Publications by authors named "Piotr Rutkowski"

295 Publications

Diagnosis strategy of adipocytic soft-tissue tumors in adults: a consensus from European experts.

Eur J Surg Oncol 2021 Oct 18. Epub 2021 Oct 18.

Department of Surgery, Institut Curie, Paris, France. Electronic address:

Fat-containing tumors are very commonly found in daily practice with benign lipoma accounting for the majority of superficial tumors. Overlap in imaging findings between benign and intermediate or malignant fat-containing tumor is common. Guidelines recommend a core needle biopsy (CNB) for all deep tumors, and superficial tumors over 3 cm. However, specific strategy for diagnosis and referral to a sarcoma center should be applied on adipocytic tumors. The aim of this consensus statement is to provide a specific algorithm for adipocytic tumors, to discriminate patients who do require a CNB for preoperative diagnosis from those who can simply undergo active surveillance or a simple excision.
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http://dx.doi.org/10.1016/j.ejso.2021.10.009DOI Listing
October 2021

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas.

Int J Mol Sci 2021 Sep 29;22(19). Epub 2021 Sep 29.

Department of Imaging and Pathology, Translational Cell and Tissue Research, University Hospitals Leuven, 3000 Leuven, Belgium.

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5-10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.
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http://dx.doi.org/10.3390/ijms221910568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508767PMC
September 2021

A discrepancy between CT angiography and transesophageal echocardiographic measurements of the annular size affect long-term survival following trans-catheter aortic valve replacement.

J Cardiovasc Thorac Res 2021 25;13(3):208-215. Epub 2021 Aug 25.

Department of Anesthesiology, University at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, NY, USA.

Accurate measurement of the aortic valve annulus is critical for proper valve sizing for the transcatheter aortic valve replacement (TAVR) procedure. While computed tomography angiography (CTA) is the widely-accepted standard, two-dimensional (2D) and three-dimensional(3D) transesophageal echocardiography (TEE) is commonly performed to measure the size of the aortic valve and to verify appropriate seating of prostheses. Patients undergoing TAVR between 2013-2015 were examined. 2D- and 3D-TEEmeasurements were compared to CTA taken as standard. Patients were followed for at least one year. The presence and effect of discrepancy (defined as a difference of more than 10%) between CTA and TEE measurements on survival were examined. One hundred eighty-five patients (70 men) were included. 2D- and 3D-TEE measurements underestimated the annulus size by -1.49 and -1.32 mm, respectively. Discrepancies > 10% between TEE and CTA methods in estimating the aortic annulus size were associated with a decrease in post implant survival. The peak pressure gradient across the aortic prosthesis measured one year after the implant was higher in patients with an initial discrepancy between 3D-TEE and CTA measurements. In a multivariate cox-regression model, the discrepancy between CTA and 2D-TEE readings and the smaller size of the aortic annular area were the predictors of long-term survival. Both 2D and 3D-TEE underestimate the aortic annulus measurements compared to CTA, with 2D-TEE being relatively more precise than 3D-TEE technology. The presence of a discrepancy between echocardiographic and CTA measurements of the aortic annulus is associated with a lower survival rate.
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http://dx.doi.org/10.34172/jcvtr.2021.39DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493236PMC
August 2021

Revealing the effect of electrocatalytic performance boost during hydrogen evolution reaction on free-standing SWCNT film electrode.

Sci Rep 2021 Oct 7;11(1):19981. Epub 2021 Oct 7.

Department of Process Engineering and Technology of Polymer and Carbon Materials, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370, Wrocław, Poland.

Large-scale sustainable hydrogen production by water electrolysis requires a highly active yet low-cost hydrogen evolution reaction (HER) electrocatalyst. Conductive carbon nanomaterials with high surface areas are promising candidates for this purpose. In this contribution, single-walled carbon nanotubes (SWCNTs) are assembled into free-standing films and directly used as HER electrodes. During the initial 20 h of electrocatalytic performance in galvanostatic conditions, the films undergo activation, which results in a gradual overpotential decrease to the value of 225 mV. Transient physicochemical properties of the films at various activation stages are characterized to reveal the material features responsible for the activity boost. Results indicate that partial oxidation of iron nanoparticles encapsulated in SWCNTs is the major contributor to the activity enhancement. Furthermore, besides high activity, the material, composed of only earth-abundant elements, possesses exceptional performance stability, with no activity loss for 200 h of galvanostatic performance at - 10 mA cm. In conclusion, the work presents the strategy of engineering a highly active HER electrode composed of widely available elements and provides new insights into the origins of electrocatalytic performance of SWCNT-based materials in alkaline HER.
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http://dx.doi.org/10.1038/s41598-021-99458-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497545PMC
October 2021

Adjuvant imatinib in GIST patients harboring exon 9 KIT mutations: results from a multi-institutional European retrospective study.

Clin Cancer Res 2021 Oct 6. Epub 2021 Oct 6.

Medical Oncology Department, Hogar.

Purpose: The effect of high-dose imatinib (800 mg/d) on survival in the adjuvant treatment of patients with resected KIT exon-9 mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathological variables with survival was evaluated in a large multi-institutional European cohort.

Methods: Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival.

Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated to the survival outcomes (RFS: HR 1.24, 95% CI 0.79-1.94; mRFS: HR 1.69, 95% CI 0.92-3.10; IFFS: HR 1.35, 95% CI 0.79-2.28). The variables consistently associated with worse survival outcomes were high mitotic index and non-gastric tumor location.

