Uncemented Customized Hollow Stems in Tumor Endoprosthetic Replacement-A Good Opportunity to Protect the Adjacent Joint in Children?

This study aimed to retrospectively analyze the follow-up results of cases in which the adjacent joint was preserved using a custom-made uncemented short-stem design (hollow stem) with optional external flanches in tumor endoprosthetic replacement due to bone sarcomas in 13 patients (with an average age of 9.6 years) between 2017 and 2023. Reconstructions were proximal femur (n = 6), intercalary femur (n = 4), intercalary tibia (n = 2), and proximal humerus (n = 1) tumor prostheses. The hollow body was used distally in 10 of the megaprotheses, proximally in 1, and both proximally and distally in 2 of them. The average distance from the joints was 6 cm in stems with flanches and 11.8 cm in stems without flanches. No aseptic loosening or deep infection was observed during an average follow-up of 34 months. Except for one case with a tibial intercalary prosthesis that needed a revision, all cases were well osteointegrated and all lower extremity cases could bear full weight without pain. In cases where the remaining bone stock after bone resection is insufficient for a standard stem implantation, reconstruction with a patient-specific short hollow-stem design appears to be a good alternative to protect healthy joints with high prosthesis survival and low revision rates in the short-term follow-up.

Slipped capital femoral epiphysis after tumor prosthesis implantation in a patient receiving chemotherapy.

While the usual etiology of slipped capital femoral epiphysis (SCFE) is idiopathic, there are many other factors that increase the predisposition to slippage. Chemotherapy can be one of them. In this article, we report a rare case of acute SCFE after tumor prosthesis implantation in a patient who received chemotherapy. A 10-year-old girl with osteosarcoma of the right distal femur underwent (neo-) adjuvant chemotherapy, wide tumor resection, and reconstruction using a growing tumor prosthesis and a short non-cemented femoral stem. Half a year after implantation, she developed aseptic loosening. Revision surgery was performed using a hydroxyapatite (HA)-coated cementless femoral stem. Postoperative plain radiographs revealed SCFE that was treated by closed reduction and screw fixation. The patient recovered without complications, and unaffected hip showed no radiographic signs of slippage on follow-up. The forces of implanting a tumor prosthesis, particularly with a non-cemented stem, can increase the risk of an acute SCFE. The controversy over prophylactic pinning of the uninvolved hip in chemotherapy-associated SCFE is unresolved. Pinning can be considered only in the presence of abnormal prodromal radiological findings.

Outcome of Surgery as Part of Palliative Care of Patients with Symptomatic Advanced or Metastatic Extra-Abdominal High-Grade Soft Tissue Sarcoma.

Background: The modern multimodal treatment of malignant tumors has increased disease-specific survival and decreased the burden of tumor-associated complications. The main focus of palliative surgery is not based primarily on quantitative success parameters of tumor response but is instead mainly on the question of quality of life. Aim: The current study was conducted to analyze the clinical and oncological outcomes of palliative patients with soft tissue sarcoma. Design: Of 309 patients with extra-abdominal high-grade soft tissue sarcoma treated between August 2012 and December 2014, our retrospective analysis revealed 33 palliative patients for this study. All patients were evaluated and managed by a multidisciplinary team with expertise and experience in sarcoma treatment. The survival analysis was made using the Kaplan-Meier method. Results: The main sarcoma symptoms were pain (27.3%) and ulcerated tumors or shortly before ulceration (24.2%). Thirteen patients (39.4%) were operated on with negative margins, 15 (45.5%) with positive margins, 2 with tumor debulking (6.1%), and 3 patients (9.1%) were treated only with palliative hyperthermic isolated limb perfusion. Ten pedicle flaps were performed after sarcoma resection. The median operation time was 85 minutes (range, 37-216 minutes). The median hospitalization stay was 9.5 days (range, 3-27 days). No patients died during hospitalization. Twelve-month disease-free survival was 48.5% (95% confidence interval: 45.4-51.6). Conclusions: Palliative surgery of metastatic or advanced soft tissue sarcoma can improve the wound care and quality of life. Closed noninfected wounds enable further treatment options, such as chemotherapy, immunotherapy, and radiotherapy. This surgery should be considered during the discussion on interdisciplinary tumor boards.

