendations.

Purpose: To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials., Methods: In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT., Results: We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40-43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry., Discussion: There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects., Conclusions: The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.

Introduction: This study evaluated the performance of magnetic resonance thermometry (MRT) during deep-regional hyperthermia (HT) in pelvic and lower-extremity soft-tissue sarcomas., Materials and Methods: 17 pelvic (45 treatments) and 16 lower-extremity (42 treatments) patients underwent standard regional HT and chemotherapy. Pairs of double-echo gradient-echo scans were acquired during the MR protocol 1.4 s apart. For each pair, precision was quantified using phase data from both echoes ('dual-echo') or only one ('single-echo') in- or excluding body fat pixels in the field drift correction region of interest. The precision of each method was compared to that of the MRT approach using a built-in clinical software tool (SigmaVision). Accuracy was assessed in three lower-extremity patients (six treatments) using interstitial temperature probes. The Jaccard coefficient quantified pretreatment motion; receiver operating characteristic analysis assessed its predictability for acceptable precision (<1 °C) during HT., Results: Compared to the built-in dual-echo approach, single-echo thermometry improved the mean temporal precision from 1.32 ± 0.40 °C to 1.07 ± 0.34 °C (pelvis) and from 0.99 ± 0.28 °C to 0.76 ± 0.23 °C (lower extremities). With body fat-based field drift correction, single-echo mean accuracy improved from 1.4 °C to 1.0 °C. Pretreatment bulk motion provided excellent precision prediction with an area under the curve of 0.80-0.86 (pelvis) and 0.81-0.83 (lower extremities), compared to gastrointestinal air motion (0.52-0.58)., Conclusion: Single-echo MRT exhibited better precision than dual-echo MRT. Body fat-based field-drift correction significantly improved MRT accuracy. Pretreatment bulk motion showed improved prediction of acceptable MRT temporal precision over gastrointestinal air motion.

Purpose: Due to poor outcomes and limited treatment options, patients with advanced bone and soft tissue sarcomas (BS/STS) may undergo comprehensive molecular profiling of tumor samples to identify possible therapeutic targets. The aim of this study was to determine the impact of routine molecular profiling in the setting of a dedicated precision oncology program in patients with BS/STS in a German large-volume sarcoma center., Methods: 92 BS/STS patients who received comprehensive genomic profiling (CGP) and were subsequently discussed in our molecular tumor board (MTB) between 2016 and 2022 were included. Patient records were retrospectively reviewed, and the clinical impact of NGS-related findings was analyzed., Results: 89.1% of patients had received at least one treatment line before NGS testing. At least one molecular alteration was found in 71 patients (82.6%). The most common alterations were mutations in TP53 (23.3% of patients), followed by PIK3CA and MDM2 mutations (9.3% each). Druggable alterations were identified, and treatment recommended in 32 patients (37.2%). Of those patients with actionable alterations, ten patients (31.2%) received personalized treatment and six patients did benefit from molecular-based therapy in terms of a progression-free survival ratio (PFSr) > 1.3., Conclusion: Our single-center experience shows an increasing uptake of next-generation sequencing (NGS) and highlights current challenges of implementing precision oncology in the management of patients with BS/STS. A relevant number of patients were diagnosed with clinically actionable alterations. Our results highlight the potential benefit of NGS in patients with rare cancers and currently limited therapeutic options., (© 2023. The Author(s).)

Objective: To evaluate the impact of a postoperative baseline (PB) MRI on diagnostic confidence and performance in detecting local recurrence (LR) of soft-tissue sarcoma (STS) of the limb., Materials and Methods: A total of 72 patients (8 with LR, 64 without LR) with primary STS of the limb were included. Routine follow-up MRI (1.5 T) at 6 and approximately 36 months (mean LR : 39.7 months; mean no LR : 34.9 months) after multimodal therapy or at time of LR were assessed by three independent readers using a 5-point Likert scale. Furthermore, the following imaging parameters were evaluated: presence of a mass, signal characteristics at T2- and T1-weighted imaging, contrast enhancement (CE), and in some of the cases signal intensity on the apparent diffusion coefficient (ADC). U-test, McNemar test, and ROC-analysis were applied. Interobserver reliability was calculated using Fleiss kappa statistics. A p value of 0.05 was considered statistically significant., Results: The presence of a PB MRI significantly improved diagnostic confidence in detecting LR of STS (p < 0.001) and slightly increased specificity (mean specificity without PE 74.1% and with presence of PB MRI 81.2%); however, not to a significant level. The presence of a mass showed highest diagnostic performance and highest interreader agreement (AUC [%]; κ: 73.1-83.6; 0.34) followed by T2-hyperintensity (50.8-66.7; 0.08), CE (52.4-62.5; 0.13), and T1-hypointensity (54.7-77.3; 0.23). ADC showed an AUC of 65.6-96.6% and a κ of 0.55., Conclusion: The presence of a PB MRI increases diagnostic confidence in detecting LR of STS of the limb., (© 2023. The Author(s).)