Conclusion: In this retrospective series of KIT exon 9-mutated GIST patients treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1665DOI Listing
October 2021

Longitudinal prognostication in retroperitoneal sarcoma survivors: Development and external validation of two dynamic nomograms.

Eur J Cancer 2021 Sep 20;157:291-300. Epub 2021 Sep 20.

Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Purpose: The aim of this study was to create and validate dynamic nomograms to predict overall survival (OS) and disease-free survival (DFS) at different time points during follow-up in patients who had undergone resection of primary retroperitoneal sarcoma (RPS).

Methods: Patients with primary RPS operated upon between 2002 and 2017 at four and six referral centres comprised the development and external validation cohorts, respectively. Landmark analysis and multivariable Cox models were used to develop dynamic nomograms. Variables were selected using two backward procedures based on the Akaike information criterion. The prediction window was fixed at 5 years. Nomogram performances were tested in terms of calibration and discrimination on the development and validation cohorts.

Results: Development and validation cohorts totalled 1357 and 487 patients (OS analysis), and 1309 and 452 patients (DFS analysis), respectively. The final OS model included age, landmark time (T), tumour grade, completeness of resection and occurrence of local/distant recurrence. The final DFS model included T, histologic subtype, tumour size, tumour grade, multifocality and the interaction terms between T and size, grade and multifocality. For OS, Harrell C indices were higher than 0.7 in both cohorts, indicating very good discriminative capability. For DFS, Harrell C indices were between 0.64 and 0.72 in the development cohort and 0.62 and 0.68 in the validation cohort. Calibration plots showed good agreement between predicted and observed outcomes.

Conclusion: Validated nomograms are available to predict the 5-year OS and DFS probability at different time points throughout the first 5 years of follow-up in RPS survivors.
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http://dx.doi.org/10.1016/j.ejca.2021.08.008DOI Listing
September 2021

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma.

N Engl J Med 2021 09;385(13):1196-1206

From Mount Vernon Cancer Centre, Northwood (P.N.), the Clatterbridge Cancer Centre NHS Foundation Trust, Wirral (J.J.S.), the University of Liverpool, Liverpool (J.J.S.), and Immunocore, Abingdon (S.E.A., C.H., H.G.) - all in the United Kingdom; the Department of Dermatology and the National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg (J.C.H.), the Department of Dermatology and Allergy, University Hospital, Ludwig Maximilian University of Munich, Munich (M.S.), the Department of Hematology and Oncology, Charité-Comprehensive Cancer Center (S.O.), Berlin, and the Department of Dermatology and the Center for Integrated Oncology, University Hospital Cologne, Cologne (C.M.) - all in Germany; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (P.R.); Institut Roi Albert II des Cliniques Universitaires Saint-Luc and Université Catholique de Louvain, Brussels (J.-F.B.); Princess Margaret Cancer Centre, Toronto (M.O.B.); Massachusetts General Hospital Cancer Center, Boston (R.J.S.); the Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland (R.D.); Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh (J.M.K.); Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia (M.O.); Kinghorn Cancer Centre, Saint Vincent's Hospital, Darlinghurst, NSW, Australia (A.M.J.); Memorial Sloan Kettering Cancer Center (A.N.S.) and Irving Medical Center, Columbia University (R.D.C.) - both in New York; Institut d'Investigació Biomèdica de Bellvitge-Centro de Investigación Biomédica en Red de Oncología, Institut Català d'Oncologia, Barcelona (J.M.P.); University of Iowa Hospitals and Clinics, Iowa City (M.M.); Duke University, Durham, NC (A.K.S.S.); Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR (B.C.); N.N. Blokhin Cancer Research Center, Moscow (L.D.); Centre Antoine Lacassagne, Nice (L.G.) and Institut Curie, Paris Sciences and Letters Research University, Paris (S.P.-N.) - both in France; Winship Cancer Institute, Emory University, Atlanta (M.Y.); and the Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles (O.H.).

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells.

Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.

Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.

Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
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http://dx.doi.org/10.1056/NEJMoa2103485DOI Listing
September 2021

TP53 in Biology and Treatment of Osteosarcoma.

Cancers (Basel) 2021 Aug 25;13(17). Epub 2021 Aug 25.

Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland.

The gene is mutated in 50% of human tumors. Oncogenic functions of mutant maintain tumor cell proliferation and tumor growth also in osteosarcomas. We collected data on mutations in patients to indicate which are more common and describe their role in in vitro and animal models. We also describe animal models with dysfunction, which provide a good platform for testing the potential therapeutic approaches. Finally, we have indicated a whole range of pharmacological compounds that modulate the action of p53, stabilize its mutated versions or lead to its degradation, cause silencing or, on the contrary, induce the expression of its functional version in genetic therapy. Although many of the described therapies are at the preclinical testing stage, they offer hope for a change in the approach to osteosarcoma treatment based on targeting in the future.
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http://dx.doi.org/10.3390/cancers13174284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8428337PMC
August 2021

Efficacy of Sirolimus Treatment in PEComa-10 Years of Practice Perspective.

J Clin Med 2021 Aug 20;10(16). Epub 2021 Aug 20.

