Technical considerations for isolated limb perfusion: A consensus paper.

BACKGROUND: Isolated 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. METHODS: Between 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. RESULTS: The 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. CONCLUSION: We 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.

Trauma and sporadic desmoid tumor development: An approach toward real incidence and aspects of causality.

OBJECTIVES: The development of desmoid tumors (DT) is associated with trauma, which is an aspect with medicolegal relevance. The objective of this study was to analyze the proportion and type of trauma (surgical, blunt/fracture, implants), its lag time, and mutations of the CTNNB1 gene in patients with sporadic DT. METHODS: We analyzed a prospectively kept database of 381 females and 171 males, median age at disease onset 37.7 years (females) and 39.3 years (males) with a histologically confirmed DT. Patients with germline mutation of the APC gene were excluded. Details of the history particularly of traumatic injuries to the site of DT were provided by 501 patients. RESULTS: In 164 patients (32.7%), a trauma anteceding DT could be verified with a median lag time of 22.9 months (SD, 7.7 months; range, 9-44 months). A prior surgical procedure was relevant in 98 patients, a blunt trauma in 35 patients, a punctuated trauma (injections, trocar) in 18 patients, and site of an implant in 10 patients. In 220 patients, no trauma was reported (43.9%), and 58 females (11.6%) had a postpregnancy DT in the rectus abdominis muscle. In 42 patients (8.4%), data were inconclusive. The distribution of mutations in the CTNNB1 gene (codon 41 vs. 45) was similar in patients with and without a history of trauma before DT development. CONCLUSIONS: A significant subgroup of patients suffers from a trauma-associated DT, predominantly at a prior surgical site including implants to breast or groin, accounting for 77.9% of the cases, whereas blunt trauma was responsible in 22.1%. We found no data to support that trauma-associated DT have different molecular features in the CTNNB1 gene.

Health related Quality of Life over time in German sarcoma patients. An analysis of associated factors - results of the PROSa study.

Introduction: Sarcomas are rare cancers and very heterogeneous in their location, histological subtype, and treatment. Health-Related Quality of Life (HRQoL) of sarcoma patients has rarely been investigated in longitudinal studies. Methods: Here, we assessed adult sarcoma patients and survivors between September 2017 and February 2020, and followed-up for one year in 39 study centers in Germany. Follow-up time points were 6 (t1) and 12 months (t2) after inclusion. We used a standardized, validated questionnaire (the European Organisation for Research and Treatment of Cancer Quality of Life Core Instrument (EORTC QLQ-C30) and explored predictors of HRQoL in two populations (all patients (Analysis 1), patients in ongoing complete remission (Analysis 2)) using generalized linear mixed models. Results: In total we included up to 1111 patients at baseline (915 at t1, and 847 at t2), thereof 387 participants were in complete remission at baseline (334 at t1, and 200 at t2). When analyzing all patients, HRQoL differed with regard to tumor locations: patients with sarcoma in lower extremities reported lower HRQoL values than patients with sarcomas in the upper extremities. Treatment which included radiotherapy and/or systemic therapy was associated with lower HRQoL. For patients in complete remission, smoking was associated with worse HRQoL-outcomes. In both analyses, bone sarcomas were associated with the worst HRQoL values. Being female, in the age group 55-<65 years, having lower socioeconomic status, and comorbidities were all associated with a lower HRQoL, in both analyses. Discussion: HRQoL increased partially over time since treatment and with sporting activities. HRQoL improved with time since treatment, although not in all domains, and was associated with lifestyle and socioeconomic factors. Bone sarcomas were the most affected subgroup. Methods to preserve and improve HRQoL should be developed for sarcoma patients.

Ten recommendations for sarcoma surgery: consensus of the surgical societies based on the German S3 guideline "Adult Soft Tissue Sarcomas".

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

Variation in response rates to isolated limb perfusion in different soft-tissue tumour subtypes: an international multi-centre study.

