Objective To investigate how patients with sarcoma present prior to diagnosis—through a general practitioner (GP) or another healthcare professional (HCP)—and describe presenting symptoms.Design International observational cohort study.Setting Data were obtained from the longitudinal ‘QUality of life and Experiences of Sarcoma Trajectories’ (QUEST) cohort study, conducted across the Netherlands, the United Kingdom (UK), Australia and New Zealand.Results Among 572 patients, 487 (85.1%) started their diagnostic trajectory at the GP (subcohort 1) and 85 (14.9%) with another HCP (subcohort 2)—mainly medical specialists treating unrelated conditions (36/85; 42.4%). Soft tissue sarcoma patients most often reported swelling, whereas bone sarcoma patients reported unexplained pain. Notably, 31/85 (36.5%) of subcohort 2 were asymptomatic. Reasons for delaying GP visits included assuming symptoms were minor and expecting them to resolve. Patients sought care when, among others, symptoms persisted and worsened.Conclusions Most patients first consulted a GP, underlining the role of primary care in sarcoma diagnosis internationally. Due to rarity and nonspecific symptoms, faster diagnosis remains challenging, requiring improvements in both primary and specialist care.Trial registration number NCT03441906; Results.

BackgroundMyxofibrosarcoma (MFS) and undifferentiated soft tissue sarcoma (USTS) are common sarcoma subtypes with overlapping molecular features. Both are treated with neoadjuvant radiotherapy followed by surgery, yet radiotherapy response is variable and unpredictable. This study investigated DNA methylation and copy number variation (CNV) profiles obtained from pre-radiotherapy biopsies as predictive biomarkers of radiotherapy response.Patients and methodsPre-radiotherapy biopsies and post-radiotherapy resections were obtained from 49 patients (27 MFS, 22 USTS). Radiotherapy response was assessed on the resection specimens using the EORTC-STBSG 5-tier system; grades A-C (<10% viable tumor) were classified as responders, D-E (≥10% viable tumor) as non-responders. Genome-wide DNA methylation and CNV data were generated from the pre-radiotherapy biopsies using Illumina MethylationEPIC BeadChips and were correlated with response grades.ResultsDNA methylation profiling yielded evaluable results in 23/49 tumors (15 MFS, 8 USTS), with 9 responders and 14 non-responders. Unsupervised methylation clustering, incorporating public datasets, showed that MFS, USTS, and pleomorphic liposarcomas formed a single, heterogeneous cluster. Similarly, CNV profiles did not distinguish MFS from USTS. Methylation patterns did not significantly differ between responders and non-responders. CNV profiles were largely comparable between responders and non-responders, except of a significantly higher frequency of chromosome 11q24.1 loss in responders compared to non-responders (100% vs 33%; P = 0.0039).ConclusionsOur findings support the concept that MFS and USTS represent a spectrum of the same disease. We could not demonstrate the value of DNA methylation profiling in radiotherapy response prediction. However, 11q24.1 loss may represent a potential predictive biomarker and merits further validation.

Background Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive sarcomas, with 40% associated with neurofibromatosis type 1 (NF1). Surgical excision is the main treatment for localized disease; however, local recurrence (LR) remains high. Radiotherapy (RTx) is increasingly used to enhance local control in STS, but its use remains controversial due to the potential for increased major wound complications and an increased risk of secondary malignancies in NF1 patients. This study investigated the use and impact of RTx on local control in MPNSTs, particularly in the NF1 setting.Methods Surgically treated primary MPNSTs from 1988 to 2019 in the MONACO multicenter cohort were included. Differences in demographics, treatment, and RTx use between NF1 and non-NF1 cases were examined. Factors influencing RTx administration and LR were assessed via multivariable analyses.Results Among 499 patients (33.1% NF1), 143 (28.7%) experienced LRs. Radiotherapy was administered to 56.3% of patients (57.0% in the NF1 group), with 27.3% receiving neoadjuvant and 72.7% adjuvant RTx. RTx was administered significantly more often to high-grade and extremity tumors. While RTx did not affect overall survival, it reduced LR risk in sporadic cases (hazard ratio [HR] 0.530; 95% confidence interval [CI], 0.354-0.793) but not in the NF1 subgroup (HR 1.00; 95% CI, 0.545-1.85). In NF1 patients, a microscopically positive margin (R1) was the only risk factor for LR development (HR 2.1; 95% CI, 1.19-3.79).Conclusions RTx is frequently used in the treatment of MPNSTs, regardless of NF1 status. While it may affect the LR rate in sporadic cases, its impact on NF1 patients is less clear.