Department of Soft Tissue/Bone, Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Perivascular epithelioid cell tumors (PEComa) represent a family of rare mesenchymal tumors resultant from deregulation in mTOR pathway activity. The aim of this study is to evaluate the long-term efficacy of targeted PEComa treatment. We reviewed all consecutive patients with PEComa who started systemic treatment with sirolimus in our reference sarcoma center between January 2011 and August 2020. Histopathology of PEComa was reviewed and confirmed in all cases by a designated sarcoma pathologist. Any surviving progression-free patients were censored at the last follow-up (31 March 2021). Survival curves were calculated according to Kaplan-Meier method and compared with the log-rank test or a Cox proportional hazard model. Fifteen (12 females and 3 males) consecutive PEComa patients were treated. The median age of patients treated systemically was 50 years. Median progression-free survival (PFS) was 4.9 months (95% CI: 3.8-NA) for first-line chemotherapy and was not reached (95% CI: 42.0-NA) for sirolimus as first-line therapy. There was one objective response (OR) in the chemotherapy group. The OR rate reached 73% (11/15 cases) for sirolimus regardless of the treatment line. All patients archived disease control. Three patients died due to disease progression after 55, 32, and 32 months since metastatic disease diagnosis. After a median follow-up of 55.7 (range: 3.2-220) months, the 5 yr OS was 65% (CI 95% 39-100). Our study is the largest single-institution report on PEComa systemic targeted therapy and fills the gap in the field of advanced PEComa care since the FDA/EMEA approval of sirolimus.
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http://dx.doi.org/10.3390/jcm10163705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396894PMC
August 2021

Age as a Prognostic Factor in Patients with Ewing Sarcoma-The Polish Sarcoma Group Experience.

J Clin Med 2021 Aug 17;10(16). Epub 2021 Aug 17.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Ewing sarcoma (ES) is a rare and aggressive disease that requires multidisciplinary treatment with the use of chemotherapy, radiotherapy, and surgery. Our retrospective study aimed to analyze the prognostic factors and treatment results in different age groups of patients. Between 1998 and 2018, 569 patients with ES were treated in two referral centers. The patients were divided into four age groups (≤10 years; 11-18 years; 19-25, and >25). The treatment results and prognostic factors were assessed for each group. For statistical analyses, we used the Chi2 test, the Kaplan-Meier estimator with a log-rank test, and the multivariate Cox model. Five-year overall survival (OS) rate was 56%. In the age subgroups: ≤10 years, 11-18 years, 19-25 years, and >25 years, the 5-year OS rates were 75%, 58%, 41%, and 52%, respectively. Favorable prognostic factors: female gender ( = 0.024), non-axial localization ( = 0.005), VIDE regimen ( < 0.001), and surgery as a local treatment ( < 0.001) dominated in the group ≤10 years. In multivariate analysis, male (HR = 1.53), axial localization (HR = 1.46), M1 status at presentation (HR = 2.64), and age > 10 years (HR = 2.29) were associated with shorter OS. The treatment results in ES are significantly better in children aged ≤10 years; the challenge is to provide therapy for adolescents and young adults. The diagnostics and treatment of ES patients must be provided in referral centers.
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http://dx.doi.org/10.3390/jcm10163627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397138PMC
August 2021

Antiangiogenic agents combined with systemic chemotherapy in refractory osteosarcoma.

Authors:
Piotr Rutkowski

Lancet Oncol 2021 09 17;22(9):1206-1207. Epub 2021 Aug 17.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(21)00422-8DOI Listing
September 2021

Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study.

J Clin Oncol 2021 Oct 3;39(28):3128-3139. Epub 2021 Aug 3.

Department of Medical Oncology, Sarcoma Center, West German Cancer Center, DKTK-Partner-Site, University of Duisburg-Essen, Essen, Germany.

Purpose: Primary or secondary mutations in or platelet-derived growth factor receptor alpha () underlie tyrosine kinase inhibitor resistance in most GI stromal tumors (GISTs). Avapritinib selectively and potently inhibits KIT- and PDGFRA-mutant kinases. In the phase I NAVIGATOR study (NCT02508532), avapritinib showed clinical activity against PDGFRA D842V-mutant and later-line KIT-mutant GIST. VOYAGER (NCT03465722), a phase III study, evaluated efficacy and safety of avapritinib versus regorafenib as third-line or later treatment in patients with unresectable or metastatic GIST.

Patients And Methods: VOYAGER randomly assigned patients 1:1 to avapritinib 300 mg once daily (4 weeks continuously) or regorafenib 160 mg once daily (3 weeks on and 1 week off). Primary end point was progression-free survival (PFS) by central radiology per RECIST version 1.1 modified for GIST. Secondary end points included objective response rate, overall survival, safety, disease control rate, and duration of response. Regorafenib to avapritinib crossover was permitted upon centrally confirmed disease progression.

Results: Four hundred seventy-six patients were randomly assigned (avapritinib, n = 240; regorafenib, n = 236). Median PFS was not statistically different between avapritinib and regorafenib (hazard ratio, 1.25; 95% CI, 0.99 to 1.57; 4.2 5.6 months; = .055). Overall survival data were immature at cutoff. Objective response rates were 17.1% and 7.2%, with durations of responses of 7.6 and 9.4 months for avapritinib and regorafenib; disease control rates were 41.7% (95% CI, 35.4 to 48.2) and 46.2% (95% CI, 39.7 to 52.8). Treatment-related adverse events (any grade, grade ≥ 3) were similar for avapritinib (92.5% and 55.2%) and regorafenib (96.2% and 57.7%).

Conclusion: Primary end point was not met. There was no significant difference in median PFS between avapritinib and regorafenib in patients with molecularly unselected, late-line GIST.
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http://dx.doi.org/10.1200/JCO.21.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478403PMC
October 2021

The utility of fluorescence in situ hybridization (FISH) in determining DNA damage-inducible transcript 3 (DDIT3) amplification in dedifferentiated liposarcomas - an important diagnostic pitfall.

