Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing

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The patient was treated with a multidisciplinary approach associating neoadjuvant and adjuvant chemotherapy with excisional surgery. The femoral reconstruction consisted of a ``Capasquelet'' reconstruction combining an induced membrane and a vascularized fibula allograft allowing a good functional result with an early weight-bearing. We managed to complete our histological analysis in this patient, in order to evaluate the tumor vascularization. Indeed, using the syngeneic osteosarcoma MOS-J mouse model, we highlighted previously that CD31+/\ensuremath{\alpha}-SMA+ vessels may be indicators of vasculature normalization and therefore may be used as specific markers of a good therapeutic response. Thus, we search for its interest in this specific case as preliminary work. The aim was to assess the feasibility and technical validity of the vascularization analysis of a human osteosarcoma tumor specimen. Therefore, we propose an immunohistochemistry methodology with multiplexed immunofluorescence to assess the vascularization as a promising marker in human osteosarcoma tissue." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/11-1066/v2", "name": "Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient:..." } } ] } Home Browse Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient:... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Tran G, Amiaud J, Combal A et al. Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.12688/f1000research.124846.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Case Report Revised Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] Guillaume Tran 1,2 , Jerome Amiaud 2 , Alexis Combal 1 , [...] Franck Duteille 3 , Françoise Redini 2 , Franck Verrecchia 2 , Vincent Crenn https://orcid.org/0000-0002-6563-8895 1,2 Guillaume Tran 1,2 , Jerome Amiaud 2 , [...] Alexis Combal 1 , Franck Duteille 3 , Françoise Redini 2 , Franck Verrecchia 2 , Vincent Crenn https://orcid.org/0000-0002-6563-8895 1,2 PUBLISHED 30 Sep 2024 Author details Author details 1 Clinique Chirurgicale Orthopédique et Traumatologique, Nantes université, CHU Nantes, Nantes, France 2 Team 9 CHILD (CHromatin and Transcriptional Deregulation in Pediatric Bone Sarcoma), CRCI2NA (Centre de Recherche en Cancérologie et Immunologie Nantes-Angers), INSERM UMR 1307, CNRS UMR 6075, Nantes, France 3 Chirurgie plastique et reconstructrice, Nantes université, CHU Nantes, Nantes, France Guillaume Tran Roles: Data Curation, Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing Jerome Amiaud Roles: Data Curation, Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing Alexis Combal Roles: Investigation, Writing – Review & Editing Franck Duteille Roles: Data Curation, Writing – Review & Editing Françoise Redini Roles: Writing – Review & Editing Franck Verrecchia Roles: Writing – Review & Editing Vincent Crenn Roles: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract We describe the case report of an Osteosarcoma patient, with a Li-Fraumeni Syndrome, presenting with a pathological femoral fracture. The patient was treated with a multidisciplinary approach associating neoadjuvant and adjuvant chemotherapy with excisional surgery. The femoral reconstruction consisted of a ``Capasquelet'' reconstruction combining an induced membrane and a vascularized fibula allograft allowing a good functional result with an early weight-bearing. We managed to complete our histological analysis in this patient, in order to evaluate the tumor vascularization. Indeed, using the syngeneic osteosarcoma MOS-J mouse model, we highlighted previously that CD31+/\ensuremath{\alpha}-SMA+ vessels may be indicators of vasculature normalization and therefore may be used as specific markers of a good therapeutic response. Thus, we search for its interest in this specific case as preliminary work. The aim was to assess the feasibility and technical validity of the vascularization analysis of a human osteosarcoma tumor specimen. Therefore, we propose an immunohistochemistry methodology with multiplexed immunofluorescence to assess the vascularization as a promising marker in human osteosarcoma tissue. READ ALL READ LESS Keywords Osteosarcoma, intercalary reconstruction, vascularized fibula, immunohistochemistry, vascular analysis, Endomucin Corresponding Author(s) Vincent Crenn ( [email protected] ) Close Corresponding author: Vincent Crenn Competing interests: No competing interests were disclosed. Grant information: This study was supported by the Fondation pour la Recherche Médicale (grant number DEA20150633177). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Tran G et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Tran G, Amiaud J, Combal A et al. Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.12688/f1000research.124846.2 ) First published: 20 Sep 2022, 11 :1066 ( https://doi.org/10.12688/f1000research.124846.1 ) Latest published: 30 Sep 2024, 11 :1066 ( https://doi.org/10.12688/f1000research.124846.2 ) Revised Amendments from Version 1 According to the first reviewer comment we have checked on TCGA expression of EMCN and aSMA in osteosarcoma. We have modified our discussion According to the first reviewer comment we have checked on TCGA expression of EMCN and aSMA in osteosarcoma. We have modified our discussion See the authors' detailed response to the review by Mo-Fan Huang READ REVIEWER RESPONSES Introduction Osteosarcoma care remains a challenge in various ways, such as determining chemotherapy response on biopsy, but as well with challenging reconstruction, especially in intercalary bone tumor resections. We propose in this case report to put highlight on these two points, describing an original technique of massive bone loss reconstruction, and focusing on innovative immunohistochemestry multiplexing techniques in order to better assess vascularization of osteosarcoma as a possible prognosis factor. Massive diaphyseal bone defects are a reconstruction challenge, and several surgical methods have been described 1 – 3 (vascularized fibula, autograft, bone transport, massive endoprosthesis, etc. ). There is no gold-standard, and indications are a matter of debate, with variable results. We here described an innovative technique for managing a critical femoral bone defect of 24 cm using the Capasquelet procedure. 4 This original two-stage technique combine the allograft technique with a centromedullary inlaid vascularized fibula ( i.e. , “Capanna technique”) 5 and the induced membrane technique ( i.e. , “Masquelet technique”). 6 The combination of these, called the “Capasquelet” technique get several advantages: the biological receptacle with the induced membrane prevents graft resorption and has also an osteoinductive role 7 ; it also decreases infection risks, and avoids a long one-stage surgery. This case report describes this hybrid surgical technique on a massive femur defect. We assessed the bone healing, the delay to complete weight-bearing, and a functional score analysis in this patient. On the other hand, predicting the chemotherapy response of osteosarcoma patients, with treatment such as high-dose methotrexate or doxorubicin cocktail, remains a challenge. 8 – 10 Moreover, the prognostic value of induced necrosis analysis is questionable, and is only available after neo-adjuvant treatment is done on resection piece. New markers of prognostic response are urgently needed, focusing on tumor microenvironment. 11 As we showed in our preclinical mouse model, using the syngeneic osteosarcoma MOS-J mouse model, vascular analysis of tumor depicted with immunohistochemestry fluorescent multiplexing might play a role as being a potential prognosis factor of tumor response. 10 , 12 Our results may have suggested that the presence of CD31+/ α -SMA+ vessels could be considered to be indicators of mature and functional vasculature able to deliver drugs adequately, and may be used as specific markers of a good therapeutic response. Nonetheless, no human tissue analysis using this method has been made until now. And before proposing a quantitative analysis, we propose in this case report to describe the feasibility of this method and a preliminary observation of the vascular heterogeneity analysis with Endomucin+, CD31+, and α -SMA+ immunohistochemistry. Case presentation The 28-year-old patient presented to the ER department with a femur fracture occurring while playing football. The lytic aspect of the fracture was considered suspect, a CT-scan, an MRI and an open surgical biopsy were performed confirming the pathological fracture ( Figure 1 ). Osteosarcoma primitive tumor was suspected in this case on biopsy samples, and as its sister already had been treated for a proximal tibia Osteosarcoma, a Li-Fraumeni Syndrom was diagnosed due to its family anteriority 13 ( Table 1 ). Figure 1. Left femur pathologic fracture. A: AP X-Ray view with osteolytic lesions; B: MRI T2sagittal view showing tumor invasion. Table 1. Epidemiological data concerning the case. Epidemiology data Gender Age (years) BMI (kg/m 2 ) Etiology Fracture stabilization Neo-adjuvant treatment Male 28 22.3 Osteosarcoma (Li-Fraumeni Syndrom) Long leg cast API-AI protocol * * neo-adjuvant chemotherapy combined three doxorubicin-ifosfamide-cisplatin (API) and two doxorubicin-ifosfamide (AI) courses. Capasquelet surgical technique First stage The patient underwent initial wide margin (R0) oncologic resection, with a 20 cm diaphysis resection, at this time the femoral fracture has healed during neo-adjuvant CT ( Table 2 ). The femur was prepared with a clean cut transversally. A cement spacer using high-viscosity Heraeus Palacos ® R + G cement (Hanau, Germany) was modelled; it fills the bone loss as fully as possible. Due to pathological fracture and limb length discrepancy, the spacer was made 2 cm longer than the resection (22 cm). We also preferred to oversize it somewhat in width as the soft tissue coverage was not an issue, as it increases reconstruction space and facilitate induced membrane closure for the second stage. The spacer was covering the bone–host interfaces as recommended in the Masquelet technique. 