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Anna M Czarnecka,1 Jacek Skoczylas,1 Ewa Bartnik,2,3 Tomasz Świtaj,1 Piotr Rutkowski1 1Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland; 2Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland; 3Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, PolandCorrespondence: Anna M Czarnecka, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, W.K. Roentgena 5 street, Warsaw, 02-781, Poland, Tel + 48 22 546 2194, Email anna.czarnecka@gmail.comAbstract: PEComa (PEC tumor; perivascular epithelioid cell tumors) is a rare group of tumors of mesenchymal origin composed of perivascular epithelioid cells (PEC) with features of melanotic and smooth muscle differentiation. In this article, we would like to present the current treatment options for this group of tumors. PEComas are classified as tumors of uncertain malignant potential because recurrences occur after radical treatment. The primary treatment is surgical resection with negative margins. Due to the different locations of the tumors, often the cooperation of multispecialty surgeons is required during the operations. In locally advanced cases, cytoreduction and HIPEC may be effective but still are an experimental treatment. For nonresectable PEComa chemotherapy, mTOR inhibitors and VEGFR inhibitors are used.Keywords: PEComa, sarcoma, surgery, chemotherapy, oncology more...

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells' invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma. more...

Immune checkpoint inhibitors (ICI) can achieve durable responses in patients with advanced melanoma, and results from clinical trials suggest cure may be possible for a subset of patients. Despite clinical trial data, little is known about the risk, character, and clinical outcome of late recurrences after ICI. This study aimed to explore the disease outcomes and survival in a cohort of patients with long-term responses to ICI. We retrospectively identified patients treated with ICI for advanced melanoma with long-term disease control, defined as not requiring a subsequent line of systemic therapy within 3 years of ICI commencement. We analysed disease characteristics, treatment, toxicity, recurrence patterns, management, and outcomes. A total of 567 patients were identified with a median follow-up of 7.1 years: 504 (89 %) without disease progression within 3 years (cohort 1) and 63 (11.1 %) with disease progression within 3 years managed without a change in systemic therapy (cohort 2). Subsequent progression after 3 years occurred for 39 (7.7 %) patients in cohort 1, compared to 14 (22 %) in cohort 2. Predictors for late progression after 3 years were a non-complete radiological response (CR) best response and prior progression within 3 years. Thirty-two patients (5.6 %) died during follow-up, 8 (1.4 %) from melanoma, 6 (1.2 %) from cohort 1 and 2 (3.2 %) from cohort 2. In this population of patients with advanced melanoma with long-term disease control from ICI, the risk of subsequent disease progression and death was low. This suggests that a significant proportion of long-term ICI responders are likely cured and may inform the frequency and duration of follow-up., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RJS reports having served on advisory boards/performed consulting for BMS, Merck, Marengo, Pfizer, Novartis, and Replimune and received research funding from Merck. DBJ reports having served on advisory boards or as a consultant for AstraZeneca, BMS, Jackson Laboratories, Merck, Novartis, Pfizer, and Teiko. MSC reports having served on advisory boards or as a consultant for Amgen, BMS, Eisai, Ideaya, MSD, Nektar, Novartis, Oncosec, Pierre-Fabre, Qbiotics, Regeneron, Roche, Merck, Strand Pharmaceuticals, Onchilles and Sanofi, and received honoraria from BMS, MSD, and Novartis. GVL is consultant advisor for Agenus, Amgen, Array Biopharma, AstraZeneca, Bayer, BioNTech, Boehringer Ingelheim, Bristol Myers Squibb, Evaxion, GI Innovation, Hexal AG (Sandoz Company), Highlight Therapeutics S.L., IOBiotech, Immunocore, Innovent Biologics USA, MSD, Novartis, PHMR Ltd, Pierre Fabre, Regeneron, Scancell, SkylineDX B.V. SNL has received fees for professional services from SkylineDx and a stipend for editorial services at the British Journal of Dermatology. AMM has served on advisory boards for BMS, MSD, Novartis, Roche, Pierre-Fabre, QBiotics. PR has received honoraria for lectures and Advisory Boards from MSD, BMS, Novartis, Pierre Fabre, Merck, Genesis Pharma, Medison Pharma outside of the scope of this study. AMC reports having served as a speaker for Pierre Fabre, MSD, BMS and Novartis. PAA has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Pierre-Fabre, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Boehringer-Ingelheim, Regeneron, Pfizer, Nouscom, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer, Erasca, Philogen, Biontech, Anaveon, Genmab, Menarini. He also received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer, Sanofi. Travel support by Pfizer, Bio-Al Health, Replimmune, MSD, Pierre Fabre, Philogen. BN reports having served on advisory boards or as a consultant for Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, and Novartis and his institution (UZ Brussel) received research funding outside the scope of this study. CL reports having served on advisory boards or as a consultant or speaker for BMS, Pierre Fabre, Sanofil, Novartis, MSD, Amgen, Merck Senoro, Roche, Inflax, Pfizer, Incyte and has received research funding from BMS and Roche outside the scope of this study. CA reports having served as a speaker for Novartis. LZ served as consultant and has received honoraria from BMS, MSD, Novartis, Pierre Fabre, Sanofi, and Sunpharma and travel support from MSD, BMS, Pierre Fabre, Sanofi, Sunpharma and Novartis, outside the submitted work. MO has served as a speaker for BMS, Novartis and MDS. LJA received honoraria from Novartis, Sunpharma and Bristol-Myers Squibb and travel support from Sunpharma, Takeda and Sanofi, outside the submitted work. JIK has received honoraria from AMGEN, BMS, Janssen. Travel support by LEO pharma, UCB and Janssen. Research funds from LEO pharma. RD has intermittent, project focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, T3 Pharma, MaxiVAX SA, Pfizer and Simcere outside the submitted work. JM has intermittent project focused consultant or advisory relationships with Merck Sharp & Dohme, Novartis, Johnson & Johnson, Bristol Myers Squibb and Pierre Fabre and has received travel support from L′ oreal, Merck Sharp & Dohme, Bristol Myers and Squibb und Pierre Fabre outside of the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.) more...

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that is usually diagnosed between the ages of 20 and 40. Changes in the immune system also observed in cancer may suggest a higher prevalence of cancer in the MS patient population. In recent years, many highly effective immunosuppressive drugs have been introduced into disease-modifying therapy (DMT) which may be associated with a higher risk of cancer development in patients with MS. This paper presents current data on the oncological risk of individual drugs. In addition, it provides recommendations on the management for qualifying for DMT and monitoring the safety of the therapy from anoncological perspective. more...

