Search

The application of [18F]FDG PET/CT in predicting histologic response to induction chemotherapy in patients with Ewing sarcoma (EWS) has been proposed using the values of pre-post treatment SUVmax as a referral parameter, although with heterogeneous results. The aim of this retrospective study was to evaluate the diagnostic accuracy of [18F]FDG PET/CT volumetric parameters (metabolic tumour volume (MTV) and total lesion glycolysis (TLG)) as compared to SUVmax to predict response to chemotherapy and clinical outcome in patients with localised EWS of bone and soft-tissue. Twenty-eight patients with non-metastatic EWS of bone (n = 20) and soft tissues (n = 8) who underwent a [18F]FDG PET/CT scan before (PET1) and after induction chemotherapy (PET2) were enclosed in the analysis. Values of PET metrics (SUVmax, MTV, TLG) at diagnosis and after neoadjuvant chemotherapy as well as the percentage change between PET1 and PET2 (ΔSUV, ΔMTV and ΔTLG) were correlated to histological response and to progression-free survival (PFS). ΔTLG (cut-off: -60%) is the best predictor for histologic response with 100% sensitivity and 77.8% specificity. MTV1 > 33.4 cm3 and TLG1 > 112 were also associated with a favourable histologic response (sensitivity 80% and specificity 77.8% for both). On multivariate analysis, SUV2 (> 3.3) and ΔTLG (< -18%) were independent predictors of worse PFS. [18F]FDG PET/CT could accurately predict histologic response to neoadjuvant chemotherapy in patients with EWS, also showing a possible prognostic value for future disease relapse. • The variation of the PET parameter tumour lesion glycolysis (TLG) can predict the histologic response to induction chemotherapy (sensitivity 100%, specificity 77.8%), in patients with Ewing sarcoma. • The percentage variation of TLG and the value of the SUVmax at PET scan after chemotherapy show a prognostic role for future disease relapse. The combination of both the parameters identifies three prognostic classes of patients with low, intermediate and high risk of disease relapse.

The use of massive bone allografts after the resection of bone tumours is still a challenging process. However, to overcome some issues related to the processing procedures and guarantee the best three-dimensional matching between donor and recipient, some tissue banks have developed a virtual tissue database based on the scanning of the available allografts for using their 3D shape during virtual surgical planning (VSP) procedures. To promote the use of future VSP bone-shaping protocols useful for machining applications within a cleanroom environment, in our work, we simulate a massive bone allograft machining with two different machines: a four-axes (computer numerical control, CNC) vs. a five-axes (robot) milling machine. The allograft design was based on a real case of allograft reconstruction after pelvic tumour resection and obtained with 3D Slicer and Rhinoceros software. Machining simulations were performed with RhinoCAM and graphically and mathematically analysed with CloudCompare and R, respectively. In this case, the geometrical differences of the allograft design are not clinically relevant; however, the mathematical analysis showed that the robot performed better than the four-axes machine. The proof-of-concept presented here paves the way towards massive bone allograft cleanroom machining. Nevertheless, further studies, such as the simulation of different types of allografts and real machining on massive bone allografts, are needed.

Background. Guidelines for the implementation of narrative medicine in clinical practice exist; however, in Italy, no standard methodology is currently available for the management of oncological patients. Since 2017, at the “Regina Elena” National Cancer Institute, studies using “digital narrative diaries” (DNMLAB platform) have been carried out; this article focuses on a pilot, uncontrolled, real-life study aiming to evaluate the utility of DNM integrated with the care pathway of patients with bone and limb soft tissue sarcomas. Methods. Adult patients completed the diary during treatment or follow-up by writing their narrative guided by a set of narrative prompts. The endpoints were: (a) patients’ opinions about therapeutic alliance, awareness, and coping ability; (b) healthcare professionals’ (HCPs’) opinions about communication, therapeutic alliance, and information collection. Open- and closed-ended questions (Likert score: 1–5) were used to assess the items. Results. At the interim analysis of data from seven patients and five HCPs, DNM was shown to improve: (a) the expression of patients’ point of view, the perception of effective taking charge, disease awareness, and self-empowerment (score: 4.8/5); (b) patients’ communication, relationships, and illness knowledge (score: 4.6–4.8/5). Conclusions. The preliminary results supported the need to integrate patients’ narratives with clinical data and encourage further research.