6 It was enhanced on a locked intramedullary nailing, positioned back and forth ( Figure 2 ). Patient was considered good responder in pathology analysis with 1.5% residual viable cells ( Table 3 ). Table 2. Surgery data concerning the case. Surgical data Spacer stabilization Total operative time (T1; T2) (minutes) Fibula graft length (mm) Graft stabilization Delay T1 and T2 (weeks) Allograft length (mm) IMN 774 (295; 479) 280 Single plate 22 220 Figure 2. Capasquelet technique reconstruction, using a femoral radiograph view: (A) preoperative radiograph, pathological fracture of the high-grade osteosarcoma with a limb length discrepancy of 80 mm; (B) postoperative radiograph of the first stage after carcinologic resection and the spacer placement on an intramedullary nail with limb length discrepancy of 60 mm (post-T1 delay: 1 month); (C) postoperative radiograph at 1 year, residual limb length discrepancy of 40 mm. Table 3. Post-operative data concerning the case. Pathology data Postoperative consolidation data Functional results Margins quality Viables cells Bone healing delay (months) ISOLS score 3 months (%) ISOLS score 6 months (%) Full weight-bearing (weeks) EQ 5D at six months R0 Margins 1.5% 7 73.3 95.6 12 75 Interstage planification The femoral allograft dimension was determined to be as close as possible of the patient femur; the diaphyseal shaft width must allow the fibula to slide into it. We used a cryopreserved allograft, in compliance with the criteria of the French Agency of Biomedicine, from the Nantes Multi-Tissue Bank. The delay between the two stages was of 22 weeks due to adjuvant chemotherapy. Second stage The length aimed (24 cm) and the rotational axes were determined before the spacer was removed. The vascularized fibula graft required microsurgical technique for harvesting and vascular anastomoses. The fibula graft was 28 cm in our case, and it was four centimeters longer than the planned bone allograft length. Graft harvesting was done from the contralateral limb by a second surgical team with microsurgical expertise in order to decrease the surgery duration. The harvesting was performed under a tourniquet, ensuring at least 8 cm 14 of the distal fibula was spare in order to limit malleolar instability risk. A lateral surgical approach was used to raise the osseous graft. The bone was vascularized by an artery from the peroneal artery that entered the middle-third of the fibula. The section must include this area. After identification of the artery and its origin from the tibio-fibular trunk, the vessel was dissected. 15 The allograft was warmed for one hour in a hot physiological serum bath and then cut with an oscillating saw with transverse cut similar to the bone defect aimed. One specific team was devoted to set the hybrid graft: the allograft was filled with the fibula after a progressive reaming, care was taken to not hurt the vessels of the fibula, a bone window was performed on the allograft for allowing its mobilization and sliding in the allograft. 2 cm of fibula were planned for overlapping the bone interfaces. Then, the hybrid graft was stabilized and compressed with a 4.5mm locking compression plate, taking care to orientate the fibula vessels towards anastomosis area. Lastly, the microsurgical anastomosis was performed at the terminal branches of the profunda femoris artery ( Figure 2 ). Postoperative management Early mobilization and progressive weight-bearing were allowed postoperatively. Strictly limited weight-bearing was prescribed for the first six weeks, with progressive full weight-bearing depending on the patient’s pain and condition ( Table 3 ). Full weight bearing was obtained at twelve weeks, with a functional quality of life of 75% on the EQ 5D score. Adjuvant chemotherapy was then performed with two doxorubicin-ifosfamide and two cisplatin-ifosfamide courses. Long term follow up At last follow-up (38 months following tumor resection), no local complication nor local recurrence occurred, with full weight bearing on his lower limb, allowing walking without cane. Nonetheless, despite beeing a good responder with R0 resection, the patient relapsed with pulmonary metastasis at 13 months follow up, needing surgical excision. Early pulmonary recurrence make us introduce a complementary targeted therapy with cabozantinib and chemotherapy ifosfamide and VP16. Vascular analysis On bone biopsy we first suspected a bone undifferentiated pleomorphic sarcoma (UPS), due to the low level of osteoïd matrix on the sample; the diagnosis of Li-Fraumeni Syndrom was also made due to oncological family anteriorities. Nonetheless, an osteosarcoma chemotherapy protocol was performed with an API-AI protocol. On bone tumor resection piece, osteosarcoma pathology diagnosis was made due to visualization of many osteoïd matrix on various places among the tumor. The unusual pejorative oncological evolution, despite an initial good pathology response and good margins was unusual in this case, thus, we performed a complementary histologic analysis. Our aim was to assess the vascularization of patient osteosarcoma on biopsy prior to any chemotherapy treatment, and also to assess technical feasibility of our previous methodology (described on preclinical mouse model) on multiplexing analysis. 