OBJECTIVE: The aim of this study was to investigate the response rates of different extremity soft-tissue sarcoma subtypes (eSTS) after isolated limb perfusion (ILP), based on an international multi-centre study. MATERIALS AND METHODS: The retrospective cohort comprised eSTS patients from 17 specialised ILP centres that underwent melphalan-based ILP, with or without recombinant human tumour necrosis factor (rhTNFα) (TM-ILP and M-ILP, respectively). Response was measured on imaging (magnetic resonance imaging) and/or clinical response, for which M-ILPs were excluded. RESULTS: A total of 1109 eSTS patients were included. The three most common histological subtypes were undifferentiated pleomorphic sarcoma (17%, n = 184), synovial sarcoma (16%, n = 175) and myxofibrosarcoma (8%, n = 87). rhTNFα was used in 93% (TM-ILP) and resulted in a significantly better overall response rate (ORR, p = 0.031) and complete responses (CR, p < 0.001) in comparison to M-ILP, without significant differences among histological subgroups. The ORR of TM-ILP was 68%, including 17% CR. Also, 80% showed progressive disease. Significantly higher response rates were shown for Kaposi sarcoma (KS) with 42% CR and 96% ORR (both p < 0.001), and significantly higher CR rates for angiosarcoma (AS, 45%, p < 0.001) and clear cell sarcoma (CCS, 31%, p = 0.049). ILP was followed by resection ≤ 6 months in 80% of the patients. The overall limb salvage rate was 88%, without significant differences among histological subgroups, but was significantly higher for ILP responders compared to non-responders (93% versus 76%, p < 0.001). CONCLUSION: ILP resulted in high response and LRS among all eSTS subtypes, however, with significant differences between subtypes with most promising results for KS, AS and CCS.

Quality Measurement for Soft Tissue Sarcomas in Germany: First Results of the Certified Sarcoma Centres.

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

Controversies in the management of patients with soft tissue sarcoma: Recommendations of the Conference on State of Science in Sarcoma 2022.

BACKGROUND: Owing to the rarity and heterogeneity in biology and presentation, there are multiple areas in the diagnosis, treatment and follow-up of soft tissue sarcoma (STS), with no, low-level or conflicting evidence. METHODS: During the first Consensus Conference on the State of Science in Sarcoma (CSSS), we used a modified Delphi process to identify areas of controversy in the field of sarcoma, to name topics with limited evidence-based data in which a scientific and knowledge gap may remain and a consensus statement will help to guide patient management. We determined scientific questions which need to be addressed in the future in order to generate evidence and to inform physicians and caregivers in daily clinical practice in order to improve the outcomes of patients with sarcoma. We conducted a vote on STS key questions and controversies prior to the CSSS meeting, which took place in May 2022. RESULTS: Sixty-two European sarcoma experts participated in the survey. Sixteen strong consensus (≥95%) items were identified by the experts, as well as 30 items with a ≥75% consensus on diagnostic and therapeutic questions. Ultimately, many controversy topics remained without consensus. CONCLUSIONS: In this manuscript, we summarise the voting results and the discussion during the CSSS meeting. Future scientific questions, priorities for clinical trials, registries, quality assurance, and action by stakeholders are proposed. Platforms and partnerships can support innovative approaches to improve management and clinical research in STS.

[Fluorescence-guided Lymph Vessel Sealing in Systematic Nodal Dissection: a New Surgical Technique to Prevent Lymphorrhea and Lymphocele.] / Fluoreszenzgesteuerte Lymphgefäßversiegelung bei der systematischen Lymphknotendissektion zur Vermeidung von Lymphfisteln und Lymphozelen.

INTRODUCTION: The primary morbidities of inguinal and axillary systematic nodal dissection are lymphatic fistulas and seromas. Intraoperative fluorescence imaging-guided sealing of lymph vessels may prevent these postoperative complications. METHODS: Indocyanine dye was injected intracutaneously into the distal limb before the beginning of the lymphadenectomy. Systematic nodal dissection was performed according to standard protocols. Near-infrared imaging was applied throughout the procedure and real-time fluorescence-guided lymph vessel sealing was performed. RESULTS: Fluorescence-guided lymph vessel sealing was implemented in three patients undergoing axillary systematic lymph node dissection. No adverse events occurred following fluorescence dye injection. All patients could be discharged free of wound complications. CONCLUSION: Fluorescence-guided lymph vessel sealing might be a promising new technique for preventing lymphatic fistulas and lymphocele after systematic lymphadenectomy.

Accelerating the Front End of Medicine: Three Digital Use Cases and HCI Implications.

Digital applications in health care are a concurrent research and management question, where implementation experiences are a core field of information systems research. It also contributes to fighting pandemic crises like COVID-19 because contactless information flow and speed of diagnostics are improved. This paper presents three digital application case studies from emergency medicine, administration management, and cancer diagnosis with AI support from the University Medical Centers of Münster and Göttingen in Germany. All cases highlight the potential of digitalization to increase speed and efficiency within the front end of medicine as the crucial phase before patient treatment starts. General challenges for health care project implementations and human-computer interaction (HCI) concepts in health care are derived and discussed, including the importance of specific processes together with user analysis and adaption. A derived concept for HCI includes the criteria speed, accuracy, modularity, and individuality to achieve sustainable improvements within the front end of medicine.