Background: Undifferentiated soft-tissue sarcomas (USTS) are one of the most common sarcoma histotypes in adults. The standard of care is surgical excision plus adjuvant radiotherapy, while the use of perioperative chemotherapy is still controversial. The aim of this study was to investigate the value of pre-treatment [18F]FDG PET/CT conventional metrics and textural features in predicting disease-free survival (DFS) and overall survival (OS) in patients with USTS of the limbs and trunk. Methods: [18F]FDG PET/CT scans of 51 consecutive patients with locally advanced USTS were retrospectively evaluated. Conventional and textural PET parameters were analysed and tested as predictive factors for DFS and OS. Results: During a median follow up of 50.7 months, 23 (45.1%) and 29 (56.9%) patients had death or disease progression, respectively. Univariate analysis revealed a significant association for perioperative treatment, PET volumetric parameters and the textural feature GLCM_correlation with DFS and OS. In multivariate analysis, perioperative treatment and GLCM_correlation were the only independent factors, allowing stratification of the population into three different prognostic classes. Conclusion: GLCM_correlation can identify USTS at high risk of relapse and death, thus helping to optimize the perioperative treatment of patients.

Cartilaginous bone tumors represent a wide variety of neoplasms ranging from benign to extremely aggressive malignant lesions. Unlike other tumors, the biopsy cannot easily predict the histological grade, sometimes not allowing choosing the best therapeutic approach. The aim of the study was to evaluate the ability of 18F-FDG PET/CT to differentiate enchondroma from chondrosarcoma and to predict the histological grade as compared to biopsy. 18F-FDG PET/CT of 95 patients with chondroid lesions were retrospectively evaluated. The best SUVmax cutoff to predict the post-surgical histological grade were correlated to those of biopsy and to several radiologic aggressiveness features, which were summarized in the parameter “Radiologic Aggressiveness Score” (AgSCORE). A concordance between the preoperative biopsy and the definitive histological grade was observed overall in 78.3% of patients, the lowest accuracy (58.6%) being in the identification of intermediate/high-grade chondrosarcoma (G2/G3). The best SUVmax cutoff was 2.6 to discriminate enchondroma vs. low-grade chondrosarcoma (sensitivity 0.68, specificity 0.86), 3.7 to differentiate low-grade vs. intermediate/high-grade chondrosarcoma (sensitivity 0.83, specificity 0.84) and 7.7 to differentiate intermediate/high-grade vs. dedifferentiated chondrosarcoma (sensitivity 0.92, specificity 0.9). The AgSCORE also showed a high accuracy to differentiate between G1 and G2/G3 chondrosarcoma (cutoff = 4; sensitivity 0.76; specificity 0.89). An even higher accuracy was observed in those cases in which both SUVmax and AgSCORE cutoff were concordant. Results in this large series of patients suggest a potential role of 18F-FDG PET/CT for histological grading of cartilaginous tumors, thus helping the orthopedic surgeon towards the most appropriate surgical procedure.

Giant cell tumour of bone (GCTB) is a benign, locally aggressive primary bone neoplasm that represents 5% of all bone tumours. The principal treatment approach is surgery. Although generally GCTB is considered only a locally aggressive disease, it can metastasise, and lung metastases occur in 1–9% of patients. To date, only the use of denosumab has been approved as medical treatment for GCTB. Even more rarely, GCTB undergoes sarcomatous transformation into a malignant tumour (4% of all GCTB), but history of this malignant transformation is unclear and unpredictable. Considering the rarity of the event, the data in the literature are few. In this review, we summarise published data of GCTB malignant transformation and we analyse three cases of malignant transformation of GCTB, evaluating histopathology, genetics, and radiological aspects. Despite the rarity of this event, we conclude that a strict follow up is recommended to detect early malignant transformation.