Pathol Res Pract 2021 Sep 21;225:153555. Epub 2021 Jul 21.

Maria Skłodowska-Curie National Research Institute of Oncology, Department of Pathology and Laboratory Diagnostics, Warsaw, Poland; Institute of Hematology and Transfusion Medicine, Diagnostic Hematology Department, Warsaw, Poland. Electronic address:

Background And Objective: Dedifferentiated liposarcoma (DDLPS) is characterized by non-lipogenic sarcoma fields coexisting with adipocyte-rich well-differentiated areas. Amplification of the 12q13-15 region includes the MDM2 and DDIT3 genes. MDM2 amplification is considered a genetic hallmark of DDLPS, while DDIT3 is typically rearranged in myxoid liposarcoma. Recent studies showed that DDIT3 amplification is associated with myxoid liposarcoma-like (LPS-like) morphology in DDLPS. Our study aimed to evaluate the status of MDM2 and DDIT3 by FISH in DDLPS and correlate it with MLPS-like features.

Material And Methods: Six patients with MLPS-like morphology DDLPS were investigated pathologically, immunohistochemically, and genetically. The control groups of patients with classical DDLPS morphology and well-differentiated liposarcoma (WDLPS) were established and molecularly assessed as well. Fluorescence in situ hybridization (FISH) used in routine diagnostics was performed to determine the status of MDM2 and DDIT3 genes.

Results: The patient's mean age was 64 (range from 43 to 85 years) with a 5:4 male to female ratio. Tumors were localized retroperitoneally (15) and extra-retroperitoneally (3). All cases demonstrated amplification of the 12q15 region containing MDM2 gene and co-amplification of the 5' DDIT3 FISH Probe representing DDIT3 telomeric tag. However, we did not find the relation of myxoid LPS-like morphology with DDIT3 amplification as previously reported.

Conclusions: The biopsy material from DDLPS with myxoid areas can be misclassified as myxoid liposarcoma. Indeed, according to the histological image, DDIT3 status may be evaluated first. In these cases, we show that the DDIT3 telomeric tag amplification assessed by FISH, is a common, nonspecific feature, which is also found in classical DDLPS and WDLPS. Therefore, we believe that co-amplification of DDIT3 and MDM2 may be considered a spectrum of the 12q13-15 region amplification due to the specification of FISH methodology.
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http://dx.doi.org/10.1016/j.prp.2021.153555DOI Listing
September 2021

Characterization and Clinical Utility of Mutation Detection Using Cell-Free DNA in Patients with Advanced Melanoma.

Cancers (Basel) 2021 Jul 17;13(14). Epub 2021 Jul 17.

Department of Medical Oncology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium.

Tissue-based tests for mutation-positive melanoma involve invasive biopsy procedures, and can lead to an erroneous diagnosis when the tumor samples degrade. Herein, we explored a minimally invasive, cell-free deoxyribonucleic acid (cfDNA)-based platform, to retest patients for mutations. This phase 2 study enrolled adult patients with unresectable/metastatic melanoma. A prescreening testing phase evaluated the concordance between a prior tissue-based mutation test result and a subsequent plasma cfDNA-based test result. A treatment phase evaluated the patients who were confirmed as mutation-positive, and were treated with cobimetinib plus vemurafenib. It was found that 35/54 patients (64.8%) with a mutant status by prior tissue test had a positive  mutation with the cfDNA test. Further, 7/118 patients (5.9%) with a wild-type status had a positive  mutation cfDNA test; tissue retests on archival samples confirmed  mutation positivity in 5/7 patients (71.4%). One of these patients received BRAF pathway-targeted therapy (cobimetinib plus vemurafenib), and had progression-free survival commensurate with previous experience. In the overall cobimetinib plus vemurafenib-treated population, 29/36 patients (80.6%) had an objective response. The median progression-free survival was 13.6 months (95% confidence interval, 9.5-16.5). Cell-free DNA-based tests may be a fast and convenient option to identify mutation status in melanoma patients, and help inform treatment decisions.
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http://dx.doi.org/10.3390/cancers13143591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305047PMC
July 2021

Merkel Cell Carcinoma from Molecular Pathology to Novel Therapies.

Int J Mol Sci 2021 Jun 11;22(12). Epub 2021 Jun 11.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Merkel cell carcinoma (MCC) is an uncommon and highly aggressive skin cancer. It develops mostly within chronically sun-exposed areas of the skin. MCPyV is detected in 60-80% of MCC cases as integrated within the genome and is considered a major risk factor for MCC. Viral negative MCCs have a high mutation burden with a UV damage signature. Aberrations occur in , , and genes as well as in the PI3K-AKT-mTOR pathway. MCC is highly immunogenic, but MCC cells are known to evade the host's immune response. Despite the characteristic immunohistological profile of MCC, the diagnosis is challenging, and it should be confirmed by an experienced pathologist. Sentinel lymph node biopsy is considered the most reliable staging tool to identify subclinical nodal disease. Subclinical node metastases are present in about 30-50% of patients with primary MCC. The basis of MCC treatment is surgical excision. MCC is highly radiosensitive. It becomes chemoresistant within a few months. MCC is prone to recurrence. The outcomes in patients with metastatic disease are poor, with a historical 5-year survival of 13.5%. The median progression-free survival is 3-5 months, and the median overall survival is ten months. Currently, immunotherapy has become a standard of care first-line therapy for advanced MCC.
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http://dx.doi.org/10.3390/ijms22126305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231245PMC
June 2021

Efficacy and Safety of Hypofractionated Preoperative Radiotherapy for Primary Locally Advanced Soft Tissue Sarcomas of Limbs or Trunk Wall.