Purpose: Limited data are available about the influence of KIT and PDGFRA mutations on overall survival (OS) of patients with gastrointestinal stromal tumor (GIST) treated with adjuvant imatinib., Patients and Methods: The Scandinavian Sarcoma Group XVIII/AIO multicenter trial accrued 400 patients with a high risk for GIST recurrence after macroscopically complete surgery between February 4, 2004, and September 29, 2008. The patients received adjuvant imatinib 400 mg/day for either 1 year or 3 years based on random allocation. We analyzed using conventional sequencing KIT and PDGFRA mutations centrally from 341 (85%) patients who had localized, centrally confirmed GIST, and correlated the results with recurrence-free survival (RFS) and OS in exploratory analyses., Results: During a median follow-up time of 10 years, 164 RFS events and 76 deaths occurred. Most patients were re-treated with imatinib when GIST recurred. Patients with KIT exon 11 deletion or indel mutation treated with 3 years of adjuvant imatinib survived longer than patients treated for 1 year [10-year OS 86% versus 64%, respectively; HR, 0.34; 95% confidence interval (CI), 0.15-0.72; P = 0.007], and also had longer RFS (10-year RFS 47% versus 29%; HR, 0.48; 95% CI, 0.31-0.74; P < 0.001). Patients with KIT exon 9 mutation had unfavorable OS regardless of the duration of adjuvant imatinib., Conclusions: Compared with 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation., (©2023 The Authors; Published by the American Association for Cancer Research.)

The medical use of Cannabis has gained popularity in Europe and Northern America in recent years. Cannabinoids are available as finished pharmaceuticals, flowers and extracts. This article focuses on supportive medicine for oncological patients. Possible indications are pain, chemotherapy-induced nausea and vomiting, loss of appetite and altered taste perception. Despite the enormous cannabis hype in medicine, the evidence for its use in oncology patients is insufficient. However, palliative patients with refractory symptoms could be candidates for a therapeutic trial. The key parameter for choosing a cannabis medicinal product is the THC/CBD ratio. Oral forms of administration are particularly suitable for cannabis-naive and older patients. Mental and cardiovascular side effects should not be underestimated., Competing Interests: Anton Burkhard-Meier arbeitet nebenberuflich als Medical Advisor für die HEYDAY AG. Für die übrigen Autoren bestehen keine Interessenskonflikte., (Thieme. All rights reserved.)

Purpose: The evidence-based (S3) guideline "Adult Soft Tissue Sarcomas" (AWMF Registry No. 032/044OL) published by the German Guideline Program in Oncology (GGPO) covers all aspects of sarcoma treatment with 229 recommendations. Representatives of all medical specialties involved in sarcoma treatment contributed to the guideline. This paper compiles the most important recommendations for surgeons selected by delegates from the surgical societies., Methods: A Delphi process was used. Delegates from the surgical societies involved in guideline process selected the 15 recommendations that were most important to them. Votes for similar recommendations were tallied. From the resulting ranked list, the 10 most frequently voted recommendations were selected and confirmed by consensus in the next step., Results: The statement "Resection of primary soft tissue sarcomas of the extremities should be performed as a wide resection. The goal is an R0 resection" was selected as the most important term. The next highest ranked recommendations were the need for a preoperative biopsy, performing preoperative MRI imaging with contrast, and discussing all cases before surgery in a multidisciplinary sarcoma committee., Conclusion: The evidence-based guideline "Adult Soft Tissue Sarcomas" is a milestone to improve the care of sarcoma patients in Germany. The selection of the top ten recommendations by surgeons for surgeons has the potential to improve the dissemination and acceptance of the guideline and thus improve the overall outcome of sarcoma patients., (© 2023. The Author(s).)