The aim of this study was to investigate symptoms, their variation over time and their relationship with quality of life (QoL)/psychological distress in sarcoma patients, as few data regarding QoL and psychological distress in this set of patients are currently available. A total of 188 sarcoma patients from an Italian referral center were involved. Symptoms and financial difficulties were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire from the first treatment and over the follow-up period, up to 6 years. The authors found that patients with sarcoma experience several symptoms, especially fatigue and pain, which may dramatically worsen QoL and psychological distress. In conclusion, patients with sarcoma often experience fatigue, pain and financial difficulties, which negatively impacts QoL and psychological distress. To ameliorate overall QoL, proper control of symptoms is necessary.

The importance of skeletal muscle tissue is undoubted being the controller of several vital functions including respiration and all voluntary locomotion activities. However, its regenerative capability is limited and significant tissue loss often leads to a chronic pathologic condition known as volumetric muscle loss. Here, we propose a biofabrication approach to rapidly restore skeletal muscle mass, 3D histoarchitecture, and functionality. By recapitulating muscle anisotropic organization at the microscale level, we demonstrate to efficiently guide cell differentiation and myobundle formation both in vitro and in vivo. Of note, upon implantation, the biofabricated myo‐substitutes support the formation of new blood vessels and neuromuscular junctions—pivotal aspects for cell survival and muscle contractile functionalities—together with an advanced muscle mass and force recovery. Altogether, these data represent a solid base for further testing the myo‐substitutes in large animal size and a promising platform to be eventually translated into clinical scenarios., The regenerative capability of skeletal muscle tissue is limited and significant tissue loss often leads to a chronic pathologic condition known as volumetric muscle loss. By exploiting the potentials of our biofabrication approach, one can manufacture advanced cell‐laden myo‐substitutes that ultimately may restore the functionalities of severely damaged skeletal muscles in vivo.

Introduction The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. Materials and methods The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. Results Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42–65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22–25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. Conclusions Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

Joint mega-prosthesis after bone tumors, severe trauma or infection is associated with high rates of post-surgical septic complications. A fast-resorbable antibacterial hydrogel coating (DAC®, Defensive Antibacterial Coating) has previously been shown to be able to significantly reduce surgical site infection in various clinical settings. Aim of the present study was to evaluate the safety and efficacy of the DAC hydrogel coating to prevent early periprosthetic joint infection after joint mega-prosthesis. In this three-centers, case–control study, 43 patients, treated with an antibacterial hydrogel coated mega-prosthesis for oncological (N = 39) or non-oncological conditions (N = 4), were retrospectively compared with 43 matched controls, treated with mega-implants without the coating. Clinical, laboratory and radiographic examinations were performed to evaluate the occurrence of post-surgical infection, complications and adverse events. At a mean follow-up of 2 years, no evidence of infection or adverse events were observed in the DAC-treated group, compared to six cases of post-surgical infection in the control group. This matched case–control study shows that a fast-resorbable, antibiotic-loaded coating can be safely used to protect joint mega-prosthesis, providing a reduction of early surgical site infections with no side effects. Larger prospective trials with longer follow-ups are warranted to confirm this report. RS1229/19 (Regina Elena National Cancer Institute Experimental Registry Number)

The high complexity of multimodality treatment frequently results in undertreatment of elderly sarcoma patients, and this may be one of the factors that influence their prognosis. We describe the real-life approach to a population of patients aged over 70 with both soft tissue (STS) and bone sarcomas (BS) followed by our Sarcoma Disease Management Team from 2012 to 2017. One-hundred and twenty-three patients with a median age of 77 years (range: 70&ndash, 92) were identified. STS were the most common histological subtypes (94%) and the grade was high in 79/123 patients (64%). At diagnosis, 88% of patients had localized disease (LD) and 12% were metastatic (MD). Overall, 96% of patients with LD underwent surgery, 46/54 (85%) with high grade STS patients underwent complementary radiotherapy, and 10/54 (19%) received adjuvant treatments. Twelve out of 33 patients who relapsed (36%) underwent local therapies. Seventeen (52%) and eight (24%) patients were treated with first-line and second-line medical treatments, respectively. Tolerability to systemic treatments was fairly good. Overall, 21% of the patients with advanced disease were candidates for best supportive care alone. Our case series of elderly patients with both STS and BS shows that personalized multidisciplinary treatment can nevertheless be offered to this frail population in order to control the evolution of disease.