INTRODUCTION:Understanding short-term morbidity following extremity soft-tissue sarcoma (ESTS) treatment remains complex due to diverse findings and the absence of a standardized wound complication assessment. This retrospective cohort study evaluated short-term morbidity following primary closure, skin grafting, and flap reconstruction. MATERIALS AND METHODS:All ESTS patients treated in a sarcoma center in the Netherlands from 1-1-2010 until 1-8-2022 were included. Short-term morbidity, defined as a wound complication following surgery, was assessed by the Toronto Sarcoma Flap Score (TSFS). The TSFS is an ordinal scale, where 0 indicates the absence of complications, while 10 signifies reconstructive failure necessitating amputation. Hospital stay duration and readmission rates were also analyzed. RESULTS:Limb preservation was achieved in 128 (97.7 %) of 131 patients. Wound complications occurred in 43 (44.3 %) of patients with primary closure, 8 (57.1 %) with skin grafting and 16 (80.0 %) with flap reconstruction, p = 0.01. Patients undergoing flap reconstructions had higher TSFSs (6 [IQR 7], versus 0 [IQR 3] for primary closure and 3 [IQR 6] for skin grafting), longer duration of hospital stays (14 [IQR 18] days versus 4 [IQR 3] days for primary closure and 5 [IQR 7] days for skin grafting, p < 0.01) and were more frequently readmitted (40.0 %, versus 17.5 % for primary closure and 21.4 % for skin grafting, p = 0.09). CONCLUSION:High limb preservation rates were achieved. Reconstructive surgery allows for the closure of extensive soft-tissue defects following ESTS resection, but it adds to surgical complexity. Patients undergoing flap reconstruction seem to be at a higher risk of short-term morbidity.

Purpose: Moderate hypofractionation was adopted to reduce hospital visits during the COVID-19 pandemic aiming to maintain treatment efficacy for soft tissue sarcoma (STS) patients, shifting preoperative schedules from 25 fractions of 2 Gy to 14-15 fractions of 3 Gy. This study evaluates the clinical implications and outcomes of this schedule, focusing on wound complications, radiation toxicity, local tumour control, and distant metastases. Patients and Methods: Data was collected from patients treated between 01 and 01-2020 and 31-12-2023. Outcomes included wound complications within 120 days post-surgery, local-recurrence, distant metastases and radiation toxicity. Logistic regression was performed to identify factors associated with wound complications. The cumulative incidence of local recurrence and distant metastases were estimated with a competing risk model. Results: Sixty-six patients were analysed, with a mean age of 74 years (standard deviation (SD)+/- 11). Tumours were mainly localized in the lower extremities (64 %), mean size 103 mm (SD +/- 58). Median follow-up was 29 months (range 2-50). A R0 resection margin was achieved in 77% of the operated patients. The wound complication rate was 33%, with moderate complications in 13 patients and severe in 6. The cumulative incidences of local recurrence and distant metastases at 2 years were 7.6% (standard error (SE) 3.7%) and 29% (SE 6 %, Fig. 1) respectively. Acute grade 3 dermatitis occurred in one patient (1.5 %)and two patients experienced late grade 3 toxicity (fractures, 3.0 %). Twenty patients developed distant metastases, two diagnosed before start of the treatment. Eighteen patients died, with six deaths from distant metastases and one from the primary tumour. Conclusion: Preoperative moderate hypofractionation for STS during COVID-19 showed promising results, with no increase in postoperative wound complications and favourable local failure rates.