Dexamethasone (DXM) is a potent glucocorticoid with an anti-inflammatory and anti-angiogenic activity which is widely clinically used. Systemic side effects limit the long-term use of DXM in patients requiring formulations which deliver and selectively release the drug to the diseased tissues. This in vitro study compares the suitability of DXM and commonly used prodrugs dexamethasone-21-phosphate (DXMP) and dexamethasone-21-palmitate (DP) as well as DXM complexed by 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) for the use in thermosensitive liposomes (TSL). DXM showed a poor retention and a low final drug:lipid ratio in a 1,2-dipalmitoyl-sn‑glycero-3-phosphodiglycerol-based TSL (DPPG 2 -TSL) and a low-temperature sensitive liposome (LTSL). In contrast to DXM, DXMP and DP were stably retained at 37 °C in TSL in serum and could be encapsulated with high drug:lipid ratios in DPPG 2 -TSL and LTSL. DXMP showed a rapid release at mild hyperthermia (HT) from both TSL in serum, whereas DP remained incorporated in the TSL bilayer. According to release experiments with carboxyfluorescein (CF), HP-γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) are suitable vehicles for the loading of DXM into DPPG 2 -TSL and LTSL. Complexation of DXM with HP-γ-CD increased the aqueous solubility of the drug leading to approx. ten times higher DXM:lipid ratio in DPPG 2 -TSL and LTSL in comparison to un-complexed DXM. Both DXM and HP-γ-CD showed increased release at HT in comparison to 37 °C in serum. In conclusion, DXMP and DXM complexed by HP-γ-CD represent promising candidates for TSL delivery., Competing Interests: Declaration of Competing Interest Martin Hossann and Lars H. Lindner have founder's equity shares in Thermosome GmbH, which develops drug candidates based on phosphatidyl-oligo-glycerols. All other authors declare no conflict of interest., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Purpose: Accurate histopathological grading of percutaneous biopsies is essential to guide adequate management of patients with suspected retroperitoneal liposarcoma. In this regard, however, limited reliability has been described. Therefore, we conducted a retrospective study to assess the diagnostic accuracy in retroperitoneal soft tissue sarcomas and simultaneously investigate its impact on patients' survival., Materials and Methods: Reports of an interdisciplinary sarcoma tumor board between 2012 and 2022 were systematically screened for patients with well-differentiated (WDLPS) and dedifferentiated retroperitoneal liposarcoma (DDLPS). Histopathological grading on pre-operative biopsy was correlated with corresponding postoperative histology. Additionally, patients' survival outcomes were examined. All analyses were performed in two subgroups: patients with primary surgery and patients with neoadjuvant treatment., Results: A total of 82 patients met our inclusion criteria. Diagnostic accuracy of patients who underwent upfront resection (n = 32) was significantly inferior to patients with neoadjuvant treatment (n = 50) (66% versus 97% for WDLPS, p < 0.001; 59% versus 97% for DDLPS, p < 0.001). For patients with primary surgery, histopathological grading on biopsy and surgery was concordant in only 47% of cases. Sensitivity for detecting WDLPS was higher than for DDLPS (70% versus 41%). Higher histopathological grading in surgical specimens correlated with worse survival outcomes (p = 0.01)., Conclusion: Histopathological grading of RPS may no longer be reliable after neoadjuvant treatment. The true accuracy of the percutaneous biopsy may need to be studied in patients who do not receive neoadjuvant treatment. Future biopsy strategies should aim to improve identification of DDLPS to inform patient management., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

(1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor on T cells, has been associated with dismal outcomes and advanced tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods: Tumor cell expression of TIM-3 on protein level was analyzed in pre-treatment biopsies of patients with HR-STS. TIM-3 expression was correlated with clinicopathological parameters including tumor-infiltrating lymphocyte (TIL) counts, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) expression in patients with HR-STS. Survival dependent on the expression of TIM-3 was analyzed. (3) Results: TIM-3 expression was observed in 101 (56%) out of 179 pre-treatment biopsies of patients with HR-STS. TIM-3 expression was significantly more often observed in undifferentiated pleomorphic sarcomas (UPS) compared to other histological subtypes ( p < 0.001), high TIL counts ( p < 0.001), and high PD-1 ( p < 0.001) and PD-L1 expression ( p < 0.001). TIM-3 expression did not have a prognostic impact on survival in patients with HR-STS. (4) Conclusions: This is the first study to demonstrate a significant tumor cell expression of TIM-3 in specific subsets of patients with HR-STS. TIM-3 qualifies as a potential immunotherapeutic target in HR-STS.