12 Indeed, on a preclinical osteosarcoma MOS-J syngenic mouse model we identified two different kinds of vessels on confocal multiplexing analysis: CD31+/ α -SMA+ elements and CD31+/Endomucin+elements. The CD31+/ α -SMA+ elements exhibited a structured and straight architecture, with a sizeable diameter, and they resembled mature vessels. On the other hand, the CD31+/Endomucin+ elements were much more sinusoidal, with a more serpiginous and unorganized structure. They also had a smaller diameter and they look like immature sinusoidal vessels, which might be linked to tumor neo-angiogenesis ( Figure 3 ). Figure 3. Confocal analysis of CD31+/ α -SMA+ and CD31+/Endomucin+ costaining in a control center lesion. A: CD31+/ α -SMA+ elements. B: CD31+/Endomucin+ elements. The images are Z-stack projections at 63× magnification, the scale bars =20 μm. DAPI: nuclear staining (from Crenn et al. 12 ). Immunohistochemestry tissue processing The patient biopsy was collected surgically under complete anesthesia through a direct open approach, as soon as the pathological fracture was suspected. Samples were immediately fixed in 4% buffered formalin for 24 hours. The sample was then decalcified in 4.13% EDTA, 0.2% paraformaldehyde, in 1× pH 7,4 PBS buffer for 10 to 15 days at 50°C in the KOS microwave tissue processor (Milestone, Michigan, USA). It was finaly dehydrated through graded ethanol baths, cleared in 2-butanol and embedded in paraffin. Serial 5- μ m-thick sections were cut from each sample and stained for H&E and Masson trichrome. Other sections were immunostained for α -SMA, Endomucin, and CD31 markers. Three-color immunofluorescence histochemistry Sections were deparaffinized, subjected to 20 h antigen retrieval in Tris-EDTA buffer (1 mM Tris, 0.5 mM EDTA, pH 9.0) at 60°C, and blocked with 2% normal donkey serum and 1% BSA in 1× Tris-buffered saline with 0.05% Tween 20 pH 7.4 to reduce unspecific binding. Sections were first immunostained with rabbit to CD31 (1:40, Abcam, ab28364) antibody for an hour at room temperature. After three washes in 1×TBS Tween 0.05% pH 7.4, sections were then incubated for an hour with biotinylated donkey anti-rabbit (1:200; Jackson ImmunoResearch 711-065-152), followed with Alexa Fluor 488-conjugated streptavidin (1:200; Jackson ImmunoResearch 016-540-084) another hour. To avoid non specific binding of both second primary rabbit antibody and secondary donkey anti-rabbit antibody, sections were then blocked with 5% normal rabbit serum in 1× TBS Tween 0.05% pH 7.4 for 30 min at room temperature followed by a blocking step with donkey anti-rabbit Fab fragments (1:10; Jackson ImmunoResearch 711-007-003) in 1× TBS Tween 0.05% pH 7.4 overnight at 4°C. The next day, after three washes in 1× TBS Tween 0.05% pH 7.4, sections were then incubated with rabbit to Endomucin (1:100; Thermo Fisher PA5-21395), and mouse to α -SMA (1:1000; R&D Biotechne, MAB1420) antibodies for an hour at room temperature. After three washes in 1× TBS Tween 0.05% pH 7.4, the following secondary antibodies were applied for another hour: Alexa Fluor 594-conjugated donkey anti-rabbit (1:200; Jackson ImmunoResearch 711-585-152), and Alexa Fluor 647-conjugated donkey anti-mouse (1:200; Jackson ImmunoResearch 715-605-150). Finally, nuclei were counterstained with DAPI (1:1000; ThermoFisher Scientific, D1306) and coverslipped with Prolong Gold Antifade reagent (ThermoFisher Scientific, P36930). Acquisition and histomorphometry Confocal images were obtained by using a Nikon AI N-SIM confocal microscope and subsequently treated by smoothing and noise reduction of each channels, following by a Z-projection treatment on ImageJ software. 16 All histomorphometric analysis were conducted on scans of the immunostained sections. Acquisitions of sections 4-7 were made with a NanoZoomer Slide Scanner (Hamamatsu, Japan), then pictures were saved using the NDP viewer software (Hamamatsu, version 2.2.6) at ×5 and export at ×10 using tiff format and analysed with ImageJ software. Each of the chromogenics immunostained sections were individually analyzed on 3 specific region of interest (ROI): one was defined by a representative 0.5-mm thick ROI which contained the tumors tissue along the bone; the other was a full representative picture of the core of the tumor; the last one was defined by a representative 0.5-mm thick ROI, that was contained the tumoral growth front. All analysis was carried out on each of the four levels of all samples. Briefly, pictures were subjected to color deconvolution using [H DAB] vector, thresholded, and unspecific noise was reduced. The results were shown as the mean value for each compartment of the number of positive elements per square millimeter. For the triple-immunostaining sections (section 3), analysis was achieved using two levels that was considered, according results of ones that had been obtained on the chromogenics immunostained sections, as enough to give consistent values. Quantification of CD31+/ α -SMA+ (mature vessels), and CD31+/Endomucin+ (sinusoid vessels) were realized using the virtual microscope (NDP viewer) at a selected magnification of ×20 on a representative field of 0.366 mm 2 . Double-positive vessels were counted in the same manner as up described in the different compartment by selecting the two fluorochromes channels corresponding of the two markers of interest. Results were shown as the mean value of each level of each sample of double positive elements per square millimeter. HE and Masson trichrome staining in the patient biopsy lesion Immunohistochemistry analysis was performed on the biopsy lesion with Masson’s trichrome staining ( Figure 4 ), and showed a highly cellular malignant tumoral tissue, with a lack of osteoid matrix. We also observed some vessel-like structures. Figure 4. HE and Masson’s trichrome staining of the biopsy lesion at 10× and 20× magnification showing a low level of osteoïd matrix. Confocal analysis of CD31+, α -SMA+ and Endomucin+ and costaining in the patient biopsy lesion Immunohistochemistry analysis on the biopsy lesion ( Figure 5 ) showed CD31+ elements and α -SMA+ elements which looked like vascular mature structures. On the other hand, tumor cells