Sarcomas are a rare type of malignancy with limited treatment options so far. This analysis aimed to describe the impact of lymphadenectomy on treating sarcoma patients. Sarcomas characterized by lymphatic spread are rare. For this reason, lymphadenectomy is not a procedure that is performed frequently. However, there are histological subtypes that spread more frequently through lymphatic vessels, such as rhabdomyosarcoma (RMS), epithelioid sarcoma (ES), clear cell sarcoma (CCS), and angiosarcoma. On the other hand, synovial sarcoma (SS) is not characterized by an increased tendency to lymphogenous metastases. In our study, we focus on these subtypes of sarcomas. The relationship between lymphadenectomy results and the subsequent prognosis of the patients was investigated. Metastases in the lymph nodes are diagnosed synchronously with distant metastases or when the primary tumor is detected. At the same time, despite lymphadenectomy, sarcoma patients developed further distant metastases. Currently, lymphadenectomy is not a routinely recommended method of treatment for patients with sarcomas. Most often, its potential use is indicated in the case of epithelioid sarcoma, clear cell sarcoma, and rhabdomyosarcoma after a previous positive sentinel lymph node biopsy (SLNB) result. Multicenter randomized prospective clinical trials on the role of lymphadenectomy in the treatment of sarcomas are needed., Competing Interests: The 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 © 2024 Dunaj, Żukowska, Czarnecka, Krotewicz, Borkowska, Chmiel, Świtaj and Rutkowski.) more...

Recent years have brought new, highly effective systemic treatments to clinical practice, which can be used to treat patients with locally advanced or metastatic skin cancers. Using these regimens in neoadjuvant strategy influences surgical treatment by facilitating surgical resection, avoiding extensive resections with complex reconstructions and even omitting surgery in some cases. Integrating systemic therapy with surgery is ongoing and requires novel quality measures of surgical treatment to capture the clinical benefits of multidisciplinary strategies better. The Textbook Outcome (TO) is a novel measure of surgical quality, which captures the short-term outcomes of surgery and reflects long-term survival. Textbook Outcomes match a particular type of surgery, are intuitive to interpret, and may be widely applied in surgical oncology and general surgery. Therefore, this review aims to describe recent findings on neoadjuvant skin cancer treatment and their implications for surgical proceedings in the context of Textbook Outcomes. more...

Background: Genomic tumour profiling has a crucial role in the management of patients with solid cancers, as it helps selecting and prioritising therapeutic interventions based on prognostic and predictive biomarkers, as well as identifying markers of hereditary cancers. Harmonised approaches to interpret the results of genomic testing are needed to support physicians in their decision making, prevent inequalities in precision medicine and maximise patient benefit from available cancer management options., Methods: The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group assembled a group of international experts to propose recommendations for preparing clinical genomic reports for solid cancers. These recommendations aim to foster best practices in integrating genomic testing within clinical settings. After review of available evidence, several rounds of surveys and focused discussions were conducted to reach consensus on the recommendation statements. Only consensus recommendations were reported. Recommendation statements were graded in two tiers based on their clinical importance: level A (required to maintain common standards in reporting) and level B (optional but necessary to achieve ideal practice)., Results: Genomics reports should present key information in a front page(s) followed by supplementary information in one or more appendices. Reports should be structured into sections: (i) patient and sample details; (ii) assay and data analysis characteristics; (iii) sample-specific assay performance and quality control; (iv) genomic alterations and their functional annotation; (v) clinical actionability assessment and matching to potential therapy indications; and (vi) summary of the main findings. Specific recommendations to prepare each of these sections are made., Conclusions: We present a set of recommendations aimed at structuring genomics reports to enhance physician comprehension of genomic profiling results for solid cancers. Communication between ordering physicians and professionals reporting genomic data is key to minimise uncertainties and to optimise the impact of genomic tests in patient care., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...

Osteosarcoma (OSa) is the most prevalent primary malignant bone tumor in children and adolescents, characterized by complex genetic and epigenetic alterations. Traditional treatments face significant challenges due to high rates of drug resistance and lack of targeted therapies. Recent advances in microRNA (miRNA) research have opened new avenues for understanding and treating osteosarcoma. This review explores the many critical functions of miRNAs in osteosarcoma, particularly their potential for clinical use. The review highlights two key areas where miRNAs could be beneficial. Firstly, miRNAs can act as biomarkers for diagnosing osteosarcoma and predicting patient prognosis. Secondly, specific miRNAs can regulate cellular processes like proliferation, cell death, migration, and even resistance to chemotherapy drugs in osteosarcoma. This ability to target multiple pathways within cancer cells makes miRNA-based therapies highly promising. Additionally, though the interaction between miRNAs and circular RNAs (circRNAs) falls outside the scope of the paper, it has also been discussed briefly. While miRNA-based therapies offer exciting possibilities for targeting multiple pathways in osteosarcoma, challenges remain. Efficient delivery, potential off-target effects, tumor complexity, and rigorous testing are hurdles to overcome before these therapies can reach patients. Despite these challenges, continued research and collaboration among scientists, clinicians, and regulatory bodies hold the promise of overcoming them. This collaborative effort can pave the way for the development of safe and effective miRNA-based treatments for osteosarcoma., (© 2024. The Author(s).) more...