Purpose: The combination of hyperthermia (HT) with radio(chemo)therapy or chemotherapy (CT) is an established treatment strategy for specific indications. Its application in routine clinical practice in Europe depends on regulatory and local conditions. We conducted a survey among European clinical centers to determine current practice of HT., Methods: A questionnaire with 22 questions was sent to 24 European HT centers. The questions were divided into two main categories. The first category assessed how many patients are treated with HT in combination with radio(chemo)therapy or CT for specific indications per year. The second category addressed which hyperthermia parameters are recorded. Analysis was performed using descriptive methods., Results: The response rate was 71% (17/24) and 16 centers were included in this evaluation. Annually, these 16 centers treat approximately 637 patients using HT in combination with radio(chemo)therapy or CT. On average, 34% (range: 3-100%) of patients are treated in clinical study protocols. Temperature readings and the time interval between HT and radio(chemo)therapy or CT are recorded in 13 (81%) and 9 (56%) centers, respectively. The thermal dose quality parameter "cumulative equivalent minutes at 43 °C" (CEM43°C) is only evaluated in five (31%) centers for each HT session. With regard to treatment sequence, 8 (50%) centers administer HT before radio(chemo)therapy and the other 8 in the reverse order., Conclusion: There is a significant heterogeneity among European HT centers as to the indications treated and the recording of thermometric parameters. More evidence from clinical studies is necessary to achieve standardization of HT practice., (© 2022. The Author(s).)