Cancers (Basel) 2021 Jun 14;13(12). Epub 2021 Jun 14.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Background: The use of adjuvant radiotherapy (RT) shows a significantly decreased incidence of local recurrence (LR) in soft tissue sarcomas (STS). This study aimed to assess the treatment scheme's effect in patients with primary STS treated at one institution.

Methods: In this phase 2 trial, 311 patients aged ≥18 years with primary, locally advanced STS of the extremity or trunk wall were assigned to multimodal therapy conducted at one institution. The preoperative RT scheme consisted of 5 Gy per fraction for a total dose of 25 Gy. Surgery was performed within 2-4 days from the last day of RT. The primary endpoint was LR-free survival (LRFS). Adverse events of the treatment were assessed.

Results: We included 311 patients with primary locally advanced STS. The median tumor size was 11 cm. In total, 258 patients (83%) had high-grade tumors. In 260 patients (83.6%), clear surgical margins (R0) were obtained. Ninety-six patients (30.8%) had at least one type of treatment adverse event. LR was observed in 13.8% patients. The 5-year overall survival was 63%.

Conclusion: In this group, with a significant percentage of patients with extensive, high-grade STS, hypofractionated preoperative RT was associated with good local control and tolerance.
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http://dx.doi.org/10.3390/cancers13122981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232096PMC
June 2021

Feasibility and Long-Term Efficacy of PEComa Treatment-20 Years of Experience.

J Clin Med 2021 May 19;10(10). Epub 2021 May 19.

Department of Soft Tissue/Bone, Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Perivascular epithelioid cell tumors (PEComas) represent a family of rare mesenchymal neoplasms, some of which are malignant. There are no specific management guidelines for PEComas, and factors correlating with the disease course are not well defined. This analysis aimed to describe the outcomes of PEComa patients treated radically, including those treated exclusively in the national reference sarcoma center. The secondary aim of the study was to analyze factors associated with PEComa treatment efficacy. We performed an analysis of 27 patients subsequently treated radically for PEComa between 1999 and 2019 who were in follow-up in the national sarcoma reference center. The proportional-hazards model was used to compare the risk of death. The median age at diagnosis was 45 (21-67) years, and 67% of patients were female. The median follow-up period was 68 months (95% CI: 39-101). At the time of analysis, eleven patients (40.7%) experienced progression of the disease and four (14.8%) died. Surgery in the reference sarcoma center was associated with a longer disease control (log-rank < 0.001). The 5-year-OS rate was 88% (95% CI: 74-100) for the whole analyzed group. We concluded that PEComa treatment should be managed in reference sarcoma centers by a multidisciplinary tumor board with an experienced surgical team. Microscopically radical resection is associated with a longer disease-free survival. Patients requiring long-term follow-ups as late recurrence may be expected.
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http://dx.doi.org/10.3390/jcm10102200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160690PMC
May 2021

Chondrosarcoma-from Molecular Pathology to Novel Therapies.

Cancers (Basel) 2021 May 14;13(10). Epub 2021 May 14.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Chondrosarcoma (CHS) is the second most common primary malignant bone sarcoma. Overall survival and prognosis of this tumor are various and often extreme, depending on histological grade and tumor subtype. CHS treatment is difficult, and surgery remains still the gold standard due to the resistance of this tumor to other therapeutic options. Considering the role of differentiation of CHS subtypes and the need to develop new treatment strategies, in this review, we introduced a multidisciplinary characterization of CHS from its pathology to therapies. We described the morphology of each subtype with the role of immunohistochemical markers in diagnostics of CHS. We also summarized the most frequently mutated genes and genome regions with altered pathways involved in the pathology of this tumor. Subsequently, we discussed imaging methods and the role of currently used therapies, including surgery and the limitations of chemo and radiotherapy. Finally, in this review, we presented novel targeted therapies, including those at ongoing clinical trials, which can be a potential future target in designing new therapeutics for patients with CHS.
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http://dx.doi.org/10.3390/cancers13102390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155983PMC
May 2021

Current Diagnosis and Treatment Options for Cutaneous Adnexal Neoplasms with Apocrine and Eccrine Differentiation.

Int J Mol Sci 2021 May 11;22(10). Epub 2021 May 11.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Adnexal tumors of the skin are a rare group of benign and malignant neoplasms that exhibit morphological differentiation toward one or more of the adnexal epithelium types present in normal skin. Tumors deriving from apocrine or eccrine glands are highly heterogeneous and represent various histological entities. Macroscopic and dermatoscopic features of these tumors are unspecific; therefore, a specialized pathological examination is required to correctly diagnose patients. Limited treatment guidelines of adnexal tumor cases are available; thus, therapy is still challenging. Patients should be referred to high-volume skin cancer centers to receive an appropriate multidisciplinary treatment, affecting their outcome. The purpose of this review is to summarize currently available data on pathogenesis, diagnosis, and treatment approach for apocrine and eccrine tumors.
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http://dx.doi.org/10.3390/ijms22105077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151110PMC
May 2021

Development of immunity-related adverse events correlates with baseline clinical factors, survival and response to anti-PD-1 treatment in patients with inoperable or metastatic melanoma.

J Dermatolog Treat 2021 Jun 14:1-7. Epub 2021 Jun 14.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

Background: The relationship between immune related adverse events (irAEs) and efficacy is not definitively proven, and data on the relationship between irAE and treatment efficacy are contradictory.