Background: Neoadjuvant-adjuvant therapy for locally advanced or potentially resectable metastatic melanoma was expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment only., Methods: Forty-seven consecutive patients were treated with neoadjuvant-adjuvant BRAF inhibitors (BRAFi)/MEK inhibitors (MEKi) and surgery., Results: Twelve (26%) patients achieved a pathological complete response and 10 (21%) patients achieved a near-complete response. In the whole group, median recurrence-free survival was 19.4 months and median distant metastasis-free survival (mDMFS) was 21.9 months. In patients with a pathological complete response (pCR)/near-pCR median recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) were significantly longer than in patients with minor pathological response with hazard ratio (HR) = 0.37 (p = .005) for RFS and HR = 0.33 (p = .002) for DMFS. After median follow-up of 52.5 months, median progression-free survival since BRAFi/MEKi therapy initiation was 25.1 months. The median time-to-treatment-failure since initiation of neoadjuvant therapy was 22.2 months and was significantly longer in patients with pCR/near-pCR (HR = 0.45; p = .022). Neoadjuvant therapy did not result in any new specific complications of surgery. After 48 months, RFS and overall survival were 36.3% and 64.8% or 20% and 37.4% in patients with pCR/near-pCR and pathological partial response/pathological nonresponse, respectively., Conclusions: The authors confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of stage III/IV melanoma. Major pathological response to neoadjuvant treatment is a surrogate marker of recurrence including DMFS in these patients., Plain Language Summary: Our study presents a large comprehensive analysis of neoadjuvant-adjuvant systemic therapy in patients diagnosed with marginally resectable stage III or IV melanoma. Neoadjuvant therapy effectively reduced the volume of the disease, which facilitated subsequent surgical resection. After median follow-up of 52.5 months, median progression-free survival since therapy initiation was 25.1 months. Twelve patients had complete pathological response and 10 patients had a near-complete pathological response-and together they had median recurrence-free survival and distant metastasis-free survival significantly longer than in patients with pathological partial response or nonresponse. Complete/near-complete pathological response to neoadjuvant treatment is a surrogate marker of recurrence-free, including distant metastasis-free, survival in these patients., (© 2024 American Cancer Society.) more...

Our study was carried out to define the efficacy of treatment with sequential chemotherapy lines in patients with epithelioid sarcoma (ES) at referral centres for sarcoma. From 1998 to 2023, 22 patients with ES were treated with chemotherapy and included in the analysis. The median age at the start of palliative treatment was 35 (20-68). The median follow-up was 22.1 months. In the first line, 13 patients (59%) received anthracycline-based chemotherapy and 6 (27%) high-dose ifosfamide. One patient (4.5%) achieved PR, 15 (68%) SD, and 6 (32%) PD as the best response. The median progression-free survival (PFS) in the first line was 6.4 months (95% CI: 3.02-12.9), but 9.7 months (95% CI: 4.37-NR) for chemotherapy based on anthracycline, indicating a more favourable PFS ( p  = 0.027). Twenty (90%) patients received second-line treatment, and eleven received third-line chemotherapy. The median OS from the start of first-line palliative chemotherapy was 22.1 months (95% CI: 10.5-41.4) and 14.7 months from the beginning of the second line. Perioperatively, patients pretreated with anthracycline had a median PFS of 2.9 months in the M1 setting. Second-line long-time responses were achieved with pazopanib or vincristine with actinomycin D. Despite chemoresistance, an advantage associated with anthracycline-based chemotherapy was confirmed in the ES cohort. Poor responses underscore the need for further research on targeted therapies for ES. Second-line chemotherapy or clinical trials should be offered to all eligible patients. more...

Clear cell sarcoma is an ultra-rare chemoresistant subtype of soft tissue sarcoma. This retrospective analysis aimed to clarify the efficacy of palliative chemotherapy in CCS by assessing response rates, progression-free survival (PFS), and overall survival (OS) at a referral center. A retrospective analysis of palliative treatment was conducted on patients with CCS treated at the sarcoma unit from 1997 to 2023. Treatment responses were assessed using RECIST criteria, and the Kaplan-Meier method was used to calculate PFS and OS. The analysis covered 23 CCS chemotherapy-treated patients with 11 (47.8%) men. The median age at the palliative treatment start was 32 years (range 18-59). The median follow-up was 8.2 months. Four patients were referred to our centre for M1 disease, and 6 received perioperative chemotherapy and progressed during follow-up. In the first line, 14 patients received anthracycline-based chemotherapy (60.9%), five were treated with ifosfamide (HD-IFO), and four received other regimens. One patient (4.3%) achieved partial response (PR), and 12 patients (52.2%) achieved stable disease (SD) as the best response. Median PFS in 1 line was 2.79 months (95% CI: 2.04-8.38), and 1.76 months (95% CI: 0.72-6.97) in the second line. The median OS from first-line palliative chemotherapy was 8.2 months (95% CI: 6.2-14), and the second-line palliative chemotherapy mOS was 4.6 months (95% CI: 3.9-NA). Perioperatively anthracycline-pretreated worsened patients' median PFS in the M1 setting. Poor responses to conventional chemotherapy were observed in CCS, indicating a need for further clinical trials in this indication. more...