Background: Dermatofibrosarcoma protuberans (DFSP) is a rare malignancy of the skin with an invasive growth pattern that requires effective surgical treatment to prevent recurrences. Objective: To compare recurrence rates after Mohs micrographic surgery (MMS) and wide local excision (WLE) for the treatment of DFSP. Methods: Recurrence rates were determined using data from the nationwide pathology bank (Palga) on DFSPs treated between 2000 and 2022 in three university medical centres. Results: Outcomes were analysed for 393 patients. After WLE, 27 of 209 (13 %) patients developed at least one recurrence over the course of a mean follow-up of 9.8 years (95 % CI 9.1-10.5). For (slow) MMS, there were no recurrences during a mean follow-up time of 6.2 years (95 % CI 5.6-6.8). Most recurrences occurred within five years (85 %). Conclusion: In line with the NCCN Guidelines (R) and the EDF-EADO-EORTC guideline, this study recommends treating DFSP primarily with (slow) MMS as this treatment leads to a substantially lower recurrence rate than WLE.

INTRODUCTION:To improve care for patients with colorectal peritoneal metastases (CRC-PM) or pseudomyxoma peritonei (PMP), the Dutch CRS-HIPEC quality registry was initiated in 2019. The aims are to describe the development and content of this registry and to give insight into the data collected during the first years. MATERIALS AND METHODS:The registry is an observational cohort in the Netherlands. All patients with CRC-PM or PMP who intend to undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) from 6 hospitals are included. Clinical data and outcomes (including hospital variation) were analyzed. RESULTS:In 2019-2022, 889 patients were included in the CRS-HIPEC quality registry: 749 (84 %) with CRC-PM and 140 (16 %) with PMP. Peritoneal metastases were diagnosed synchronously in 51 % of CRC-PM patients and in 94 % of PMP patients. In patients undergoing complete CRS, the median peritoneal cancer index was 8 (IQR 4-13) for CRC-PM and 15 (IQR 6-26) for PMP. Complete cytoreduction was achieved in 639 CRC-PM patients (97 %) and 108 PMP patients (82 %). HIPEC was mainly performed with mitomycin C (CRC-PM: 94 %, PMP: 92 %). Major postoperative complications (Clavien-Dindo grade ≥3) occurred in 148 CRC-PM patients (22 %) and 30 PMP patients (23 %) with 90-day mortality rates of 2 %. In CRC-PM, differences between hospitals were observed regarding proportions of diagnostic laparoscopies/laparotomies, (neo)adjuvant treatment, ostomy formations and re-admissions. CONCLUSION:The CRS-HIPEC quality registry provides insight into the outcomes of CRS-HIPEC and enables clinical auditing and observational cohort studies aiming to improve treatment outcomes for patients with CRC-PM and PMP.

Novel systemic therapies for advanced melanoma improve survival, but carry potential serious side effects and high costs. This study aimed to assess the timing and use of systemic therapies in the months before death. Patients diagnosed with advanced melanoma (July 2017-June 2020) who died before July 2020 were selected from the Netherlands Cancer Registry. We evaluated the timing of systemic therapies within 30 days and 3 months before death, and studied patient and tumor characteristics associated with systemic therapy use between diagnosis and death. Out of 1097 patients 68% received systemic therapy. Almost 25% and 10% started a new therapy within 90 days and within 30 days before death, respectively. Female sex, elevated LDH, BRAF mutation, poor ECOG performance status (>= 3), and high comorbidity index reduced the odds of receiving immune therapy. Poor performance status and high comorbidity decreased the odds for both therapies. A considerable number of patients started systemic therapy shortly before death, emphasizing the importance of considering potential benefits and drawbacks through shared decision-making.