Classic Type of Epithelioid Sarcoma of the Distal Upper Extremity: Clinical and Oncological Characteristics.

BACKGROUND: The classic type of epithelioid sarcoma (ES) is a rare, aggressive soft tissue neoplasm that most commonly affects the distal upper extremities of young patients. This study aimed to assess clinical features and provide a long-term report of the oncological outcome. METHODS: We retrospectively analyzed our clinical database for patients with ES of the distal upper extremities. RESULTS: Twenty-three patients with ES of the distal upper extremity were treated surgically between January 1990 and August 2018. ES affected most commonly the palmar side of young patients. The most common site affected by a sarcoma was the wrist in 47.8% of cases, followed by metacarpals and fingers with 34.8% and 17.4%, respectively. Most of the patients were treated according to the protocols of interdisciplinary tumor boards with multimodal therapy. A local recurrence was observed in 7 patients (30.4%). The 5 - and 10-year recurrence-free survival was 80.4% (95% confidence interval [CI]: 68.6-76.8) and 60.9% (95% CI: 53.5-68.3), respectively. The 5- and 10-years disease-specific survival was 89.9% (95% CI: 87-92.8) and 61.9% (95% CI: 56.5-67.3), respectively. Five patients (21.7%) had metastasis in regional lymph nodes. CONCLUSION: The classic type of ES represents a group of high-grade sarcomas, which affect the dominantly distal upper extremity. Specific clinical, diagnostic, and oncological characteristics make it difficult to diagnose and therapy. Wide tumor resection as a part of multimodal therapy remains a more viable and common treatment option for patients with ES on distal extremities. High rates of lymph node metastasis are typical for ES.

Optimization of the preoperative requirements of blood units for the surgical treatment of extra-abdominal soft tissue sarcoma: the TRANSAR score.

BACKGROUND AND OBJECTIVES: Excessive preoperative blood orders frequently occur during the preoperative planning of resections of sarcomas. We aimed to develop a prediction score model that would be able to identify a patient cohort in which the cross-matching could be safely evaded. PATIENTS AND METHODS: We retrospectively analyzed data of 309 consecutive patients with extra-abdominal soft tissue sarcomas treated between September 2012 and December 2014. Scorecard scores for variables were calculated and summarized to a total score that can be used for risk stratification. The score was used in a logistic regression model. Results of the optimized model were described as a receiver operating characteristic curve. RESULTS: Preoperative units of red blood cells were requested for 206 (66.7%) patients, of which only 31 (10%) received them. Five parameters were identified with high predictive power. In the visualized barplot, there was an increased risk of blood transfusion with a higher score of TRANSAR. CONCLUSION: A TRANSAR score is a new tool that can predict the probability of transfusion for patients with sarcoma. This may reduce the number of preoperative cross-matching and blood product ordering and associated costs without compromising patient care.

Pathological Fractures in Benign Bone Lesions - Diagnosis and Therapy. / Die pathologische Fraktur bei benignen Knochenläsionen - Diagnostik und Therapie.