Background: Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice., Methods: The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility., Results: As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available., Conclusion: Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer., Competing Interests: Disclosure MFM reports receipt of a fee to institution as an invited speaker from Novartis; part-time employment in PEGASCY. CBW reports receipt of a fee for participation in Advisory Board from BMS, Celgene, Rafael, RedHill, Roche, Shire/Baxalta; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Bayer, BMS, Celgene, Chugai, Falk, GSK, Janssen, Merck, MSD, Roche, Servier, Sirtex, Taiho; receipt of a fee for an expert testimony from Janssen; receipt of travel support from Bayer, Celgene, RedHill, Roche, Servier, Taiho; non-financial interest for receipt of research grant both personal and to institution from Roche; non-financial interest for serving as an officer in AIO—Arbeitsgemeinschaft Internistische Onkologie (Germany); non-financial interest for advisory role in EU Commission—DG RTD as a member of the EU Commission Mission Board for Cancer. ASt reports receipt of a fee for participation in Advisory Board from Aignostics, Amgen, AstraZeneca, Bayer, Eli Lilly, Illumina, Janssen, MSD, Pfizer, Seattle Genetics, Thermo Fisher; receipt of a fee to institution for participation in Advisory Board from BMS, Novartis, Takeda; receipt of a fee as an invited speaker from Incyte, Roche; receipt of research grant to institution from Bayer, BMS, Chugai, Incyte. FB reports receipt of a fee to institution for participation in Advisory Board from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Ignyta, Merck, Mirati, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi Aventis, Seattle Genetics, Takeda; non-financial interest as a principal investigator from AstraZeneca, BMS, F. Hoffmann-La Roche Ltd., Innate Pharma, Merck, Mirati, Piere Fabre. AB reports receipt of a fee for participation in Advisory Board from Sanofi; receipt of a fee as an invited speaker from Roche. IB reports receipt of a fee as an invited speaker from AstraZeneca. JB reports receipt of a fee for participation in Advisory Board from BMS, Janssen, MSD; receipt of funding for study to institution from BMS. EC reports receipt of a fee for participation in Advisory Board from Astellas, AstraZeneca, Bayer, Daiichi Sankyo, Janssen, Eli Lilly, Medscape, MSD, Novartis, Pfizer; receipt of a fee as an invited speaker from Astellas, AstraZeneca, Clovis, Janssen, Medscape, Pfizer; receipt of funding to institution from AstraZeneca; receipt of research grants to institution from Bayer, Janssen, Pfizer; receipt of a fee to institution as a local principal investigator from Janssen, MSD, Pfizer. RD reports receipt of a fee for participation in Advisory Board from Foundation Medicine, Roche; receipt of a fee as an invited speaker from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, GlaxoSmithKline, Ipsen, Janssen, Libbs, Eli Lilly, Merck Sharp & Dohme, Roche, Sanofi, Servier, Takeda; part-time employment in Oncoclinicas; owning stocks/shares in Trialing; receipt of a research grant from Merck; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Novartis. AK reports receipt of a fee to institution for participation in Advisory Board from Roche; receipt of a fee as an invited speaker from Roche; funding to institution from Bristol Myers Squibb (BMS); non-financial interest as a principal investigator from Roche. AC reports receipt of a fee as an invited speaker from BMS, MSD, Novartis, Pierre Fabre. FMB reports receipt of a fee for participation in Advisory Board from Biovica, Eisai, Karyopharm, Protai, Seagen, Theratechnologies, Zentalis Pharmaceuticals; receipt of a fee for consultancy from AbbVie, AstraZeneca, Black Diamond Therapeutics, EcoR1, F. Hoffmann-La Roche Ltd., GT Aperion Therapeutics, Infinity Pharmaceuticals, Lengo Therapeutics, Loxo Oncology, Menarini Group, OnCusp Therapeutics, Seagen, Tallac Therapeutics, Zymeworks; non-financial interest as a coordinating principal investigator from AstraZeneca; non-financial interest as a local principal investigator from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, Calithera Biosciences, Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., KLUS Pharma, Novartis, Taiho Pharmaceuticals Co.; receipt of research grants to institution from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Puma Biotechnology, Repare Therapeutics, Taiho Pharmaceuticals Co., Takeda Pharmaceuticals Co.; non-financial interest for serving as a Steering Committee Member from Genentech Inc.; receipt of travel support from Cholangiocarcinoma Foundation, European Organisation for Research and Treatment (EORTC), European Society for Medical Oncology (ESMO). SM reports receipt of a fee for participation in Advisory Board, Study Scientific Committee member from Roche, receipt of a fee as DSMB member from Biophytis, IQVIA, Kedrion Biopharma, Servier, Yuhan Corporation. RM reports receipt of a fee for participation in Advisory Board from GSK, AstraZeneca, Merck; receipt of a fee as an invited speaker from GSK, AstraZeneca, Clovis Oncology; receipt of a fee for expert testimony from Shionogi and Ellipses. NN reports receipt of a fee for participation in Advisory Board from Amgen, AstraZeneca, Bayer, Biocartis, Incyte, Novartis, Roche; receipt of a fee as an invited speaker from Eli Lilly, Illumina, Merck, MSD, Thermo Fisher, Roche, Novartis, Sophia Genetics, GSK, Servier; receipt of research grants to institution from AstraZeneca, Biocartis, Illumina, Incyte, Merck, QIAGEN, Roche, Thermo Fisher. JRF reports receipt of a fee for participation in Advisory Board from AstraZeneca, Bain Capital, Daiichi Sankyo, Merck, MultiplexDX, Inc., Paige.AI, Personalis, Repare Therapeutics, Roche Tissue Diagnostics; receipt of a fee for consulting from Eli Lilly, Goldman Sachs, Paige.AI, Repare Therapeutics, Saga Diagnostics; financial interest as a member of Board of Directors from Grupo Oncoclinicas, Odyssey Bio; owning stock options in Paige.AI, Repare Therapeutics; non-financial interest from a leadership role as a President of International Quality Network for Pathology (IQN Path) and a Past President of Italian Cancer Society (SIC). JR reports receipt of grants/research support from MSD, AstraZeneca; receipt of a fee to institution for participation in Advisory Board from AstraZeneca, EDIMARK; for conducting sponsored research to institution from Merck; receipt of a fee to institution as an invited speaker from AstraZeneca, Sanofi, Takeda, Janssen, Roche; non-financial interest for a leadership role as a Secretary of EORTC Lung Cancer Group. MR reports receipt of a fee for participation in Advisory Board from myMedEd; receipt of a fee as an invited speaker from Clinical Care Options, MJH Holdings, myMedEd, Physician’s Education Resource; receipt of a fee for review guideline pathways from Change Healthcare; receipt of a fee to institution as a local principal investigator from AstraZeneca, Merck, or co-principal investigator from Merck and local co-principal investigator from Pfizer; non-financial interest for serving as a Steering Committee Member from AstraZeneca, Merck; non-financial interest for advisory role in Tempus Labs, Zenith Pharmaceuticals; non-financial interest for providing editorial services for medical writing from AstraZeneca, Pfizer; non-financial interest as a member of ASCO. ER reports receipt of a fee to institution for participation in Advisory Board from Amgen, AstraZeneca, GSK, Roche; receipt of a fee to institution as an invited speaker from BMS, Clovis; receipt of funding for data base to institution from AstraZeneca. ASc reports receipt of a fee for participation in Advisory Board from Incyte; receipt of a fee as an invited speaker from Amgen, Aristea—MSD, Tesaro-GSK. CS reports receipt of a fee for participation in Advisory Board from Blueprint Medicines, Cogent Biosciences, Deciphera Pharmaceuticals, IDRx, Immunicum, New Bay; receipt of a fee as an invited speaker from Roche, PharmaMar; receipt of a fee as Steering Committee Member, both personal and to institution, from Deciphera, NewBay; receipt of research grants to institution from IDRx; receipt of travel grant from Bayer AG, Gilead, Pfizer, PharmaMar; non-financial interest as ESMO Faculty member and serving as a member of Board of Directors in the Spanish Group for Sarcoma Research (GEIS) and Spanish Society of Medical Oncology (SEOM). JM reports receipt of a fee for participation in Advisory Board from Amgen, Amunix Pharmaceuticals, AstraZeneca, Janssen, Pfizer, Roche; receipt of a fee to institution for participation in Advisory Board from Nuage Therapeutics; receipt of a fee as an invited speaker from AstraZeneca, GuardantHealth, MSD; receipt of research grants to institution from Amgen, AstraZeneca, Pfizer Oncology; non-financial interest from receiving product samples for access to drugs in early development for preclinical testing from AstraZeneca. FA reports receipt of a fee to institution for participation in Advisory Board from AstraZeneca, Boston Pharmaceutics, Daiichi Sankyo, Gilead, Guardant Health, Eli Lilly, N-Power Medicine, Novartis, Owkin, Pfizer, Roche, Servier; receipt of a personal fee for participation in Advisory Board from Lilly France; receipt of research grants to institution from AstraZeneca, Daiichi Sankyo, Guardant Health, Ely Lilly, Novartis, Owkin, Pfizer, Roche., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.) more...