Background and aim of the work: Proximal humeral fractures incidence in the elderly population is increasing. Treatment management is complicated by fracture complexity and patients’ comorbidities. The aim of our prospective study is the outcome evaluation of the role of minimally invasive plate osteosynthesis (MIPO) for elderly patients with a 3- or 4-parts proximal humeral fractures having an intact medial wall. Methods: N=45 patients were selected using inclusion criteria (>75yo, unilateral 3- or 4-parts proximal humeral fracture and with a surgical indication). We analyzed n=42 fractures treated with MIPO (3 patients had been reversed to ORIF and arthroplasty intraoperatively): n=20 4-parts fractures and n=22 were 3-parts. Of the 42 operated patients 17 identified as male and 25 as female (mean age 84yo). A trans-deltoid approach has been used with minimal surgical exposure and tissue damage to preserve the local tissue for early shoulder mobilization. Results: At follow-up, the DASH recorded mean value was 72, while the Constant mean score was 68. Complications have been recorded in 23,8% of patients with 4-parts fractures having the highest complication frequency. Mean shoulder joint ROM was recorded: anterior elevation 75°, lateral elevation 80°, abduction 90°, intra-rotation 50°, extra-rotation 25°. The following factors were identified influencing the outcome: >8mm calcar fragment, head valgus impaction and periosteal medial hinge preservation. Conclusions: The increase in population longevity matches the increase in complex humeral fracture frequency. We strongly for management consensus for proximal humerus fracture, in a similar way as for neck femoral fractures. MIPO is excellent in reducing soft tissue damage and complications for elderly patients with limited functional demand. (www.actabiomedica.it)

Since the World Health Organization declared the novel coronavirus outbreak a global health emergency, Italy&rsquo, s lockdown was declared on 9 March 2020. Elective orthopedic surgery was forced to stop to allow the healthcare system to face the emergency. However, many orthopedic oncology cases could not be postponed. The aim of this study was to report the experience in managing sarcoma patients and the reorganization of a cancer center in an attempt to maintain it free from COVID-19. A Coronavirus Crisis Unit was established by the health directorate coordination in order to adopt specific procedures. General rules of screening and social distancing were applied in different health settings (entrance check point, hospital inward, outpatient clinic, operative room). Regarding oncologic orthopedics, priority was given to bone and soft tissue sarcomas, metastases and aggressive benign tumors at risk of impending or pathologic fracture. Precise indications were followed to manage first outpatient visits, patients undergoing surgery and follow-up. Meticulous adherence to rules among patients and personnel and collaboration between leadership and medical staff in order to continue to perform multidisciplinary treatment protocols, maintain the availability of infrastructural spaces and source protective equipment, swabs and screening samples have been successful in the aim towards a safe cure for cancer patients.

The importance of skeletal muscle tissue is undoubted being the controller of several vital functions including respiration and all voluntary locomotion activities. However, its regenerative capability is limited and significant tissue loss often leads to a chronic pathologic condition known as volumetric muscle loss. Here, we propose a biofabrication approach to rapidly restore skeletal muscle mass, 3D histoarchitecture and functionality. By recapitulating muscle anisotropic organization at the microscale level, we demonstrate to efficiently guide cell differentiation and myobundle formation both in vitro and in vivo. Of note, upon implantation, the biofabricated myo-substitutes support the formation of new blood vessels and neuromuscular junctions – pivotal aspects for cell survival and muscle contractile functionalities – together with an advanced along with muscle mass and force recovery. Together, these data represent a solid base for further testing the myo-substitutes in large animal size and a promising platform to be eventually translated into clinical scenarios.