INTRODUCTION: Most tumour-related pathological fractures occur in patients with bone metastases. However, in mostly younger patients, a pathological fracture can be due to both a benign or a malignant bone tumour. Making the correct diagnosis from among these two differential diagnoses is enormously important. If the tumour is malignant, treating the fracture inevitably leads to tumour cell contamination and can significantly worsen the oncological situation. The aim of this review article is firstly to provide the reader with diagnostic assistance in the case of suspected pathological fractures, and secondly to focus on the treatment of pathological fractures occurring with benign bone tumours. METHODS: This is a non-systematic review of the diagnosis and treatment of pathological fractures in benign bone tumours or tumour-like lesions, based on an electronic PubMed database search. We also present our own procedures, in particular for ruling out a malignant bone tumour. RESULTS AND DISCUSSION: Whenever a fracture occurs in the absence of sufficient traumatic force, the possibility of a pathological fracture should always be considered. As well as taking a general history for a possible primary tumour, it is particularly important to ask the patient whether they had any pain before the fracture occurred. If the findings from clinical examination or conventional radiological imaging give rise to suspicion of a pathological fracture, an MRI of the affected skeletal section with contrast medium should be carried out before commencing any fracture treatment. A CT scan is also helpful for accurately assessing bone destruction. If a malignant or locally aggressive benign bone tumour such as giant cell tumour (GCT) or aneurysmal bone cyst (ABC) cannot be definitively ruled out through imaging, a biopsy is essential. The bone biopsy must always be carried out on the assumption that the histological work-up will reveal a malignant bone tumour; it must therefore be performed according to strict oncological criteria. If the radiological diagnosis is unambiguous, e. g., a juvenile bone cyst (JBC) or a non-ossifying fibroma (NOF), conservative treatment of the fracture can be considered, depending on the location. In the presence of a locally aggressive benign bone tumour such as a GCT or ABC, curettage of the tumour must be carried out as well as treating the fracture. With GCT in particular, neoadjuvant therapy with denosumab prior to curettage and osteosynthesis or en bloc resection of the tumour should be considered, depending on the extent of the tumour. CONCLUSION: Pathological fractures, especially in younger patients, should not be overlooked. Only after a malignant or benign locally aggressive bone tumour has been definitively ruled out should fracture treatment be performed. In the presence of a locally aggressive bone tumour, as well as treating the fracture, it is usually necessary to perform curettage of the tumour - also en bloc resection, where applicable, in the case of a GCT. Depending on the location, benign, non-aggressive tumours can be treated conservatively if necessary.

68Ga-FAPI as a Diagnostic Tool in Sarcoma: Data from the 68Ga-FAPI PET Prospective Observational Trial.

Bone and soft-tissue sarcomas express fibroblast activation protein (FAP) on tumor cells and associated fibroblasts. Therefore, FAP is a promising therapeutic and diagnostic target. Novel radiolabeled FAP inhibitors (e.g., 68Ga-FAPI-46) have shown high tumor uptake on PET in sarcoma patients. Here, we report the endpoints of the 68Ga-FAPI PET prospective observational trial. Methods: Forty-seven patients with bone or soft-tissue sarcomas undergoing clinical 68Ga-FAPI PET were eligible for enrollment into the 68Ga-FAPI PET observational trial. Of these patients, 43 also underwent 18F-FDG PET. The primary study endpoint was the association between 68Ga-FAPI PET uptake intensity and histopathologic FAP expression analyzed with Spearman r correlation. Secondary endpoints were detection rate, positive predictive value (PPV), interreader reproducibility, and change in management. Datasets were interpreted by 2 masked readers. Results: The primary endpoint was met, and the association between 68Ga-FAPI PET uptake intensity and histopathologic FAP expression was significant (Spearman r = 0.43; P = 0.03). By histopathologic validation, PPV was 1.00 (95% CI, 0.87-1.00) on a per-patient and 0.97 (95% CI, 0.84-1.00) on a per-region basis. In cases with histopathologic validation, 27 of 28 (96%) confirmed patients and 32 of 34 (94%) confirmed regions were PET-positive, resulting in an SE of 0.96 (95% CI, 0.82-1.00) on a per-patient and 0.94 (95% CI, 0.80-0.99) on a per-region basis. The detection rate on a per-patient basis in 68Ga-FAPI and 18F-FDG PET was 76.6% and 81.4%, respectively. In 8 (18.6%) patients, 68Ga-FAPI PET resulted in an upstaging compared with 18F-FDG PET. 68Ga-FAPI PET readers showed substantial to almost perfect agreement for the defined regions (Fleiss κ: primary κ = 0.78, local nodal κ = 0.54, distant nodal κ = 0.91, lung κ = 0.86, bone κ = 0.69, and other κ = 0.65). Clinical management changed in 13 (30%) patients after 68Ga-FAPI PET. Conclusion: We confirm an association between tumoral 68Ga-FAPI PET uptake intensity and histopathologic FAP expression in sarcoma patients. Further, with masked readings and independent histopathologic validation, 68Ga-FAPI PET had a high PPV and sensitivity for sarcoma staging.