Introduction: Perioperative therapy has gained significant importance in patients with advanced melanoma. Currently, there is little data on the routine use of preoperative immunotherapy in metastatic melanoma outside clinical trials. This study aimed to evaluate the effectiveness of preoperative treatment in patients with borderline resectable stage III or IV melanoma as well as in oligoprogressing stage IV cases; the secondary aim is to describe the safety of surgery after immunotherapy., Materials and Methods: Since 1/Jan/2016 seventeen patients were treated with curative intent neoadjuvant immunotherapy, surgery, and adjuvant immunotherapy, while nineteen patients were operated due to oligoprogression while treted with immunotherapy. Survival was analyzed using the Kaplan-Meier method and association between variables was tested using the chi-squared test., Results: R0 resection was achieved in 76.5 % of cases after neoadjuvant immunotherapy. 24 % of patients achieved objective RECIST response and 35 % complete or major pathological response. At the median follow-up time of 51.4 months, 64.7 % of patients were free of PD after perioperative treatment, while 3-year RFS and OS rates were 68 % and 80.9 %, respectively. R0 resection was achieved in 73.7 % of oligo-progressing nodules. The median time to PD on immunotherapy after the first oligoprogression was 10.3 months. Immunotherapy did not result in any unexpected surgical complications. No patient died during preoperative treatment due to immunotherapy toxicity or disease progression., Conclusions: We confirmed treatment safety and long-term disease control after perioperative immunotherapy. Patients with borderline resectable melanoma should be referred to reference centers using neoadjuvant immunotherapy., 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., (© 2024 Published by Elsevier Ltd.) more...

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 Chmiel et al.) more...

Introduction: Soft tissue sarcomas (STS) are a rare and diverse group of tumors. Curative options are limited to localized disease, with surgery being the mainstay. Advanced stages are associated with a poor prognosis. Currently, the prognosis of the patient is based on histological classification and clinical characteristics, with only a few biomarkers having entered clinical practice., Areas Covered: This article covers extensive recent research that has established novel potential biomarkers based on genomics, proteomics, and clinical characteristics. Validating and incorporating these biomarkers into clinical practice can improve prognosis, prediction of recurrence, and treatment response. Relevant literature was collected from PubMed, Scopus, and clinicaltrials.gov databases (November 2023)., Expert Opinion: Currently, defining prognostic markers in soft tissue sarcomas remains challenging. More studies are required, especially to personalize treatment through advanced genetic profiling and analysis using individual tumor and patient characteristics. more...

Opinion Statement: Soft tissue sarcomas (STS) are rare tumours of mesenchymal origin, most commonly occurring in the extremity but also in the retroperitoneum. The curative treatment for STS is radical surgery with wide margins, in some cases in combination with perioperative radiotherapy and chemotherapy. Nonradical resection (R2) of STS has been an emerging issue in recent decades, as optimal subsequent management remains debatable. Similarly, there is still no consensus on optimal surgical margins. Combining multiple treatment modalities in adjuvant therapy can achieve local and distant control in patients following surgery with positive margins. Patients who have undergone nonradical resection therefore require additional surgical interventions, and adjuvant radiotherapy resulting in a better prognosis but a higher number of complications. Following non-radical treatment, patients with limb and trunk wall sarcomas and retroperitoneal sarcomas should also undergo increased oncological surveillance. Given the potential issues that may emerge in such clinical situations, it is crucial to up-date the current guidelines to enhance the long-term prognosis of these patients., (© 2024. The Author(s).) more...

Neoadjuvant systemic therapy is emerging as the best medical practice in patients with resectable stage III melanoma. As different regimens are expected to become available in this approach, the improved optimization of treatment strategies is required. Personalization of care in each individual patient-by precisely determining the disease-related risk and the most efficient therapeutic approach-is expected to minimize disease recurrence, but also the incidence of treatment-related adverse events and the extent of surgical intervention. This can be achieved through validation and clinical application of predictive and prognostic biomarkers. For immune checkpoint inhibitors, there are no validated predictive biomarkers until now. Promising predictive molecular biomarkers for neoadjuvant immunotherapy are tumor mutational burden and the interferon-gamma pathway expression signature. Pathological response to neoadjuvant treatment is a biomarker of a favorable prognosis and surrogate endpoint for recurrence-free survival in clinical trials. Despite the reliability of these biomarkers, risk stratification and response prediction in the neoadjuvant setting are still unsatisfactory and represent a critical knowledge gap, limiting the development of optimized personalized strategies in everyday practice. more...

Chondrosarcoma, the second most common primary malignant bone tumor, originates from cartilaginous tissue and accounts for almost 20% of all primary bone tumors. The management of chondrosarcoma remains challenging due to its diverse clinical course and prognosis, which can range from benign to highly aggressive with a huge risk of metastasis. Emerging research has demonstrated the importance of microRNA (miRNA) dysregulation in the pathogenesis of chondrosarcoma. MiRNAs are small, noncoding RNA molecules that play an essential role in gene expression regulation by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. This article provides an extensive review of current miRNA research in chondrosarcoma, focusing on diagnostic strategies, cell cycle regulation, drug resistance, biomarkers of progression, and stem cell phenotype. We will examine recent studies identifying differentially expressed miRNAs in chondrosarcoma compared to normal cartilage tissue, exploring their potential as diagnostic and prognostic biomarkers. Furthermore, we will discuss the role of miRNAs in regulating cell cycle progression and their potential as therapeutic targets to overcome drug resistance. We will also investigate the prospective utility of miRNAs as biomarkers of progression and their role in modulating the stem cell phenotype of chondrosarcoma cells. This article offers a comprehensive analysis of current miRNA research in chondrosarcoma, focusing on its potential as diagnostic and prognostic biomarkers, therapeutic targets, and regulators of disease progression. By integrating the latest discoveries in this field, we aim to contribute to the development of novel approaches to the prevention, diagnosis, and treatment of chondrosarcoma, ultimately enhancing patient outcomes. more...