Background This study aimed to assess the performance of currently available risk calculators in a cohort of patients with malignant peripheral nerve sheath tumors (MPNST) and to create an MPNST-specific prognostic model including type-specific predictors for overall survival (OS).Methods This is a retrospective multicenter cohort study of patients with MPNST from 11 secondary or tertiary centers in The Netherlands, Italy and the United States of America. All patients diagnosed with primary MPNST who underwent macroscopically complete surgical resection from 2000 to 2019 were included in this study. A multivariable Cox proportional hazard model for OS was estimated with prespecified predictors (age, grade, size, NF-1 status, triton status, depth, tumor location, and surgical margin). Model performance was assessed for the Sarculator and PERSARC calculators by examining discrimination (C-index) and calibration (calibration plots and observed-expected statistic; O/E-statistic). Internal-external cross-validation by different regions was performed to evaluate the generalizability of the model.Results A total of 507 patients with primary MPNSTs were included from 11 centers in 7 regions. During follow-up (median 8.7 years), 211 patients died. The C-index was 0.60 (95% CI 0.53-0.67) for both Sarculator and PERSARC. The MPNST-specific model had a pooled C-index of 0.69 (95%CI 0.65-0.73) at validation, with adequate discrimination and calibration across regions.Conclusions The MPNST-specific MONACO model can be used to predict 3-, 5-, and 10-year OS in patients with primary MPNST who underwent macroscopically complete surgical resection. Further validation may refine the model to inform patients and physicians on prognosis and support them in shared decision-making. Malignant peripheral nerve sheath tumors (MPNST) are a type of cancer that develops from nerves in the body. It is difficult to know how long someone will live after being diagnosed with MPNST. The authors in this study aimed to find a way to predict survival after diagnosis of MPNST using factors such as age, tumor size, location, depth, NF-1 status, and other relevant information. To do this, they created a computer model that used the above information to predict survival. They tested the model on patients who had surgery for MPNST in the United States, the Netherlands, or Italy between 2000 and 2019. Their results show that these factors can be combined to predict survival at 3-, 5-, and 10- years after surgery with good, but not perfect, accuracy.

As the importance of the patient’s perspective on treatment outcome is becoming increasingly clear, the availability of patient-reported outcome measures (PROMs) has grown accordingly. There remains insufficient information regarding the quality of PROMs in patients with soft-tissue sarcomas (STSs). The objectives of this systematic review were (1) to identify all PROMs used in STS patients and (2) to critically appraise the methodological quality of these PROMs. Literature searches were performed in MEDLINE and Embase on April 22, 2024. PROMs were identified by including all studies that evaluate (an aspect of) health-related quality of life in STS patients by using a PROM. Second, studies that assessed measurement properties of the PROMs utilized in STS patients were included. Quality of PROMs was evaluated by performing a COSMIN analysis. In 59 studies, 39 PROMs were identified, with the Toronto Extremity Salvage Score (TESS) being the most frequently utilized. Three studies evaluated methodological quality of PROMs in the STS population. Measurement properties of the TESS, Quick Disability of the Arm, Shoulder and Hand (QuickDASH) and European Organization for Research and Treatment for Cancer Quality of Life Questionnaire (EORTC-QLQ-C30) were reported. None of the PROMs utilized in the STS population can be recommended for use based on the current evidence and COSMIN analysis. To ensure collection of reliable outcomes, PROMs require methodological evaluation prior to utilization in the STS population. Research should prioritize on determining relevant content and subsequently selecting the most suitable PROM for assessment.

BACKGROUND:Especially in the era of successful systemic therapy, there is an urgent need to detect early disease recurrence in stage III melanoma patients. This study investigates if serum S100 calcium-binding protein B (S100B) can detect disease recurrence in stage III melanoma patients. METHODS:A retrospective cohort study was conducted at the University Medical Center Groningen (UMCG). Adult AJCC 8th stage III melanoma patients in whom serum S100B was measured as part of follow-up from January 2010 until April 2023 were included. The association between serum S100B and disease recurrence was evaluated using standard definitions for sensitivity and positive predictive value (PPV). RESULTS:Overall, 147 patients were included (mean age was 60.4 years, 53.1 % were female). Most patients were classified as stage IIIB (39, 26.5 %) and IIIC (73, 49.7 %). During median follow-up of 56 months, 69 (46.9 %) patients experienced disease recurrence. Seventeen out of 18 patients with elevated serum S100B (≥0.15 μg/L) experienced disease recurrence (PPV of 94.4 %). However, 52 out of 69 patients with disease recurrence had normal serum S100B (sensitivity of 24.6 %). Eight out of 17 (47.1 %) patients were asymptomatic (P = 0.608), twelve (70.6 %) patients had at least four distant metastases (P < 0.001). CONCLUSION:The clinical value of serum S100B to detect disease recurrence in stage III melanoma patients is negligible since only one out of four patients with disease recurrence have elevated serum S100B. Furthermore, half of stage III melanoma patients with elevated S100B experienced symptoms, and most patients already have multiple distant metastases.