Comparing Apparent Diffusion Coefficient and FNCLCC Grading to Improve Pretreatment Grading of Soft Tissue Sarcoma-A Translational Feasibility Study on Fusion Imaging.

Histological subtype and grading are cornerstones of treatment decisions in soft tissue sarcoma (STS). Due to intratumoral heterogeneity, pretreatment grading assessment is frequently unreliable and may be improved through functional imaging. In this pilot study, 12 patients with histologically confirmed STS were included. Preoperative functional magnetic resonance imaging was fused with a computed tomography scan of the resected specimen after collecting core needle biopsies and placing radiopaque markers at distinct tumor sites. The Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading criteria of the biopsies and apparent diffusion coefficients (ADCs) of the biopsy sites were correlated. Concordance in grading between the specimen and at least one biopsy was achieved in 9 of 11 cases (81.8%). In 7 of 12 cases, fusion imaging was feasible without relevant contour deviation. Functional analysis revealed a tendency for high-grade regions (Grade 2/3 (G2/G3)) (median (range) ± standard deviation: 1.13 (0.78-1.70) ± 0.23 × 10-3 mm2/s) to have lower ADC values than low-grade regions (G1; 1.43 (0.64-2.03) ± 0.46 × 10-3 mm2/s). In addition, FNCLCC scoring of multiple tumor biopsies proved intratumoral heterogeneity as expected. The ADC appears to correlate with the FNCLCC grading criteria. Further studies are needed to determine whether functional imaging may supplement histopathological grading.

Distress in soft-tissue sarcoma and gastrointestinal stromal tumours patients-Results of a German multicentre observational study (PROSa).

OBJECTIVE: Soft tissue sarcomas (STS) and gastrointestinal stromal tumours (GIST) are a group of rare malignant tumours with a high and heterogenous disease burden. As evidence is scarce, we analysed the prevalence of increased emotional distress and identified distress-associated factors in these patients. METHODS: The PROSa-study (Burden and medical care of sarcoma) was conducted between 2017 and 2020 in 39 study centres. Cross-sectional data from adult STS and GIST patients were analysed. Distress was measured with the Patient Health Questionnaire (PHQ-4). The relation of socioeconomic and clinical factors with distress was explored in adjusted logistic regression models. RESULTS: Among 897 patients, 17% reported elevated anxiety and 19% reported depression. Unemployed patients (odds ratio [OR] 6.6; 95% CI 2.9-15.0), and those with a disability pension (OR 3.1; 95% CI 1.9-5.0) were more likely to experience distress compared to employed patients. Also, patients with a disability pass had higher odds of increased distress than those without (OR 1.8; 95% CI 1.2-2.7). Lowest distress was observed in patients 2 to <5 years and ≥5 years after diagnosis (comparison: <6 months) (OR 0.4; 95% CI 0.2-0.6) and (0.3; 95% CI 0.2-0.6). Patients with thoracic STS (vs. lower limbs) had twice the odds to experience distress (OR 2.0; 95% CI 1.1-3.6). Distress was seen almost twice as often in patients with progressive disease (vs. complete remission) (OR 1.7; 95% CI 1.1-2.8). CONCLUSION: The prevalence of elevated distress in STS and GIST patients is high. In unemployed patients, in those with a disability pension and in newly diagnosed patients a noticeable increase was observed. Clinicians should be aware of these factors and consider the social aspects of the disease.

Transferability of Health-Related Quality of Life Data of Large Observational Studies to Clinical Practice: Comparing Retroperitoneal Sarcoma Patients from the PROSa Study to a TARPS-WG Cohort.

INTRODUCTION: Health-related quality of life (HRQoL) is crucial for shared decision-making. The "Patient-Reported Outcome measures in Sarcoma" (PROSa) study evaluated HRQoL in general. We evaluated the transferability of PROSa data to clinical practice for the subgroup of retroperitoneal sarcoma (RPS). METHODS: To obtain a PROSa-RPS cohort, we excluded patients with bone sarcomas and gastrointestinal stromal tumors from the complete PROSa cohort (n = 1,113), limited tumor localization to trunk and retroperitoneum, and excluded patients with metastases. We evaluated the HRQoL data of the resulting 76 patients and compared their clinical data to those of the Transatlantic Autralasian Retroperitoneal Sarcoma Working Group (TARPS-WG, n = 1,007). RESULTS: Confidence intervals for patient sex, histological subtype (LPS vs. non-LPS), grading (G1 vs. G2/3), surgical margins (R2 vs. no R2), and perioperative chemo- and radiotherapy (yes vs. no) were overlapping in both cohorts. EORTC QLQ-C30 from RPS-PROSa patients demonstrated that two-thirds had clinically relevant restrictions in physical functioning. Two-thirds reported dyspnea, followed by fatigue and pain. CONCLUSION: Clinical data from RPS-PROSa patients are comparable to those of an RPS reference cohort from expert centers. We believe that HRQoL data of RPS patients extracted from PROSa are transferable to clinical practice.