Molecular biology studies of uveal melanoma have resulted in the development of novel immunotherapy approaches including tebentafusp-a T cell-redirecting bispecific fusion protein. More biomarkers are currently being studied. As a result, combined immunotherapy is being developed as well as immunotherapy with bifunctional checkpoint inhibitory T cell engagers and natural killer cells. Current trials cover tumor-infiltrating lymphocytes (TIL), vaccination with IKKb-matured dendritic cells, or autologous dendritic cells loaded with autologous tumor RNA. Another potential approach to treat UM could be based on T cell receptor engineering rather than antibody modification. Immune-mobilizing monoclonal T cell receptors (TCR) against cancer, called ImmTAC TM molecules, represent such an approach. Moreover, nanomedicine, especially miRNA approaches, are promising for future trials. Finally, theranostic radiopharmaceuticals enabling diagnosis and therapy with the same molecule bring hope to this research. more...

Soft tissue sarcomas (STS) originating from connective tissue rarely affect the lymph nodes. However, involvement of lymph nodes in STS is an important aspect of prognosis and treatment. Currently, there is no consensus on the diagnosis and management of lymph node metastases in STS. The key risk factor for nodal involvement is the histological subtype of sarcoma. Radiological and pathological evaluation seems to be the most effective method of assessing lymph nodes in these neoplasms. Thus, sentinel lymph node biopsy (SLNB), which has been shown to be valuable in the management of melanoma or breast cancer, may also be a beneficial diagnostic option in some high-risk STS subtypes. This review summarizes data on the risk factors and clinical characteristics of lymph node involvement in STS. Possible management and therapeutic options are also discussed. more...

Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms that account for less than 2% of all soft tissue masses. In the latest WHO 2020 Classification of Soft Tissue Tumors, extrameningeal SFT was listed as intermediate (rarely metastasizing) or malignant neoplasms. Due to the lack of characteristic clinical features, their diagnosis and treatment remain challenging. The pathogenesis of SFT is often associated with the presence of fusions of the NAB2-STAT6 gene on the 12q13 chromosome. Cytoplasmic CD34 positive staining is considerably characteristic for most SFTs; less frequently, factor XII, vimentin, bcl-2, and CD99 are present. A key factor in the diagnosis is the prevalent nuclear location of STAT6 expression. Radical resection is the mainstay of localized SFTs. In the case of unresectable disease, only radiotherapy or radio-chemotherapy may significantly ensure long-term local control of primary and metastatic lesions. To date, no practical guidelines have been published for the treatment of advanced or metastatic disease. Classical anthracycline-based chemotherapy is applicable. The latest studies suggest that antiangiogenic therapies should be considered after first-line treatment. Other drugs, such as imatinib, figitumumab, axitinib, and eribulin, are also being tested. Definitive radiotherapy appears to be a promising therapeutic modality. Since standards for the treatment of advanced and metastatic diseases are not available, further investigation of novel agents is necessary. more...

Sarcomas are a heterogeneous group of malignant mesenchymal tumors, including soft tissue and bone sarcomas. Macrophages in the tumor microenvironment, involved in immunosuppression and leading to tumor development, are called tumor-associated macrophages (TAMs). TAMs are very important in modulating the microenvironment of sarcomas by expressing specific markers and secreting factors that influence immune and tumor cells. They are involved in many signaling pathways, such as p-STAT3/p-Erk1/2, PI3K/Akt, JAK/MAPK, and JAK/STAT3. TAMs also significantly impact the clinical outcomes of patients suffering from sarcomas and are mainly related to poor overall survival rates among bone and soft tissue sarcomas, for example, chondrosarcoma, osteosarcoma, liposarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma. This review summarizes the current knowledge on TAMs in sarcomas, focusing on specific markers on sarcoma cells, cell-cell interactions, and the possibly involved molecular pathways. Furthermore, we discuss the clinical significance of macrophages in sarcomas as a potential target for new therapies, presenting clinical relevance, possible new treatment options, and ongoing clinical trials using TAMs in sarcoma treatment. more...

Mesenchymal chondrosarcoma (MCS) is a rare subtype of chondrosarcoma with a poor prognosis. Although these tumors are sensitive to radiotherapy/chemotherapy, the standard treatment for localized MCS is only surgical resection, and there are no established treatment guidelines for patients with advanced and metastatic MCS. Due to the low incidence of MCS, the pathology of these tumors is still unknown, and other therapeutic options are lacking. Some studies show the potential role of the PDGF/PPI3K/AKT, PKC/RAF/MEK/ERK, and pRB pathways, and BCL2 overexpression in the pathogenesis of MCS. These findings provide an opportunity to use protein kinases and BCL2 inhibitors as potential therapy in MCS. In this review, we summarize the current knowledge about MCS diagnosis and treatment options. We show the immunological and molecular biomarkers used in the diagnosis of MCS. In addition, we discuss the known prognostic and predictive factors in MCS. Finally, we present the novel trends, including targeted therapies and ongoing clinical trials using protein kinase inhibitors and the death receptor 5 (DR5) agonist, which may be the focus of future MCS treatment studies. more...

Dedifferentiated chondrosarcoma (DDCS) is a rare subtype of chondrosarcoma, a primary cartilaginous malignant neoplasm. It accounts for up to 1-2% of all chondrosarcomas and is generally associated with one of the poorest prognoses among all chondrosarcomas with the highest risk of metastasis. The 5-year survival rates range from 7% to 24%. DDCS may develop at any age, but the average presentation age is over 50. The most common locations are the femur, pelvis humerus, scapula, rib, and tibia. The standard treatment for localised disease is surgical resection. Most patients are diagnosed in unresectable and advanced stages, and chemotherapy for localised and metastatic dedifferentiated DDCS follows protocols used for osteosarcoma. more...