Localized Angiosarcoma, Not One Disease: A Retrospective Single-Center Study on Prognosis Depending on the Primary Site and Etiology.

BACKGROUND: Angiosarcomas are rare and heterogeneous tumors with poor prognosis. The clinical subtypes are classified depending on the primary site and etiology. METHODS: We conducted a retrospective, monocentric study of 136 patients with localized AS between May 1985 and November 2018. Overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS) were estimated using the Kaplan-Meier method. To identify prognostic factors, univariate and multivariate analyses were performed based on Cox regressions. RESULTS: The median age was 67 years (19-72.8 years). Primary sites were cutaneous (27.2%), breast (38.2%), and deep soft tissue (34.6%). The majority was primary angiosarcomas (55.9%) followed by postradiation (40.4%) and chronic lymphedema angiosarcomas (2.9%). Prognosis significantly differed depending on the primary site and etiology. Shortest median OS and MFS were observed in deep soft tissue angiosarcomas, whereas cutaneous angiosarcomas, angiosarcomas of the breast, and radiation-associated angiosarcomas displayed worse median LRFS. Univariate analyses showed better OS for tumor size <10 cm (p = 0.009), negative surgical margins (p = 0.021), and negative lymph node status (p = 0.007). LRFS and MFS were longer for tumor size <10 cm (p = 0.012 and p = 0.013). In multivariate analyses, age <70 years was the only independent positive prognostic factor for OS in all subgroups. For LRFS, secondary AS of the breast was a negative prognostic factor (HR: 2.35; p = 0.035). CONCLUSIONS: Different behaviors and prognoses depending on the primary site and etiology should be considered for the treatment of this heterogeneous disease. In cutaneous angiosarcomas of the head/neck and postradiation angiosarcomas of the breast, local recurrence seems to have a crucial impact on OS. Therefore, improved local therapies and local tumor staging may have to be implemented. However, in deep soft tissue angiosarcomas, distant recurrence seems to have a major influence on prognosis, which indicates a benefit of additional perioperative chemotherapy.

Efficacy of hyperthermic isolated limb perfusion in the treatment of locally recurrent high-grade soft tissue sarcoma of the extremities.

BACKGROUND: This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities. METHODS: We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed. RESULTS: Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5-78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7-48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival. CONCLUSIONS: TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.

Secondary angiosarcoma: A fatal complication of chronic lymphedema.

Secondary Angiosarcoma (Stewart-Treves Syndrome) is a rare malignant cutaneous lesion, which arises in chronic lymphedema of the extremity, often observed after breast cancer treatment. We reviewed the history and the oncological outcome of two patients with this disease. Multimodal therapy including hyperthermic isolated limb perfusion with TNF-alpha and Melphalan, combined with radical resection of the affected skin and subcutaneous tissue including the fascia, with large safety margins may probably lead to better survival.

Extended ray resection for sarcoma of the hand: long-term survival and functional results.

In this retrospective study, we analysed the long-term oncological and functional results after extended ray resection for sarcoma of the hand. Recurrence-free and overall survivals were calculated using the Kaplan-Meier method. The function of the operated hand was assessed with the Michigan Hand Questionnaire and compared with the contralateral side. Extended ray resection was performed in 25 out of 168 consecutive patients with soft-tissue and bony sarcomas of the hand. The overall 5- and 10-year, disease-specific survival rates were 86% and 81%, respectively. Local recurrences were observed in two patients. The Michigan Hand Questionnaire score for the affected hand at follow-up in nine patients was 82 points versus 95 for the healthy contralateral hands. We conclude that extended ray resection of osseous sarcomas breaking through the bone into the soft tissue or for soft tissue sarcomas invading bone is a preferable alternative to hand ablation when excision can be achieved with tumour-free margins. Level of evidence: III.