Material And Methods: Five hundred ninety-three consecutive patients with unresectable or metastatic melanoma treated in the first line with anti-PD-1 (nivolumab or pembrolizumab) between January 2016 and December 2019 were enrolled in the study.

Results: Statistically significant differences were demonstrated between the group of patients without and with irAE in median OS and PFS ( < .0001 both) and also in OS between the group of patients without irAE and patients with irAE within 3, 6, and 9 months from the start of anti-PD-1 therapy ( = .0121,  = .0014,  < .0001; respectively) and PFS ( = .0369,  = .0052,  = .0001; respectively). A statistically significant relationship was demonstrated between the occurrence of irAE and the location of the primary tumor (skin vs. mucosa vs. unknown;  = .0183), brain metastasis (present vs. absent;  = .0032), other locations (present vs. absent,  = .0032), LDH (normal vs. elevated;  = .0046) and stage according to TNM ( = .0093).

Conclusion: The occurrence of irAE was associated with longer OS, PFS, and more frequent response to treatment. IrAE occurred statistically significantly more often in patients with mucosa primary tumor, with normal LDH levels, without brain metastases, stages III, M1a, and M1b.
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http://dx.doi.org/10.1080/09546634.2021.1937477DOI Listing
June 2021

What is the best front-line approach in patients with desmoid fibromatosis? - A retrospective analysis from a reference center.

Eur J Surg Oncol 2021 Oct 11;47(10):2602-2608. Epub 2021 May 11.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland.

Introduction: Desmoid fibromatosis (DF) is a locally aggressive, not metastasizing tumor associated with high local recurrence rates. Surgery was a standard-of-care for DF treatment; however, recently, conservative treatment and active surveillance are preferred. This study aimed to evaluate the real-life outcomes of DF treatment.

Materials And Methods: All consecutive patients diagnosed with DF and treated between 01.1999 and 12.2018 at one sarcoma reference institution were included in this retrospective analysis. Kaplan-Meier estimator, long-rank test, Cox regression model, and Chi2 tests were used for statistical analyses.

Results: The analyses included 363 patients (254 female, 109 male). 195 patients (53.7%) underwent surgical resection, and 139 (38.3%) experienced a watch-and-wait approach with or without concomitant therapy with nonsteroid anti-inflammatory drugs (NSAIDs) in the first line. Disease recurrence/progression occurred in 43.2% of patients treated with surgery and 42.6% in the watch-and-wait group, resulting in 5-year event-free survival (EFS) rates of 60% and 55%, respectively. There was no difference in EFS between both groups (HR1.28, 95%CI 0.91-1.79). Surgery without prior biopsy and extra-abdominal wall location was associated with inferior outcomes.

Conclusions: Results of DF treatment in our center showed that watch-and-wait approach ± NSAIDs has similar efficacy to upfront surgery and allows to avoid unnecessary surgery in approximately half of the patients, primarily when tumors are located in unfavorable sites, like extremities.
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http://dx.doi.org/10.1016/j.ejso.2021.05.002DOI Listing
October 2021

Current Diagnosis and Treatment Options for Cutaneous Adnexal Neoplasms with Follicular Differentiation.

Int J Mol Sci 2021 Apr 30;22(9). Epub 2021 Apr 30.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Neoplasms derived from follicular tissue are extremely rare. Clinically, they are reported as non-symptomatic, slow-growing nodules. These lesions are mainly benign, but the malignant type can occur. Mainly middle-aged people (50-60 years of age) are affected. These carcinomas are mainly localized on the head and neck or torso. They can be locally aggressive and infiltrate surrounding tissue and metastasize to regional lymph nodes. In the minority of cases, distant metastases are diagnosed. Quick and relevant diagnosis is the basis of a treatment for all types of tumors. The patient's life expectancy depends on multiple prognostic factors, including the primary tumor size and its mitotic count. Patients should be referred to a specialized skin cancer center to receive optimal multidisciplinary treatment. This article tries to summarize all the information that is currently available about pathogenesis, diagnosis, and treatment methods of follicular tumors.
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http://dx.doi.org/10.3390/ijms22094759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125718PMC
April 2021

Clinical Significance of Tumor Microenvironment in Acral Melanoma: A Large Single-Institution Study of Caucasians.

J Clin Med 2021 Apr 1;10(7). Epub 2021 Apr 1.

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.

Background: The presence of tumor-infiltrating lymphocytes (TILs) in many studies is associated with a better prognosis in melanoma patients. Programmed death-ligand 1 (PD-L1) expression has a significant value in predicting several cancers, but its role in melanoma remains ambiguous. The study aims to report a comprehensive analysis of TILs characteristics and their impact on survival in primary acral melanoma (AM).

Methods: Clinical and pathological features and survival outcomes were investigated in 70 patients with AM. Immunohistochemical quantitative analysis of TILs, including expression of CD4, CD8, FOXP3, PD-1, and PD-L1, on melanoma cells was performed.

Results: Kaplan-Meier analysis showed significant differences in overall survival (OS) for CD4+ ( = 0.021), CD8+ ( = 0.037), FOXP3+ ( = 0.007), and TILs density ( = 0.043). In univariate analysis of immunohistochemical features, FOXP3, CD4, CD8, PD-1, and Melanoma Institute of Australia (MIA) grading TILs (grade, density, and distribution) were correlated with survival. The higher density of FOXP3-positive cells was an independent factor associated with better survival.