Introduction: Up to 30% of patients with stage IIB and 50% of stage IIC melanoma experience recurrence within 5 years after radical surgery. Adjuvant treatment is expected to improve this prognosis., Areas Covered: Pembrolizumab (MK-3475) is a humanized monoclonal antibody that acts against the programmed cell death 1 (PD-1) receptor. Pembrolizumab was first approved in monotherapy for the treatment of unresectable/metastatic melanoma based on the results of the prospective KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006 trials. KEYNOTE-716 is the randomized phase III trial of pembrolizumab treatment in resected stage II melanoma. Treatment with pembrolizumab is statistically significant, reducing the risk of recurrence as well as distant metastases risk after primary tumor resection. Pembrolizumab treatment has a 24-month RFS rate of 81.2% (HR 0.64 vs placebo) and a DMFS rate of 88.1%., Expert Opinion: 1-year adjuvant pembrolizumab treatment of stage IIB/C melanoma patients significantly reduces recurrence or death risk. The safety profile of adjuvant treatment is not different from previously reported and is manageable. Longer follow-up is required to fully understand the efficacy and safety of adjuvant therapy for stage II melanoma, as the number of patients needed to treat is twice as high as for stage III patients. more...

Pembrolizumab and nivolumab (anty-PD-1 antibody) are commonly used for the treatment of melanoma patients. However, their efficacy and safety have never been directly compared, leaving little guidance for clinicians to select the best therapy. The study included patients with inoperable or metastatic melanoma treated in first line with anti-PD-1 immunotherapy (nivolumab or pembrolizumab). In total 1037 patients were enrolled in the study, 455 (44%) patients were treated with pembrolizumab and 582 (56%) with nivolumab. The estimated median overall survival (OS) in the pembrolizumab and nivolumab groups was 17.4 and 20.0 months [ P  = 0.2323; hazard ratio (HR), 1.1; 95% confidence interval (CI), 0.94-1.28], respectively, whereas the median progression-free survival (PFS) was 5.6 and 7.5 months ( P  = 0.0941; HR, 1.13; 95% CI, 0.98-1.29), respectively. The estimated 2- and 3-year OS in the pembrolizumab and nivolumab groups were 42/34% and 47/37%, respectively, and the PFS was 25/21% and 29/23%, respectively. There were 391 (49%) immune-related adverse events (irAEs) of any grade during treatment, including 133 (42%) related to pembrolizumab treatment and 258 (53%) to nivolumab treatment. A total of 72 (9.6%) irAEs were in G3 or G4, including during pembrolizumab 29 (9%) and nivolumab 48 (11%). There were no differences in OS, PFS and overall response rates between nivolumab and pembrolizumab therapy in previously untreated patients with advanced/metastatic melanoma. There were no differences in the frequency of G1/G2 or G3/G4 irAEs. The choice of treatment should be based on the preferences of the patient and the clinician., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.) more...

Background: Marginally resectable and unresectable soft tissue sarcomas (STS) remain a therapy challenge due to the lack of highly active treatment. The aim of the study was to identify a biomarker to predict the pathological response (PR) to preplanned treatment of these STSs., Methods: In the phase II clinical trial (NCT03651375), locally advanced STS patients received preoperative treatment with a combination of doxorubicin-ifosfamide chemotherapy and 5 × 5 Gy radiotherapy. PR to the treatment was classified using the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group recommendations. We have chosen HIF-1α, CD163, CD68, CD34, CD105, and γH2AFX proteins, rendering different biological phenomena, for biomarker study., Results: Nineteen patients were enrolled and in four cases a good PR was reported. The high expression of HIF-1α before surgery showed a negative correlation with PR, which means a poor response to therapy. Furthermore, the samples after surgery had decreased expression of HIF-1α, which confirmed the correlation with PR. However, high expression of γH2AFX positively correlated with PR, which provides better PR. The high number of positive-staining TAMs and the high IMVD did not correlate with PR., Conclusions: HIF1α and γH2AFX could be potential biomarkers for PR prediction after neoadjuvant treatment in STS. more...

Background: In melanoma treatment, an approach following positive sentinel lymph node biopsy (SLNB) has been recently deescalated from completion lymph node dissection (CLND) to active surveillance based on phase III trials data. In this study, we aim to evaluate treatment strategies in SLNB-positive melanoma patients in real-world practice., Methods: Five-hundred-fifty-seven melanoma SLNB-positive patients from seven comprehensive cancer centers treated between 2017 and 2021 were included. Kaplan-Meier methods and the Cox Proportional-Hazards Model were used for analysis., Results: The median follow-up was 25 months. Between 2017 and 2021, the percentage of patients undergoing CLND decreased (88-41%), while the use of adjuvant treatment increased (11-51%). The 3-year OS and RFS rates were 77.9% and 59.6%, respectively. Adjuvant therapy prolonged RFS (HR:0.69, p = 0.036)), but CLND did not (HR:1.22, p = 0.272). There were no statistically significant differences in OS for either adjuvant systemic treatment or CLND. Lower progression risk was also found, and time-dependent hazard ratios estimation in patients treated with systemic adjuvant therapy was confirmed (HR:0.20, p = 0.002 for BRAF inhibitors and HR:0.50, p = 0.015 for anti-PD-1 inhibitors)., Conclusions: Treatment of SLNB-positive melanoma patients is constantly evolving, and the role of surgery is currently rather limited. Whether CLND has been performed or not, in a group of SLNB-positive patients, adjuvant systemic treatment should be offered to all eligible patients. more...