Introduction Core biopsy is today recognized as the gold standard for the diagnosis of bone lesions; unfortunately, when the bone is too solid it can be very difficult to penetrate it; in case of failure, open biopsy is indicated but it is associated with greater contamination and complications. A possible solution is to connect a common orthopedic drill to the core biopsy needle. The aim of the presenting study was to present a technique useful for performing biopsies in case of very strong bone lesions and to evaluate the adequacy and quality of the obtained specimen. Materials and methods A standard bone biopsy set was connected to a commercial drill to perform bone biopsies. Data was collected over a 2-year period (2015–2016). Information regarding technical success, diagnostic data and complication rates was all collated to assess the technical feasibility of this technique. Results Out of 357 bone biopsies, 34 patients underwent the procedure using a common orthopedic drill connected to a core biopsy needle. Diagnostic material was obtained in each patient and the artifacts were considered irrelevant. No major complications occurred in any patient. Discussion The use of a core biopsy needle connected to a common orthopedic drill facilitates the penetration of thick cortical bone by simply applying continuous speed and pressure; nevertheless, the biopsy needle we use is not designed for a drilling procedure and for this reason it can be damaged, but if the biopsy is performed with particular attention, the mechanical failure can be avoided Conclusions Bone biopsy using a commercial hand drill has a technically high success rate with minimal complications. Further studies with more cases are necessary to verify our results.

En-bloc sacrectomy is a highly demanding surgical procedure necessary to obtain wide margin in sacral tumor. The double approach, anterior and posterior approach, is usually preferred for tumors extending proximally to S3 level where iliac internal vessels are at a higher risk for damage during posterior surgery. It can be justified also in selected cases to decrease the risk of posterior approach as in local recurrence or in patients who already underwent laparotomy. Our intent was to apply robotic-assisted techniques for performing anterior preparatory approach for sacrectomy surgery. Between December 2010 and December 2014, three cases of sacrectomies were performed in a previous robotic-assisted preparatory approach to separate the rectum from the tumor. Dissections were successfully performed in all cases close to the pelvic floor. The surgeon was able to position a Gore-Tex spacer between the anterior tumor surface and the rectum in all cases. The anterior dissections were performed with a perfect control of bleeding. No complications related to the anterior approach were reported. Robot-assisted surgery can be considered a valid and minimally invasive technique which allows a safe anterior dissection of the pelvic structures dividing tumors from surrounding tissues. It allows to place a spacer to protect organs during posterior sacral resection performed on the same day or at a later time. Further experiences are advocated to evaluate its efficiency in sacral tumors of greater size.

Because of the improvement of medical therapy and the corresponding increase in life expectancy, orthopaedic surgeons are obliged to perform more wide resections rather than intramedullary stabilization nailing for patients affected by tumours of the hip compared to the past. Wide resection often causes joint instability, so prosthetic reconstruction presents a higher risk of dislocation than in primary osteoarthritis cases. The aim of the present paper is to classify the indications for the dual mobility cup (DMC) hip prosthesis based on the anatomic structures involved in the disease and to analyse the rationale to reduce the risk of dislocation. Indications were analyzed and classified based on all the cases in which the DMC prosthesis was used for reconstruction after hip resection in an oncological research hospital. Four classes of indications were identified; for classes I and IV the indication for DMC prosthesis can be considered strong; for classes II and III the indications must be evaluated considering the specific case, based on life expectancy, performance status, presence of osteoarthritis, and availability of adjuvant local therapies. When the DMC prosthesis is indicated, the cup should always be cemented, either alone or with augmentation techniques, to decrease the risk of mobilization due to local disease progression. DMC can be a valid alternative in reconstruction of the hip after tumor removal; nevertheless, prospective, randomized studies are necessary to verify the real dislocation rate based on the entity of resection.

Interventional radiology provides local management of bone metastases (BM) with a palliative intent in most cases, or with a curative intent in selected patients. Its role has rapidly expanded in the last decade, offering new treatment solutions often in combination with surgery, radiation therapy and medical treatments. The aim of the present paper is to increase awareness, acceptance and adoption of interventional radiology procedures for the treatment of BM; and to present the joint position of the Italian College of Musculoskeletal Radiology and the Italian College of Interventional Radiology.