Introduction: Osteosarcoma is typically a disease of the young, but may affect any age. Little is known about the disease in older patients beyond retirement age. We aim to describe the characteristics, treatment, and outcomes of older adult patients registered with our cooperative group., Materials and Methods: The database of the Cooperative Osteosarcoma Study Group (COSS) was searched for osteosarcoma patients diagnosed from 1980 to 2020 who were aged 65 years or older at diagnosis. Affected individuals were analyzed for presenting factors, treatments employed, and outcomes., Results: Fifty-five eligible patients were detected (median age 68 [range: 65-84] years; male:female = 25:30). Among these patients, 15/55 (27%) tumors were secondary malignancies, 41/55 (75%) were high-grade central, 4/55 (7%) surface, and 10/55 (18%) extraosseous malignancies, and all but three high-grade. Primary metastases were present in 15/55 (27%) patients. Surgery was reported for 46/55 (84%) patients, radiotherapy for 6/54 (11%, 1 unknown), chemotherapy for 42/50 (84%, 5 unknown). A complete surgical remission was achieved in 31/55 (56%). There were two toxic deaths. With a median follow-up of 1.7 (range: 0.1-18.0) years for all 55 patients and 2.2 (0.1-12.4) years for 24 survivors, event-free and overall survival at 2/5 years were 39.6% (standard error: 6.8%) / 24.5% (6.5%) and 62.0% (7.1%) / 32.7% (7.5%), respectively. Tumor site, metastatic status, surgery, and a complete surgical remission were prognostic for event-free and/or overall survival., Discussion: Osteosarcomas can occur in older individuals. It is more often secondary, axially located, or extraosseous than in younger patients. However, the same treatment principles seem to apply, and selected patients may be cured. Multi-center cooperation is encouraged, thereby gathering expertise for such a rare disease presentation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Regional hyperthermia (RHT) with cisplatin added to gemcitabine showed efficacy in gemcitabine-pre-treated patients with advanced pancreatic ductal adenocarcinoma. We conducted a randomised clinical trial to investigate RHT with cisplatin added to gemcitabine (GPH) compared with gemcitabine (G) in the adjuvant setting of resected pancreatic ductal adenocarcinoma., Methods: This randomised, multicentre, open-label trial randomly assigned patients to either GPH (gemcitabine 1000 mg/m 2 on day 1, 15 and cisplatin 25 mg/m 2 with RHT on day 2, 3 and 15,16) or to G (gemcitabine 1000 mg/m 2 on day 1,8,15), four-weekly over six cycles. Disease-free survival (DFS) was the primary end-point. Secondary end-points included overall survival (OS) and safety., Results: A total of 117 eligible patients (median age, 63 years) were randomly allocated to treatment (57 GPH; 60 G). With a follow-up time of 56.6 months, the median DFS was 12.7 compared to 11.2 months for GPH and G, respectively (p = 0.394). Median post-recurrence survival was significantly prolonged in the GPH-group (15.3 versus 9.8 months; p = 0.031). Median OS reached 33.2 versus 25.2 months (p = 0.099) with 5-year survival rates of 28.4% versus 18.7%. Excluding eight patients who received additional capecitabine in the G-arm (investigators choice), median OS favoured GPH (p = 0.052). Adverse events CTCAE (Common Terminology Criteria for Adverse Events) grade ≥3 occurred in 61.5% (GPH) versus 63.6% (G) of patients. Two patients in the G-group died because of treatment-related toxic effects., Conclusions: The randomised controlled Hyperthermia European Adjuvant Trial study failed to demonstrate a significant difference in DFS. However, it suggests a difference in post-recurrence survival and a trend for improved OS., Clinicaltrials: gov, number NCT01077427., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Owing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence., Methods: During the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma. We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022., Results: Sixty-two European sarcoma experts participated in the survey. Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus., Conclusions: In this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS., Competing Interests: Conflict of interest statement The authors declare following conflicts of interest: CR: Consulting or Advisory Role (Payment to Institution): Bayer (Schweiz) AG, Bristol-Myers Squibb, Ipsen, MSD Oncology, Pfizer; Consulting or Advisory Role (Payment to me): Merck (Schweiz) AG; Travel Expenses (Payment to me): PharmaMar; Research Funding (Payment to Institution): Astellas Pharma AG. DA: has received institutional research support from Implantcast GmbH and invited speaker fees from PharmaMar.WGK: served as advisor to Bristol Myers Squibb, unrelated. JYB: grants or research support from AstraZeneca, Bayer, Bristol Myers Squibb, Deciphera, Glaxo SmithKline, Merck Sharp & Dohme, Novartis, PharmaMar, and Roche; has an advisory or board member role in Innate Pharma; and receives honorarium from Bayer, Deciphera, Novartis, and Roche. ID: no COI. PD: Honoraria for consultancy or advisory role: Ayala Pharmaceuticals, Deciphera. RH: no COI. JJ: has received travel expenses or honoraria for participation in advisory boards or invited speaker fees from PharmaMar, Pfizer and Belpharma. LHL: Honoraria and compensation for advisory boards: Boehringer Ingelheim, Novartis, Lilly, Eisai, EL Medconsult, Roche; Travel and research grants: Dr. Sennewald Medizintechnik; Travel grants: PharmaMar; Stockownerships: Thermosome (co-founder) CM: no COI. ABM: Trustee Sarcoma UK, no other conflict of interest. TB: reports personal fees from PharmaMar and Deciphera (lecture fee, advisory board) ABM: Trustee Sarcoma UK, no other conflict of interest. RLJ: Receipt of grants/research support: MSD, GSK. Receipt of consultation fees: Adaptimmune, Astex, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Immunicum, Karma Oncology, Lilly, Merck, Mundipharma, Pharmamar, Springworks. SynOx, Tracon, Up to Date. IJ: No conflicts of interest. PR: has received honoraria for participation in advisory boards for Bayer, Novartis, Roche, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, GSK, Boehringer Ingelheim and invited speaker fees from Clinigen, Deciphera, PharmaMar, Boehringer Ingelheim. JS: Participation in advisory boards or invited speaker fees: PharmaMar, Bayer, Roche, Lilly, Amgen; Travel expenses: PharmaMar, Roche, Lilly, Amgen, Bristol Myers Squibb; Research funding: PharmaMar, Roche, Eisai. WvdG: research grant funding from Eli Lilly, advisory board participation Springworks, Bayer, PTC Therapeutics – all to the institute. WJvH: received institutional honoraria for participation in advisory board for Belpharma, invited speaker fees from Amgen andreports expert testimony for Sanofi and MSD and personal travel grant from Novartis and institutional research grant from BMS. EW: has received honoraria for participation in advisory boards or invited speaker fees from Bayer, Roche, Deciphera, Boehringer Ingelheim, Bristol Myers Squibb, PharmaMar. SH: no COI., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alveolar soft part sarcoma (ASPS) is a rare malignancy with low sensitivity to chemotherapy. While localized ASPS has a very good prognosis after resection, the 5-year overall survival rate drops substantially in metastatic disease. We report the case of an 80-year-old male patient with ASPS of the left elbow and metastasis to the lung, lymph nodes and peritoneum. After weighing the benefits and risks, systemic treatment with the anti-PD-1 checkpoint inhibitor pembrolizumab combined with the vascular endothelial growth factor receptor tyrosinkinase inhibitor axitinib was initiated in this patient with a history of psoriasis and Crohn's disease. After only two cycles of therapy, a significant size reduction of the nodal cervical metastasis became apparent. A partial response of all metastases was then confirmed in the first computed tomography restaging. So far, side effects have remained manageable, especially with regard to the development or worsening of autoimmune adverse events. The patient continued to have a high quality of life, while also remaining in ongoing partial response for 15 months at the time of submission. While sarcomas generally have low sensitivity to immunotherapies, ASPS is an exception, and checkpoint inhibition is an integral part of its systemic therapy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Soft tissue sarcomas (STSs) are rare diseases. A high level of standardization and centralization was lacking in Germany until 2018., Methods: By developing an evidence-based guideline and a certification system for sarcoma centres, foundations for structured, guideline-based, and centralized sarcoma care were defined. First results of the certified sarcoma centres are presented., Results: The first 3 years of data collection show good results for case volume, presentation rates in pretherapeutic and postoperative tumour boards, psycho-oncological counselling, and study rates. However, other indicators (e.g., preoperative or postoperative radiotherapy for operated high-risk STS without GIST, counselling rates social services) still have potential for improvement. Based on these results, the set of indicators could be further improved., Conclusions: A sarcoma-specific quality assurance scheme that includes guideline-derived quality indicators was developed. In future, a broader database will allow further insights into sarcoma care in Germany., (© 2023 S. Karger AG, Basel.)