Objective: Initiation and development of early seizures by chemical stimuli is associated with brain cell swelling resulting in edema of seizure-vulnerable brain regions. We previously reported that pretreatment with a nonconvulsive dose of glutamine (Gln) synthetase inhibitor methionine sulfoximine (MSO) mitigates the intensity of initial pilocarpine (Pilo)-induced seizures in juvenile rats. We hypothesized that MSO exerts its protective effect by preventing the seizure-initiating and seizure-propagating increase of cell volume. Taurine (Tau) is an osmosensitive amino acid, whose release reflects increased cell volume. Therefore, we tested whether the poststimulus rise of amplitude of Pilo-induced electrographic seizures and their attenuation by MSO are correlated with the release of Tau from seizure-affected hippocampus., Methods: Lithium-pretreated animals were administered MSO (75 mg/kg ip) 2.5 h before the induction of convulsions by Pilo (40 mg/kg ip). Electroencephalographic (EEG) power was analyzed during 60 min post-Pilo, at 5-min intervals. Extracellular accumulation of Tau (eTau) served as a marker of cell swelling. eTau, extracellular Gln (eGln), and extracellular glutamate (eGlu) were assayed in the microdialysates of the ventral hippocampal CA1 region collected at 15-min intervals during the whole 3.5-h observation period., Results: The first EEG signal became apparent at ~10 min post-Pilo. The EEG amplitude across most frequency bands peaked at ~40 min post-Pilo, and showed strong (r ~ .72-.96) temporal correlation with eTau, but no correlation with eGln or eGlu. MSO pretreatment delayed the first EEG signal in Pilo-treated rats by ~10 min, and depressed the EEG amplitude across most frequency bands, to values that remained strongly correlated with eTau (r > .92) and moderately correlated (r ~ -.59) with eGln, but not with eGlu., Significance: Strong correlation between attenuation of Pilo-induced seizures and Tau release indicates that the beneficial effect of MSO is due to the prevention of cell volume increase concurrent with the onset of seizures., (© 2023 International League Against Epilepsy.) more...

Individuals with inherited hyperammonemias often present developmental and intellectual deficiencies which are likely to be exaggerated by hyperammonemia episodes in long-term outcomes. In order to find a new, systemic marker common to the course of congenital hyperammonemias, we decided to measure the plasma level of S100 calcium-binding protein B (S100B), which is associated with cerebral impairment. Further, we analyzed three mechanistically diverged but linked with oxidative-nitrosative stress biochemical parameters: 3-nitrotyrosine (3-NT), a measure of plasma proteins' nitration; advanced oxidation protein products (AOPP), a measure of protein oxidation; and glutathione peroxidase (GPx) activity, a measure of anti-oxidative enzymatic capacity. The plasma biomarkers listed above were determined for the first time in congenital hyperammonemia. Also, the level of pro- and anti-inflammatory mediators (i.e., IL-12, IL-6, IL-8, TNF-α, IL-1β, and IL-10) and chemokines (IP-10, MCP-1, MIG, and RANTES) were quantified. S100B was positively correlated with plasma ammonia level, while noticeable levels of circulating 3-NT in some of the patients' plasma did not correlate with ammonia concentration. Overall, the linear correlation between ammonia and S100B but not standard oxidative stress-related markers offers a unique perspective for the future identification and monitoring of neurological deficits risk-linked with hyperammonemia episodes in patients with inherited hyperammonemias. The S100B measure may support the development of therapeutic targets and clinical monitoring in these disorders. more...

Background: Combined treatment with BRAFi and/or MEK inhibitors (MEKi) improves outcomes in advanced melanoma patients in comparison with monotherapy., Objective: We aim to report real-world treatment efficacy and safety of vemurafenib (V) and vemurafenib + cobimetinib (V + C) from 10 years of practice., Patients and Methods: A total of 275 consecutive patients with unresectable or metastatic BRAF mutated melanoma started first-line V or V + C treatment between 1 October 2013 and 31 December 2020. Survival analyses were performed using the Kaplan-Meier method, and Log-rank and Chi-square tests were used for comparison between groups., Results: The estimated median overall survival (mOS) was 10.3 months in the V group, and 12.3 months in the V + C group (p = 0.0005; HR = 1.58, 95% CI 1.2-2.1), although the latter group of patients had lactate dehydrogenase elevated numerically more often. Estimated median progression-free survival (mPFS) was 5.5 months in the V group, and 8.3 months in the V + C group (p = 0.0002; HR = 1.62, 95% CI 1.3-2.1). Complete response, partial response, stable disease, and progressive disease as best responses were recorded in the V/V + C groups in 7%/10%, 52%/46%, 26%/28%, and 15%/16% of patients, respectively. The numbers of patients with any grade of adverse effects were similar in both groups., Conclusions: We confirmed significant improvement in the mOS and mPFS of unresectable and/or metastatic BRAF mutated-melanoma patients treated outside clinical trials with V + C as compared with V, with no major increase in toxicity for the combination., (© 2023. The Author(s).) more...

In recent years, our understanding of the epigenetic mechanisms involved in tumor pathology has improved greatly. DNA and histone modifications, such as methylation, demethylation, acetylation, and deacetylation, can lead to the up-regulation of oncogenic genes, as well as the suppression of tumor suppressor genes. Gene expression can also be modified on a post-transcriptional level by microRNAs that contribute to carcinogenesis. The role of these modifications has been already described in many tumors, e.g., colorectal, breast, and prostate cancers. These mechanisms have also begun to be investigated in less common tumors, such as sarcomas. Chondrosarcoma (CS) is a rare type of tumor that belongs to sarcomas and is the second most common malignant bone tumor after osteosarcoma. Due to unknown pathogenesis and resistance to chemo- and radiotherapies of these tumors, there is a need to develop new potential therapies against CS. In this review, we summarize current knowledge on the influence of epigenetic alterations in the pathogenesis of CS by discussing potential candidates for future therapies. We also emphasize ongoing clinical trials that use drugs targeting epigenetic modifications in CS treatment. more...

Background: Current risk models in solitary fibrous tumour (SFT) were developed using cohorts with short follow-up and cannot reliably identify low-risk patients. We recently developed a novel risk model (G-score) to account for both early and late recurrences. Here, we aimed to validate the G-score in a large international cohort with long-term follow-up., Methods: Data were collected from nine sarcoma referral centres worldwide. Recurrence-free interval (RFi) was the primary endpoint., Results: The cohort comprised 318 patients with localised extrameningeal SFTs. Disease recurrence occurred in 96 patients (33%). The estimated 5-year RFi rate was 72%, and the 10-year RFi rate was 52%. G-score precisely predicted recurrence risk with estimated 10-year RFi rate of 84% in low risk, 54% in intermediate risk and 36% in high risk (p < 0.001; C-index 0.691). The mDemicco (p < 0.001; C-index 0.749) and Salas OS (p < 0.001; C-index 0.674) models also predicted RFi but identified low-risk patients less accurate with 10-year RFi rates of 72% and 70%, respectively., Conclusions: G-score is a highly significant predictor of early and late recurrence in SFT and is superior to other models to predict patients at low risk of relapse. A less intensive follow-up schedule could be considered for patients at low recurrence risk according to G-score., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.) more...