Conclusions: High TILs content (classed as brisk Clark scale and marked/diffuse TILs MIA grade) regardless of its immunophenotype was associated with better survival outcomes in AM. PD-L1 expression on tumor cells did not influence OS and was independent of clinical and pathological characteristics. We demonstrated that TILs are significant biomarkers in sentinel lymph node status prediction.
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http://dx.doi.org/10.3390/jcm10071452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036823PMC
April 2021

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

Cancer 2021 Aug 28;127(16):2934-2942. Epub 2021 Apr 28.

Department of Epidemiology, Regional Health Council, Biomedical Research Institute of Murcia-Arrixaca, Murcia University, Murcia, Spain.

Background: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies.

Methods: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan.

Results: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types.

Conclusions: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.
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http://dx.doi.org/10.1002/cncr.33618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319065PMC
August 2021

Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

Ann Surg Oncol 2021 Nov 27;28(12):7854-7863. Epub 2021 Apr 27.

Department of Surgery, Mayo Clinic, Jacksonville, FL, USA.

Background: Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes.

Methods: Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis.

Results: A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32-48%), 73% (58-92%), 76% (68-85%), and 56% (43-73%) (p < 0.001), respectively. The 6-year second local recurrence incidence was 66% (59-73%), 63% (48-82%), 66% (57-76%), and 77% (66-90%), respectively. The 6-year distant metastasis incidence was 13% (9-19%), 3% (0.4-22%), 5% (2-11%), and 4% (1-16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p < 0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) CONCLUSION: A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.
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http://dx.doi.org/10.1245/s10434-021-10024-yDOI Listing
November 2021

Clinicopathological features and treatment outcome of oesophageal gastrointestinal stromal tumour (GIST): A large, retrospective multicenter European study.

Eur J Surg Oncol 2021 Aug 31;47(8):2173-2181. Epub 2021 Mar 31.

Department of Surgical Oncology, Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands; European School of Soft Tissue Sarcoma Surgery, Amsterdam, the Netherlands.

Background: Oesophageal gastrointestinal stromal tumours (GISTs) account for ≤1% of all GISTs. Consequently, evidence to guide clinical decision-making is limited.

Methods: Clinicopathological features and outcomes in patients with primary oesophageal GIST from seven European countries were collected retrospectively.

Results: Eighty-three patients were identified, and median follow up was 55.0 months. At diagnosis, 59.0% had localized disease, 25.3% locally advanced and 13.3% synchronous metastasis. A biopsy (Fine Needle aspiration n = 29, histological biopsy n = 31) was performed in 60 (72.3%) patients. The mitotic count was low (<5 mitoses/50 High Power Fields (HPF)) in 24 patients and high (≥5 mitoses/50 HPF) in 27 patients. Fifty-one (61.4%) patients underwent surgical or endoscopic resection. The most common reasons to not perform an immediate resection (n = 31) were; unresectable or metastasized GIST, performance status/comorbidity, patient refusal or ongoing neo-adjuvant therapy. The type of resections were enucleation (n = 11), segmental resection (n = 6) and oesophagectomy with gastric conduit reconstruction (n = 33), with median tumour size of 3.3 cm, 4.5 cm and 7.7 cm, respectively. In patients treated with enucleation 18.2% developed recurrent disease. The recurrence rate in patients treated with segmental resection was 16.7% and in patients undergoing oesophagectomy with gastric conduit reconstruction 36.4%. Larger tumours (≥4.0 cm) and high (>5/5hpf) mitotic count were associated with worse disease free survival.

Conclusion: Based on the current study, enucleation can be recommended for oesophageal GIST smaller than 4 cm, while oesophagectomy should be preserved for larger tumours. Patients with larger tumours (>4 cm) and/or high mitotic count should be treated with adjuvant therapy.
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http://dx.doi.org/10.1016/j.ejso.2021.03.234DOI Listing
August 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): health-related quality-of-life results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):655-664. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325-MG/KEYNOTE-054 trial in patients with resected, high-risk stage III melanoma demonstrated improved recurrence-free survival with adjuvant pembrolizumab compared with placebo (hazard ratio 0·57 [98·4% CI 0·43-0·74]; p<0·0001). This study reports the results from the health-related quality-of-life (HRQOL) exploratory endpoint.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with previously untreated histologically confirmed stage IIIA, IIIB, or IIIC resected cutaneous melanoma, and an Eastern Cooperative Oncology Group performance status score of 1 or 0 were eligible. Patients were randomly assigned (1:1) using a central interactive voice-response system on the basis of a minimisation technique stratified for stage and geographic region to receive intravenously 200 mg pembrolizumab or placebo. Treatment was administered every 3 weeks for 1 year, or until disease recurrence, unacceptable toxicity, or death. The primary endpoint of the trial was recurrence-free survival (reported elsewhere). HRQOL was a prespecified exploratory endpoint, with global health/quality of life (GHQ) over 2 years measured by the EORTC QLQ-C30 as the primary analysis. Analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37, and long-term follow-up is ongoing.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to pembrolizumab (n=514) or placebo (n=505). Median follow-up was 15·1 months (IQR 12·8-16·9) at the time of this analysis. HRQOL compliance was greater than 90% at baseline, greater than 70% during the first year, and greater than 60% thereafter for both groups. Because of low absolute compliance numbers at later follow-up, the analysis was truncated to week 84. Baseline GHQ scores were similar between groups (77·55 [SD 18·20] in the pembrolizumab group and 76·54 [17·81] in the placebo group) and remained stable over time. The difference in average GHQ score between the two groups over the 2 years was -2·2 points (95% CI -4·3 to -0·2). The difference in average score during treatment was -1·1 points (95% CI -3·2 to 0·9) and the difference in average score after treatment was -2·2 points (-4·8 to 0·4). These differences are within the 5-point clinical relevance threshold for the QLQ-C30 and are therefore clinically non-significant.