Background: The therapy of high-risk soft tissue sarcomas (STS) remains an interdisciplinary challenge. Regional hyperthermia (RHT) sparked interest as it has been shown to improve overall survival when added to perioperative chemotherapy (CTX). However, questions arise on how RHT should be optimally integrated into current multi-modal therapies., Materials and Methods: We performed a systematic literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies written in English and focused mainly on radiative RHT and superficial hyperthermia were evaluated and included. Studies including patients below the age of 18, with metastatic disease or review articles, were excluded., Results: We identified 15 clinical reports from 1990 until July 2022. Three articles combined RHT + CTX, and twelve focused on combined RHT + radiotherapy (RT) or neoadjuvant chemoradiotherapy (CRT). Most treatments were based on invasive thermometry, and less on magnetic resonance imaging (MRI)-based, noninvasive thermometry for STS of the extremities. Perioperative chemotherapy was used for the combination of RHT and CTX, mostly Ifosfamide-based. The effectiveness of RT appeared to be increased by RHT, especially with two RHT sessions/week. The trimodal simultaneous approach of neoadjuvant RHT and CRT was also feasible. No significant toxicity of RHT was reported., Conclusions: The gathered data strengthen the beneficial role of RHT in the multimodal setting. Further expert consensus and clinical trials are required to determine the optimal integration of RHT in treating STS.

This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23-84) and leiomyosarcoma was the most frequent histotype ( n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment ( n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3-6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6-21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.

The medical use of Cannabis has gained popularity in Europe and Northern America in recent years. Cannabinoids are available as finished pharmaceuticals, flowers and extracts. This article focuses on supportive medicine for oncological patients. Possible indications are pain, chemotherapy-induced nausea and vomiting, loss of appetite and altered taste perception. Despite the enormous cannabis hype in medicine, the evidence for its use in oncology patients is insufficient. However, palliative patients with refractory symptoms could be candidates for a therapeutic trial. The key parameter for choosing a cannabis medicinal product is the THC/CBD ratio. Oral forms of administration are particularly suitable for cannabis-naive and older patients. Mental and cardiovascular side effects should not be underestimated., Competing Interests: Anton Burkhard-Meier arbeitet nebenberuflich als Medical Advisor für HEYDAY.Für die übrigen Autoren bestehen keine Interessenskonflikte., (Thieme. All rights reserved.)