BackgroundIsolated limb perfusion (ILP) is a well-established surgical procedure for the administration of high dose chemotherapy to a limb for the treatment of advanced extremity malignancy. Although the technique of ILP was first described over 60 years ago, ILP is utilised in relatively few specialist centres, co-located with tertiary or quaternary cancer centres. The combination of high dose cytotoxic chemotherapy and the cytokine tumour necrosis factor alpha (TNFα), mandates leakage monitoring to prevent potentially serious systemic toxicity. Since the procedure is performed at relatively few specialist centres, an ILP working group was formed with the aim of producing technical consensus guidelines for the procedure to streamline practice and to provide guidance for new centres commencing the technique.MethodsBetween October 2021 and October 2023 a series of face to face online and hybrid meetings were held in which a modified Delphi process was used to develop a unified consensus document. After each meeting the document was modified and recirculated and then rediscussed at subsequent meeting until a greater than 90% consensus was achieved in all recommendations.ResultsThe completed consensus document comprised 23 topics in which greater than 90 % consensus was achieved, with 83% of recommendations having 100% consensus across all members of the working group. The consensus recommendations covered all areas of the surgical procedure including pre-operative assessment, drug dosing and administration, perfusion parameters, hyperthermia, leakage monitoring and theatre logistics, practical surgical strategies and also post-operative care, response evaluation and staff training.ConclusionWe present the first joint expert-based consensus statement with respect to the technical aspects of ILP that can serve as a reference point for both existing and new centres in providing ILP.

This feasibility study aims to explore the use of three-dimensional virtual surgical planning to preoperatively determine the need for reconstructive surgery following resection of an extremity soft-tissue sarcoma. As flap reconstruction is performed more often in advanced disease, we hypothesized that tumor volume would be larger in the group of patients that had undergone flap reconstruction. All patients that were treated by surgical resection for an extremity soft-tissue sarcoma between 1 January 2016 and 1 October 2019 in the University Medical Center Groningen were included retrospectively. Three-dimensional models were created using the diagnostic magnetic resonance scan. Tumor volume was calculated for all patients. Three-dimensional tumor volume was 107.8 (349.1) mL in the group of patients that had undergone primary closure and 29.4 (47.4) mL in the group of patients in which a flap reconstruction was performed, p = 0.004. Three-dimensional tumor volume was 76.1 (295.3) mL in the group of patients with a complication following ESTS treatment, versus 57.0 (132.4) mL in patients with an uncomplicated course following ESTS treatment, p = 0.311. Patients who had undergone flap reconstruction had smaller tumor volumes compared to those in the group of patients treated by primary closure. Furthermore, a larger tumor volume did not result in complications for patients undergoing ESTS treatment. Therefore, tumor volume does not seem to influence the need for reconstruction. Despite the capability of three-dimensional virtual surgical planning to measure tumor volume, we do not recommend its utilization in the multidisciplinary extremity soft-tissue sarcoma treatment, considering the findings of the study.

BACKGROUND:The added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of a survey study and retrospective analyses in a clinical database. METHODS:A survey study was conducted among clinical specialists to select most relevant characteristics of metastatic GIST patients considered for local treatment, defined as elective surgery or ablation. Patients were selected from the Dutch GIST Registry. A multivariate Cox-regression model for overall survival since time of diagnosis of metastatic disease was estimated with local treatment as a time-dependent variable. An additional model was estimated to assess prognostic factors since local treatment. RESULTS:The survey's response rate was 14/16. Performance status, response to TKIs, location of active disease, number of lesions, mutation status, and time between primary diagnosis and metastases, were regarded the 6 most important characteristics. Of 457 included patients, 123 underwent local treatment, which was associated with better survival after diagnosis of metastases (HR = 0.558, 95%CI = 0.336-0.928). Progressive disease during systemic treatment (HR = 3.885, 95%CI = 1.195-12.627) and disease confined to the liver (HR = 0.269, 95%CI = 0.082-0.880) were associated with worse and better survival after local treatment, respectively. CONCLUSION:Local treatment is associated with better survival in selected patients with metastatic GIST. Locally treated patients with response to TKIs and disease confined to the liver have good clinical outcome. These results might be considered for tailoring treatment, but should be interpreted with care because only specific patients are provided with local treatment in this retrospective study.