Integrated 18F-FDG PET/MRI compared to MRI alone for identification of local recurrences of soft tissue sarcomas: a comparison trial.

PURPOSE: To assess and compare the diagnostic accuracy of PET/MRI and MRI alone for the detection of local recurrences of soft tissue sarcomas (STS) after initial surgical resection of the primary tumors. MATERIAL AND METHODS: A total of 41 patients with clinically suspected tumor relapse of STS underwent an 18F-FDG-PET/MRI examination for assessment of local recurrence. Two experienced physicians interpreted the MRI data and subsequently the PET/MRI datasets in two separate reading sessions and were instructed to identify potential local tumor recurrences. Additionally, the diagnostic confidence in each reading for the identification of malignant lesions was determined. A McNemar test was applied to test for differences of both ratings and a Wilcoxon signed-rank test was used to identify differences of the confidence levels. Histopathological verification and follow-up imaging were applied for standard of reference. RESULTS: Tumor relapse was present in 27/41 patients. Calculated sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy for the detection of local tumor recurrence was 82%, 86%, 92%, 71% and 83% for MRI, and 96%, 79%, 90%, 92% and 90% for PET/MRI (p > 0.05). Furthermore, PET/MRI showed significantly higher confidence levels (p < 0.05) for the determination of malignant lesions. CONCLUSION: Our results endorse 18F-FDG PET/MRI to be an excellent imaging method in the evaluation of recurrent STS after surgical excision, yielding superior tumor detection when compared to MRI alone.

Lower limb function and quality of life after ILP for soft-tissue sarcoma.

BACKGROUND: Isolated limb perfusion with TNF-alpha and melphalan (TM-ILP) in combination with complete tumor resection is an effective treatment option for non-resectable soft-tissue sarcoma of the extremities, with limb salvage rates greater than 80%. The aim of this study was to assess quality of life (QoL) after TM-ILP, also with regard to long-term survival. METHODS: We retrospectively examined 27 patients who had primarily non-resectable soft-tissue sarcoma of the leg and who had undergone TM-ILP and complete tumor resection (with limb-sparing intent) during their follow-up examinations using the Quality of Life Questionnaire (QLQ-C30) and the German Short Musculoskeletal Function Assessment (SMFA-D). The results from the QLQ-C30 were compared to the reference values for the general population, to the "all cancer patients" reference values (both reference values published by the European Organization for Research and Treatment of Cancer (EORTC)), and to the reference values of a historical amputation group from the literature. The results of the SMFA were compared with those from a reference group of healthy individuals. RESULTS: Surprisingly, we found that the global health status/QoL in the TM-ILP group was not significantly different from the general population or from patients with amputation, but it was higher than that of patients with cancer in general. Concerning the SMFA, we did find functional impairments in patients after TM-ILP compared to the reference group. With regard to long-term survival, we found no time-dependent deterioration in QoL for longer time intervals after treatment. CONCLUSIONS: These results support the use of TM-ILP in limb-sparing multimodal therapy settings from a quality-of-life perspective, but they also encourage further research on this matter.

Inhibitor of Apoptosis Proteins (IAPs) are commonly dysregulated in GIST and can be pharmacologically targeted to enhance the pro-apoptotic activity of imatinib.