Interpretation: Pembrolizumab does not result in a clinically significant decrease in HRQOL compared with placebo when given as adjuvant therapy for patients with resected, high-risk stage III melanoma. These results support the use of adjuvant pembrolizumab in this setting.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00081-4DOI Listing
May 2021

Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 05 12;22(5):643-654. Epub 2021 Apr 12.

EORTC Headquarters, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) 1325/KEYNOTE-054 trial assessed pembrolizumab versus placebo in patients with resected high-risk stage III melanoma. At 15-month median follow-up, pembrolizumab improved recurrence-free survival (hazard ratio [HR] 0·57 [98·4% CI 0·43-0·74], p<0·0001) compared with placebo, leading to its approval in the USA and Europe. This report provides the final results for the secondary efficacy endpoint, distant metastasis-free survival and an update of the recurrence-free survival results.

Methods: This double-blind, randomised, controlled, phase 3 trial was done at 123 academic centres and community hospitals across 23 countries. Patients aged 18 years or older with complete resection of cutaneous melanoma metastatic to lymph node, classified as American Joint Committee on Cancer staging system, seventh edition (AJCC-7) stage IIIA (at least one lymph node metastasis >1 mm), IIIB, or IIIC (without in-transit metastasis), and with an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) via a central interactive voice response system to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 18 doses or until disease recurrence or unacceptable toxicity. Randomisation was stratified according to disease stage and region, using a minimisation technique, and clinical investigators, patients, and those collecting or analysing the data were masked to treatment assignment. The two coprimary endpoints were recurrence-free survival in the intention-to-treat (ITT) population and in patients with PD-L1-positive tumours. The secondary endpoint reported here was distant metastasis-free survival in the ITT and PD-L1-positive populations. This study is registered with ClinicalTrials.gov, NCT02362594, and EudraCT, 2014-004944-37.

Findings: Between Aug 26, 2015, and Nov 14, 2016, 1019 patients were assigned to receive either pembrolizumab (n=514) or placebo (n=505). At an overall median follow-up of 42·3 months (IQR 40·5-45·9), 3·5-year distant metastasis-free survival was higher in the pembrolizumab group than in the placebo group in the ITT population (65·3% [95% CI 60·9-69·5] in the pembrolizumab group vs 49·4% [44·8-53·8] in the placebo group; HR 0·60 [95% CI 0·49-0·73]; p<0·0001). In the 853 patients with PD-L1-positive tumours, 3·5-year distant metastasis-free survival was 66·7% (95% CI 61·8-71·2) in the pembrolizumab group and 51·6% (46·6-56·4) in the placebo group (HR 0·61 [95% CI 0·49-0·76]; p<0·0001). Recurrence-free survival remained longer in the pembrolizumab group 59·8% (95% CI 55·3-64·1) than the placebo group 41·4% (37·0-45·8) at this 3·5-year follow-up in the ITT population (HR 0·59 [95% CI 0·49-0·70]) and in those with PD-L1-positive tumours 61·4% (56·3-66·1) in the pembrolizumab group and 44·1% (39·2-48·8) in the placebo group (HR 0·59 [95% CI 0·49-0·73]).

Interpretation: Pembrolizumab adjuvant therapy provided a significant and clinically meaningful improvement in distant metastasis-free survival at a 3·5-year median follow-up, which was consistent with the improvement in recurrence-free survival. Therefore, the results of this trial support the indication to use adjuvant pembrolizumab therapy in patients with resected high risk stage III cutaneous melanoma.

Funding: Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00065-6DOI Listing
May 2021

Management of Primary Retroperitoneal Sarcoma (RPS) in the Adult: An Updated Consensus Approach from the Transatlantic Australasian RPS Working Group.

Ann Surg Oncol 2021 Nov 14;28(12):7873-7888. Epub 2021 Apr 14.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Retroperitoneal soft tissue sarcomas comprise a heterogeneous group of rare tumors of mesenchymal origin that include several well-defined histologic subtypes. In 2015, the Transatlantic Australasian RPS Working Group (TARPSWG) published consensus recommendations for the best management of primary retroperitoneal sarcoma (RPS). Since then, through international collaboration, new evidence and knowledge have been generated, creating the need for an updated consensus document.

Methods: The primary aim of this study was to critically evaluate the current evidence and develop an up-to-date consensus document on the approach to these difficult tumors. The resulting document applies to primary RPS that is non-visceral in origin, with exclusion criteria as previously described. The relevant literature was evaluated and an international group of experts consulted to formulate consensus statements regarding the best management of primary RPS. A level of evidence and grade of recommendation were attributed to each new/updated recommendation.

Results: Management of primary RPS was considered from diagnosis to follow-up. This rare and complex malignancy is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, and an individualized management plan should be made based on the 29 consensus statements included in this article, which were agreed upon by all of the authors. Whenever possible, patients should be enrolled in prospective trials and studies.

Conclusions: Ongoing international collaboration is critical to expand upon current knowledge and further improve outcomes of patients with RPS. In addition, prospective data collection and participation in multi-institution trials are strongly encouraged.
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http://dx.doi.org/10.1245/s10434-021-09654-zDOI Listing
November 2021
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