seem to express endomucin with a diffuse staining along a rare expression of endothelial endomucin. Figure 5. Confocal analysis of CD31+, α -SMA+ and Endomucin+ and costaining in the patient biopsy lesion. At 40× magnification, and two areas in Z-stack projections at 63× magnification. DAPI: nuclear staining. Co-staining of CD31+/endomucin vessels seemed to show smaller vascular structures diameter-wise, unfortunately we could not distinguish any elements of architecture other than size and neither localization part of the tumor site as the biopsy was realized without targeting any specific areas of the tumor. Discussion Capasquelet surgical technique The Capasquelet technique result on this patient are promising, with bone healing being achieved within a short delay (12 weeks after the second stage), therefore allowing an early weight-bearing. We obtained a short delay for radiological bone healing with radiological follow up. The bone healing delay in our case (7 months) and in previous publication 4 seems to be in the low range of an isolated Capanna technique with a 6-12 months delay or a Masquelet technique, which obtains complete bone union in 4–18 months, usually on less massive tibia defects. 6 , 17 Despite the oncological disease evolution of the patient, the capasquelet surgery outcome was satisfactory, with early full weight-bearing, good function, and neither revisions nor complications. A larger cohort, and a longer follow-up is needed to confirm these interesting results, especially in a limb length discrepancy case, for sequential restoration of femur length in pathological fractures. With our method, the osteoinductive action played by the induced membrane may exert a positive impact on the graft bone healing, with fast fibula union and allograft, early full weight-bearing, and a satisfactory functional score. However, this two-stage technique got some drawbacks, the fibula harvest might results in morbidity, 18 and it requires microsurgical expertise and access to a bone bank facility. The operating times involved in the two stages must also be noted, compared to a simpler technique. Vascular analysis, Endomucin expression and patient Survival The pejorative oncological evolution of the patient, despite an initial good pathology response (1.5% residual viable cells) and R0 margins was unusual, despite the controversial potential pejorative roles of the pathological fracture 19 , 20 and the Li-Fraumeni Syndrome. 21 In this context, it seems relevant to find new prognostic markers, to better adapt adjuvant chemotherapy in osteosarcoma patients, especially focusing on tumor microenvironment. 11 The complementary histologic analysis on bone biopsy in this patient was performed aiming to explore vascularization with original stainings. Previous preclinical report investigated the implication of Endomucin expression in endothelial cells in a mouse model. 12 We have shown that low expression in endothelial cells associated with both CD31 and α -SMA high expression could be associated as a better response to doxorubicin chemotherapy. We obtained interpretable multiplexing analysis focusing on the human bone biopsy of our patient, validating the IHC methodological process. We identified CD31+ and α -SMA+ elements which looked like vascular mature structures, as well as thinner endomucin+ and CD31+, as in our preclinical mouse model. 12 Concerning endomucin, cells seem to express endomucin with a diffuse staining along a rare expression of endothelial endomucin. Interestingly, endomucin seems to be also expressed in tumoral cells when it comes to human tumors, opposite to our previous mouse model. Other reports show endomucin expressed in HUVECs cells and related a role of endomucin in the vascular function. 22 A recent report on digestives carcinomas 23 highlight a link between survival in stomach adenocarinoma and EMCN gene, with high expression on gene datasets correlated with poorer overall survival and disease-free survival. However, our case report focused on vascular expression of Endomucin and α -SMA in a mesenchymal bone cancer and did not explore precisely the expression of endomucin in osteosarcoma tumor cells themselves. Further investigation with quantitative analysis including mass spectrometry to segregate endothelial cells and tumor cells might be needed. 24 To our knowledge, it is the first description of endomucin expression via immunofluorescence staining in human osteosarcoma tumor, its high expression might be a pejorative prognosis factor as suggested in other oncological disease. 23 Nonetheless, further works are needed to understand its relevance in an osteosarcoma prognosis context, as literature shown that endomucin could be highly expressed among cancerous cells, as well as in other human tissues ( proteinatlas.org ) with various expressions. Other experiments focusing on endomucin expression after decalcification process are also mandatory as it is well known that decalcification, and method of decalcification have an impact on antigen retrieving. 25 , 26 In our pre-clinical model of long bone osteosarcoma, endomucin expression seems not to be affected by administration of doxorubicin. 12 We could not find any clear evidence of differentiated expression of endomucin after the treatment, but model of good response seems to show a different ratio of immature/mature vessels with maturity of the vasculature associated with good response to chemotherapy. 