Needle tract seeding and abdominal recurrence following pre-treatment biopsy of gastrointestinal stromal tumors (GIST): results of a systematic review.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are rare abdominal tumors. Pretreatment biopsies may be used to diagnose a GIST and enable tailored treatment. Some experts are skeptical about biopsies because they fear tumor cell seeding. The objective of this study was to determine if pretreatment biopsy is associated with increased tumor recurrence. METHODS: We performed a systematic literature search and included studies assessing the oncological outcome of GIST patients who underwent a pre-treatment core needle biopsy or fine needle aspiration. We assessed methodological quality with the Newcastle-Ottawa-Scale for non-randomized studies. This review was registered in the PROSPERO database (CRD42021170290). RESULTS: Three non-randomized studies and eight case reports comprising 350 patients were eligible for inclusion. No prospective study designed to answer the review question was found. One case of needle tract seeding after percutaneous core needle biopsy of GIST was reported. None of the studies reported an increased rate of abdominal recurrence in patients with pretreatment biopsy. CONCLUSIONS: The existing evidence does not indicate a relevant risk of needle tract seeding or abdominal recurrence after pre-treatment biopsy of GIST. Biopsy can safely be done to differentiate GIST from other tumors and to select the most appropriate treatment.

The association of Health-Related Quality of Life and 1-year-survival in sarcoma patients-results of a Nationwide Observational Study (PROSa).

BACKGROUND: Sarcomas are rare cancers of high heterogeneity. Health-Related Quality of Life (HRQoL) has been shown to be a prognostic factor for survival in other cancer entities but it is unclear whether this applies to sarcoma patients. PATIENTS AND METHODS: HRQoL was prospectively assessed in adult sarcoma patients from 2017 to 2020 in 39 German recruiting sites using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Vital status was ascertained over the course of 1 year. HRQoL domains were analysed by multivariable cox-regressions including clinical and socio-economic risk factors. RESULTS: Of 1102 patients, 126 (11.4%) died during follow-up. The hazard ratio (HR) for global health was 0.73 per 10-point increase (95% confidence interval (CI) 0.64-0.85). HR for the HRQoL-summary score was 0.74 (CI 0.64-0.85) and for physical functioning 0.82 (CI 0.74-0.89). There was also evidence that fatigue (HR 1.17, CI 1.10-1.25), appetite loss (HR 1.15, CI 1.09-1.21) and pain (HR 1.14, CI 1.08-1.20) are prognostic factors for survival. CONCLUSION: Our study adds sarcoma-specific evidence to the existing data about cancer survival in general. Clinicians and care-givers should be aware of the relations between HRQoL and survival probability and include HRQoL in routine assessment.

Accuracy and Safety of Ultrasound-Guided Core Needle Biopsy of Soft Tissue Tumors in an Outpatient Setting: A Sarcoma Center Analysis of 392 Consecutive Patients.

BACKGROUND: The aim of this study was to investigate diagnostic accuracy, safety and histologic results of ultrasound guided core needle biopsy (CNB) in patients with soft tissue lesions (STL) at a tertiary referral center. METHODS: A retrospective analysis of all consecutive patients undergoing ultrasound guided CNB for STL at our sarcoma outpatient service between January 2015 and August 2020 was performed. RESULTS: A total of 392 patients were identified. Main histologic entities were sarcomas, lipomas and desmoid tumors. Biopsy was performed in an outpatient setting in 87.6% of the cases. Conclusive biopsies were obtained in 88.5% of the cases. In patients who underwent surgical resection after CNB, the concordance of dignity, tumor entity and histopathological grading between biopsy and resection specimen were 97.2%, 92.7% and 92.5% respectively. The risk of inconclusive CNB was highest in intraabdominal or retroperitoneal tumors (19.5%) and lowest in lesions at the lower extremity (4.4%). Major complications after CNB occurred in three cases (0.8%). No case of biopsy tract seeding was observed during the study period. CONCLUSIONS: Ultrasound guided CNB for STL at first presentation in a dedicated surgical outpatient setting is a safe procedure and yields a high diagnostic accuracy.