Purpose: MR temperature monitoring of mild radiofrequency hyperthermia (RF-HT) of cancer exploits the linear resonance frequency shift of water with temperature. Motion-induced susceptibility distribution changes cause artifacts that we correct here using the total field inversion (TFI) approach., Methods: The performance of TFI was compared to two background field removal (BFR) methods: Laplacian boundary value (LBV) and projection onto dipole fields (PDF). Data sets with spatial susceptibility change and B 0 -drift were simulated, phantom heating experiments were performed, four volunteer data sets at thermoneutral conditions as well as data from one cervical cancer, two sarcoma, and one seroma patients undergoing mild RF-HT were corrected using the proposed methods., Results: Simulations and phantom heating experiments revealed that using BFR or TFI preserves temperature-induced phase change, while removing susceptibility artifacts and B 0 -drift. TFI resulted in the least cumulative error for all four volunteers. Temperature probe information from four patient data sets were best depicted by TFI-corrected data in terms of accuracy and precision. TFI also performed best in case of the sarcoma treatment without temperature probe., Conclusion: TFI outperforms previously suggested BFR methods in terms of accuracy and robustness. While PDF consistently overestimates susceptibility contribution, and LBV removes valuable pixel information, TFI is more robust and leads to more accurate temperature estimations., (© 2022 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Encapsulation of cytotoxic drugs for a localized release is an effective way to increase the therapeutic window of such agents. In this article we present the localized release of doxorubicin (DOX) from phosphatidyldiglycerol (DPPG 2 ) based thermosensitive liposomes using MR-HIFU mediated hyperthermia in a swine model., Materials and Methods: German landrace pigs of weights between 37.5 and 53.5 kg received a 30-min infusion of DOX containing thermosensitive liposomes (50 mg DOX/m 2 ). The pigs' biceps femoris was treated locally in two separate target areas with mild hyperthermia using magnetic resonance guided high intensity focused ultrasound, starting 10 min and 60 min after initiation of the infusion, respectively. The pharmacokinetics and biodistribution of DOX were determined and an analysis of the treatment parameters' influence was performed., Results: Compared to untreated tissue, we found a 15-fold and a 7-fold increase in DOX concentration in the muscle volumes that had undergone hyperthermia starting 10 min and 60 min after the beginning of the infusion, respectively. The pharmacokinetic analysis showed a prolonged circulation time of DOX and a correlation between the AUC of extra-liposomal DOX in the bloodstream and the amount of DOX accumulated in the target tissue., Conclusions: We have demonstrated a workflow for MR-HIFU hyperthermia drug delivery that can be adapted to a clinical setting, showing that HIFU-hyperthermia is a suitable method for local drug release of DOX using DPPG 2 based thermosensitive liposomes in stationary targets. Using the developed pharmacokinetic model, an optimization of the drug quantity deposited in the target via the timing of infusion and hyperthermia should be possible., (Copyright © 2022 Elsevier B.V. All rights reserved.)

(1) Background: V domain immunoglobulin suppressor of T cell activation (VISTA) plays a critical role in antitumor immunity and may be a valuable target in cancer immunotherapy. To date, it has never been studied in a large and well-characterised cohort of soft tissue sarcomas (STS). (2) Methods: Using immunohistochemistry, we examined VISTA expression in tumour tissues of 213 high-risk STS. We then analysed whether VISTA was associated with other clinicopathological parameters, including tumour-infiltrating lymphocyte (TIL) counts, programmed death receptor-1 (PD1), programmed death ligand-1 (PDL1), CD3, grading, and long-term survival. (3) Results: We observed VISTA expression in 96 (45%) of 213 specimens with distinct patterns ranging from 26 to 63% for histological subtypes. VISTA was associated with higher grade (G3 vs. G2, p = 0.019), higher TIL counts ( p = 0.033), expression of PD1 ( p = 0.046), PDL1 ( p = 0.031), and CD3+ ( p = 0.023). In patients without CD3 + TILs, 10-year survival was higher when VISTA was expressed compared to when there was no VISTA expression ( p = 0.013). In a multivariate analysis, VISTA expression was independently associated with prolonged survival ( p = 0.043). (4) Conclusions: VISTA is expressed in different STS subtypes and is associated with increased TILs, PD-1, PD-L1, and CD3 expression. Patients with VISTA + tumours show improved survival. These results may help define future immunotherapeutic approaches in STS.