Gastrointestinal stromal tumors (GIST) exhibit a strong oncogenic dependency on KIT and KIT inhibitors confer long lasting disease stabilization in the majority of patients. Nonetheless, KIT inhibition alone does not cure GIST as a subset of GIST cells evade apoptosis and eventually develop resistance. Inhibitors of Apoptosis Proteins (IAPs) may confer resistance to drug-induced apoptosis. We observed that the mRNA and protein of IAPs XIAP (BIRC4) and survivin (BIRC5) were highly expressed in primary GIST tumors and cell line models. Amplification of the respective gene loci (BIRC2, BIRC3, BIRC4, BIRC5) was detected in 47% of GIST studied by SNP arrays. Whole exome analyses revealed a mutation of SMAC(DIABLO) in a heavily pretreated patient. Both, survivin (rank 62-92/11.194 tested proteins) and XIAP (rank 106-557/11.194) were found to be essential proteins for survival in a synthetic lethality screen. Expression of XIAP and survivin decreased upon KIT inhibition and may play a role in KIT-regulated pro-survival signaling. SMAC-mimetic treatment with LCL161 and TL32711 reduced cIAP1 and XIAP expression. Survivin inhibitor YM155 lead to transcriptional repression of BIRC5/survivin (YM155) and induced apoptosis. Combinational treatment with KIT inhibitors (imatinib, regorafenib) enhanced the proapoptotic effect. These findings support the combination of KIT inhibition with IAP antagonists in GIST.

Drug dosage in isolated limb perfusion: evaluation of a limb volume model for extremity volume calculation.

BACKGROUND: Exact drug dosing in isolated limb perfusion (ILP) and infusion (ILI) is essential. We developed and evaluated a model for calculating the volume of extremities and compared this model with body weight- and height-dependent parameters. METHODS: The extremity was modeled by a row of coupled truncated cones. The sizes of the truncated cone bases were derived from the circumference measurements of the extremity at predefined levels (5 cm). The resulting volumes were added. This extremity volume model was correlated to the computed tomography (CT) volume data of the extremity (total limb volume). The extremity volume was also correlated with the patient's body weight, body mass index (BMI) and ideal body weight (IBW). The no-fat CT limb volume was correlated with the circumference-measured limb volume corrected by the ideal-body-weight to actual-body-weight ratio (IBW corrected-limb-volume). RESULTS: The correlation between the CT volume and the volume measured by the circumference was high and significant. There was no correlation between the limb volume and the bare body weight, BMI or IBW. The correlation between the no-fat CT volume and IBW-corrected limb volume was high and significant. CONCLUSIONS: An appropriate drug dosing in ILP can be achieved by combining the limb volume with the simple circumference measurements and the IBW to body-weight ratio.

The pathologic response of resected synovial sarcomas to hyperthermic isolated limb perfusion with melphalan and TNF-α: a comparison with the whole group of resected soft tissue sarcomas.

BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan (TM-HILP) has been successfully used to treat limb soft tissue sarcomas (STSs) with high response rates. The data on the effectiveness of HILP-TM for the treatment of STSs are mainly based on various STS types. The aim of this study was to investigate the responses of synovial sarcomas (SS) to TM-HILP. METHODS: A total of 125 TM-HILP-treated tumors (STS all), including 14 SSs, were included in the study. The tumors were subdivided into proximal and distal limb localizations. Tumor typing (using the WHO classification), resection status (using the UICC classification), and response to therapy were assessed using light microscopy. The SSs were tested for the SYT-SSX translocation using RT-PCR. The following tests were applied: a chi-squared test, a t test, and the Mann-Whitney U test. RESULTS: The SSs were localized distally more often than were the STS cohort (STS(-SS)) (85.7% vs. 32.4%) and were smaller (5.8 cm vs. 10.7 cm). There were no differences in the responder/nonresponder ratios or the mean percentages of pathological regression between the SS and STS(-SS) cohorts (74.0% vs. 76.0%). A general localization-dependent difference in the tumor responses to TM-HILP could not be detected in the STS all cohort (distal, 72.0% vs. proximal, 78.0%); however, a UICC R0 status was more often observed in proximal tumors (distal, 50.0% vs. proximal, 71.4%). There was no association between the SYT-SSX type and SS responses to TM-HILP. CONCLUSIONS: Because of the high response rates, TM-HILP is recommended for the treatment of SSs. The distal limb localization of TM-HILP-treated STSs was generally (STS all cohort) associated with fewer R0 resections.