12 In this patient case, moderate to high intensity staining of endomucin among cancerous cell cause us to hypothesize whether its expression is related to the patient’s early metastatic relapse despite histologic good response. Checking on RNA-seq of EMCN and ACTA1 publicly available on TCGA ( https://portal.gdc.cancer.gov/ ) did not seem to show significant difference in survival related to the expression of endomucin and α-SMA in OS cells (supp Figures 1 and 2). Nevertheless, the latter lacks qualitative analysis on the vessel counts in the mesenchymal bone cancer and this type of analysis may be not suited to analyze the tumor and its microenvironment as we hypothesize the vessel maturity and architecture may have an influence on the chemotherapy response in OS. This hypothesis needs further exploration with simple techniques, such as tissue micro array, and survival cohort studies. Conclusions This case report of a Li-Fraumeni osteosarcoma patient illustrates two innovative specialized approaches, on one hand an original surgical reconstruction technique, with the Capasquelet reconstruction, allowing a good functional results and early weight-bearing in an intercalary large defect tumor resection. In the other hand, it shows promising data focusing on vascular tumor analysis with multiplexing immunofluorescent technique on tumor biopsy, aiming to better understand why patients with good tumor response will nonetheless still relapse. The Capasquelet technique needs larger cohort and longer follow-up to better asses its place in the therapeutic arsenal. Considering the immunofluorescent multiplexing analysis, the technique seems feasible and it needs to be analyzed on a larger human cohort in order to assess quantitatively if the CD31+/ α -SMA+, the CD31+/endomucin+ co-labelling, or Endomucin alone might be considered as potentials predictive factor of recurrence or survival in osteosarcoma. Publication information Author contributions Conceptualization, V.C.; formal analysis, G.T. and J.A.; investigation, G.T. and J.A.; data curation, G.T., J.A. F.D. and A.C.; writing—original draft preparation, G.T., J.A. and V.C.; writing—review and editing, G.T., J.A., A.C., F.D., F.R., F.V. and V.C.; supervision, V.C.; All authors have read and agreed to the published version of the manuscript. Institutional review board statement Not applicable. Informed consent statement Written informed consent has been obtained from the patient to publish this paper. Data availability statement The data sets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. Extended data Zenodo, 5 year survival in osteosarcoma, https://doi.org/10.12688/f1000research.124846.1 . 27 This project contains the following underlying data: • Supp Fig. 1. • Supp Fig. 2. Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC BY 4.0). Acknowledgments We wish to thank the MicroPIcell platform (Stéphanie Blandin, Steven Nedellec, and Philippe Hulin). This work was supported by the Fondation pour la Recherche Médicale, FRM grant number DEA20150633177 awarded to Vincent Crenn. Experimental Therapeutic unit (Guylène Hamery, UTE Phan, IRS-UN, 8 quai Moncousu, BP70721, 44007 Nantes Cedex 1). References 1. Zekry KM, Yamamoto N, Hayashi K, et al. : Reconstruction of Intercalary Bone Defect after Resection of Malignant Bone Tumor. J. Orthop. Surg. 2019; 27 : 230949901983297. PubMed Abstract | Publisher Full Text 2. Panagopoulos GN, Mavrogenis AF, Mauffrey C, et al. : Intercalary Reconstructions after Bone Tumor Resections: A Review of Treatments. Eur. J. Orthop. Surg. Traumatol. 2017; 27 : 737–746. PubMed Abstract | Publisher Full Text 3. Vidal L, Kampleitner C, Brennan MÁ, et al. : Reconstruction of Large Skeletal Defects: Current Clinical Therapeutic Strategies and Future Directions Using 3D Printing. Front. Bioeng. Biotechnol. 2020; 8 : 61–61. PubMed Abstract | Publisher Full Text 4. 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Publisher Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 20 Sep 2022 ADD YOUR COMMENT Comment Author details Author details 1 Clinique Chirurgicale Orthopédique et Traumatologique, Nantes université, CHU Nantes, Nantes, France 2 Team 9 CHILD (CHromatin and Transcriptional Deregulation in Pediatric Bone Sarcoma), CRCI2NA (Centre de Recherche en Cancérologie et Immunologie Nantes-Angers), INSERM UMR 1307, CNRS UMR 6075, Nantes, France 3 Chirurgie plastique et reconstructrice, Nantes université, CHU Nantes, Nantes, France Guillaume Tran Roles: Data Curation, Formal Analysis, Investigation, Writing – Original Draft Preparation, Writing – Review & Editing Jerome Amiaud Roles: Data Curation, Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing Alexis Combal Roles: Investigation, Writing – Review & Editing Franck Duteille Roles: Data Curation, Writing – Review & Editing Françoise Redini Roles: Writing – Review & Editing Franck Verrecchia Roles: Writing – Review & Editing Vincent Crenn Roles: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This study was supported by the Fondation pour la Recherche Médicale (grant number DEA20150633177). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 30 Sep 2024, 11:1066 https://doi.org/10.12688/f1000research.124846.2 version 1 Published: 20 Sep 2022, 11:1066 https://doi.org/10.12688/f1000research.124846.1 Copyright © 2024 Tran G et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Tran G, Amiaud J, Combal A et al. Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.12688/f1000research.124846.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 30 Sep 2024 Revised Views 0 Cite How to cite this report: Huang MF. Reviewer Report For: Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.5256/f1000research.170452.r328113 ) The direct URL for this report is: https://f1000research.com/articles/11-1066/v2#referee-response-328113 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 10 Oct 2024 Mo-Fan Huang , The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, Texas, USA; Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School (Ringgold ID: 12339), Houston, Texas, USA Approved VIEWS 0 https://doi.org/10.5256/f1000research.170452.r328113 Revision checked. no further comments to make. ... Continue reading READ ALL Revision checked. no further comments to make. (micro array should not have space between) Competing Interests: No competing interests were disclosed. Reviewer Expertise: Osteosarcoma genomics, molecular biology, system biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Huang MF. Reviewer Report For: Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.5256/f1000research.170452.r328113 ) The direct URL for this report is: https://f1000research.com/articles/11-1066/v2#referee-response-328113 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 20 Sep 2022 Views 0 Cite How to cite this report: Huang MF. Reviewer Report For: Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.5256/f1000research.137082.r262730 ) The direct URL for this report is: https://f1000research.com/articles/11-1066/v1#referee-response-262730 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 17 Apr 2024 Mo-Fan Huang , The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, Texas, USA; Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School (Ringgold ID: 12339), Houston, Texas, USA Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.137082.r262730 The research project aims to address the challenges in osteosarcoma care, focusing on two primary areas: innovative techniques for reconstructing massive bone defects and developing new prognostic markers for chemotherapy response. The proposed Capasquelet technique combines elements from two well-established ... Continue reading READ ALL The research project aims to address the challenges in osteosarcoma care, focusing on two primary areas: innovative techniques for reconstructing massive bone defects and developing new prognostic markers for chemotherapy response. The proposed Capasquelet technique combines elements from two well-established surgical methods to manage significant femoral bone defects. This hybrid approach has several advantages, including decreased infection risk and expedited bone healing, allowing early weight-bearing and satisfactory functional outcomes. In addition, the study explores the role of tumor vascularization as a potential prognostic factor for chemotherapy response in osteosarcoma patients. Through immunohistochemistry multiplexing, the research investigates the expression of specific markers, such as Endomucin and α-SMA, and their relationship with patient survival and therapeutic response. Although the results are promising and provide a foundation for further investigation, more extensive studies are needed to confirm the findings and explore their clinical relevance. Major point 1, The author gave detailed description of Capasquelet surgical technique, tissue immunofluorescence staining processing and data acquisition which would be helpful for reproductivity and practicing. However, for the benefit of future understanding of disease processes and treatment, less evidence was shown. In the discussion, you mentioned the Endomucin expression might be a pejorative prognosis marker, are there any other Osteosarcoma patient show high expression of Endomucin or any correlation between high endomucin and Osteosarcoma pathological outcomes? Since you only demonstrate one case here, it may be less convincing. Can the author check more patient gene expression or protein expression database (TCGA?) and see if there is correlation between Endomucin/α-SMA and prognosis in other patient samples? Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Osteosarcoma genomics, molecular biology, system biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Huang MF. Reviewer Report For: Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.5256/f1000research.137082.r262730 ) The direct URL for this report is: https://f1000research.com/articles/11-1066/v1#referee-response-262730 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 30 Sep 2024 Vincent Crenn , Team 9 CHILD (CHromatin and Transcriptional Deregulation in Pediatric Bone Sarcoma), CRCI2NA (Centre de Recherche en Cancérologie et Immunologie Nantes-Angers), INSERM UMR 1307, CNRS UMR 6075, Nantes, France 30 Sep 2024 Author Response Dear Reviewer, thank you for your remark, We have checked it on TCGA and modifications have been made at the end of the discussion. Competing Interests: No competing interests were disclosed. Dear Reviewer, thank you for your remark, We have checked it on TCGA and modifications have been made at the end of the discussion. Dear Reviewer, thank you for your remark, We have checked it on TCGA and modifications have been made at the end of the discussion. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 30 Sep 2024 Vincent Crenn , Team 9 CHILD (CHromatin and Transcriptional Deregulation in Pediatric Bone Sarcoma), CRCI2NA (Centre de Recherche en Cancérologie et Immunologie Nantes-Angers), INSERM UMR 1307, CNRS UMR 6075, Nantes, France 30 Sep 2024 Author Response Dear Reviewer, thank you for your remark, We have checked it on TCGA and modifications have been made at the end of the discussion. Competing Interests: No competing interests were disclosed. Dear Reviewer, thank you for your remark, We have checked it on TCGA and modifications have been made at the end of the discussion. Dear Reviewer, thank you for your remark, We have checked it on TCGA and modifications have been made at the end of the discussion. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 20 Sep 2022 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 Version 2 (revision) 30 Sep 24 read Version 1 20 Sep 22 read Mo-Fan Huang , The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, USA; The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School (Ringgold ID: 12339), Houston, USA Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Huang M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 Oct 2024 | for Version 2 Mo-Fan Huang , The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, Texas, USA; Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School (Ringgold ID: 12339), Houston, Texas, USA 0 Views copyright © 2024 Huang M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Revision checked. no further comments to make. (micro array should not have space between) Competing Interests No competing interests were disclosed. Reviewer Expertise Osteosarcoma genomics, molecular biology, system biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Huang MF. Peer Review Report For: Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.5256/f1000research.170452.r328113) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1066/v2#referee-response-328113 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Huang M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 17 Apr 2024 | for Version 1 Mo-Fan Huang , The University of Texas MD Anderson Cancer Center UTHealth Houston, Houston, Texas, USA; Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School (Ringgold ID: 12339), Houston, Texas, USA 0 Views copyright © 2024 Huang M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The research project aims to address the challenges in osteosarcoma care, focusing on two primary areas: innovative techniques for reconstructing massive bone defects and developing new prognostic markers for chemotherapy response. The proposed Capasquelet technique combines elements from two well-established surgical methods to manage significant femoral bone defects. This hybrid approach has several advantages, including decreased infection risk and expedited bone healing, allowing early weight-bearing and satisfactory functional outcomes. In addition, the study explores the role of tumor vascularization as a potential prognostic factor for chemotherapy response in osteosarcoma patients. Through immunohistochemistry multiplexing, the research investigates the expression of specific markers, such as Endomucin and α-SMA, and their relationship with patient survival and therapeutic response. Although the results are promising and provide a foundation for further investigation, more extensive studies are needed to confirm the findings and explore their clinical relevance. Major point 1, The author gave detailed description of Capasquelet surgical technique, tissue immunofluorescence staining processing and data acquisition which would be helpful for reproductivity and practicing. However, for the benefit of future understanding of disease processes and treatment, less evidence was shown. In the discussion, you mentioned the Endomucin expression might be a pejorative prognosis marker, are there any other Osteosarcoma patient show high expression of Endomucin or any correlation between high endomucin and Osteosarcoma pathological outcomes? Since you only demonstrate one case here, it may be less convincing. Can the author check more patient gene expression or protein expression database (TCGA?) and see if there is correlation between Endomucin/α-SMA and prognosis in other patient samples? Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Osteosarcoma genomics, molecular biology, system biology I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 30 Sep 2024 Vincent Crenn, Team 9 CHILD (CHromatin and Transcriptional Deregulation in Pediatric Bone Sarcoma), CRCI2NA (Centre de Recherche en Cancérologie et Immunologie Nantes-Angers), INSERM UMR 1307, CNRS UMR 6075, Nantes, France Dear Reviewer, thank you for your remark, We have checked it on TCGA and modifications have been made at the end of the discussion. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Huang MF. Peer Review Report For: Case Report: Pathological fracture in a Li-Fraumeni osteosarcoma patient: "Capasquelet'' femoral reconstruction and tumor vascular analysis with endomucin immunofluorescence multiplexing [version 2; peer review: 1 approved] . F1000Research 2024, 11 :1066 ( https://doi.org/10.5256/f1000research.137082.r262730) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/11-1066/v1#referee-response-262730 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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