Although the medical treatments of sarcoma have evolved in the last years, a significant portion of patients develops recurrence after therapies suggesting the need to identify novel targets to improve the treatments. By the use of patient-derived and established cell lines from liposarcoma, as well as specimens from patient biopsies, we found that HMGA1 is involved in the progression of dedifferentiated and myxoid liposarcoma. The immunohistochemical and RT-PCR analyses of 68 liposarcoma specimens revealed a significant high expression of HMGA1, at the protein and RNA levels, both in myxoid and dedifferentiated liposarcoma subtypes compared with differentiated ones. Loss- and gain-of-function experiments by HMGA1-specific depletion and overexpression in dedifferentiated and myxoid liposarcoma cells showed the contribution of this oncogenic factor in cell proliferation, motility, invasion, and drug resistance. The in vitro and in vivo treatment of myxoid liposarcoma with trabectedin, a drug with a potent anti-tumor activity, revealed downregulation of HMGA1, E2F1, and its-downstream targets, vimentin and ZEB1, indicating a critical role of trabectedin in inhibiting the mesenchymal markers of these tumors through the HMGA1/E2F1 axis. These data were also confirmed in patients' tumor biopsies being HMGA1, E2F1, and vimentin expression significantly reduced upon trabectedin therapy, administered as neo-adjuvant chemotherapy. Furthermore, trabectedin treatment inhibits in vitro NFkB pathway in mixoyd liposarcoma sensitive but not in resistant counterparts, and the inhibition of NFkB pathway re-sensitizes the resistant cells to trabectedin treatment. These data support the rational for combining NFkB inhibitors with trabectedin in liposarcoma patients, who have become resistant to the drug.

Sarcomas are rare tumors with generally poor prognosis, for which current therapies have shown limited efficacy. Histone deacetylase inhibitors (HDACi) are emerging anti-tumor agents; however, little is known about their effect in sarcomas. By using established and patient-derived sarcoma cells with different subtypes, we showed that the pan-HDACi, ITF2357, potently inhibited in vitro survival in a p53-independent manner. ITF2357-mediated cell death implied the activation of mitochondrial apoptosis, as attested by induction of pro-apoptotic BH3-only proteins and a caspases-dependent mechanism. ITF2357 also induced autophagy, which protected sarcoma cells from apoptotic cell death. ITF2357 activated forkhead box (FOXO) 1 and 3a transcription factors and their downstream target genes, however, silencing of both FOXO1 and 3a did not protect sarcoma cells against ITF2357-induced apoptosis and upregulated FOXO4 and 6. Notably, ITF2357 synergized with Doxorubicin to induce cell death of established and patient-derived sarcoma cells. Furthermore, combination treatment strongly impaired xenograft tumor growth in vivo, when compared to single treatments, suggesting that combination of ITF2357 with Doxorubicin has the potential to enhance sensitization in different preclinical models of sarcoma. Overall, our study highlights the therapeutic potential of ITF2357, alone or in rational combination therapies, for bone and soft tissue sarcomas management.

// Federica Mori 1 , Andrea Sacconi 2 , Valeria Canu 2 , Federica Ganci 2 , Mariangela Novello 3 , Vincenzo Anelli 4 , Renato Covello 5 , Virginia Ferraresi 6 , Paola Muti 7 , Roberto Biagini 8 , Giovanni Blandino 2,7 and Sabrina Strano 1,7 1 Molecular Chemoprevention Unit, Regina Elena National Cancer Institute, Rome, Italy 2 Translational Oncogenomics, Regina Elena National Cancer Institute, Rome, Italy 3 Department of Pathology, Catholic University, Rome, Italy 4 UOC Radiology, Regina Elena National Cancer Institute, Rome, Italy 5 UOC Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy 6 Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy 7 Department of Oncology, McMaster University, Hamilton, ON, Canada 8 UOC Orthopedic Surgery, Regina Elena National Cancer Institute, Rome, Italy Correspondence: Giovanni Blandino, email: // Keywords : giant cell tumor, osteosarcoma, miRNA profiling, relapse Received : December 11, 2014 Accepted : February 17, 2015 Published : March 12, 2015 Abstract High-grade osteosarcoma (OS) is characterized by low incidence, high aggressiveness and moderate 5-years survival rate after aggressive poly-chemotherapy and surgery. Here we used miRNA profiling as a tool to possibly predict and monitor OS’s development and therapeutic outcome. First, we evaluated the altered expression of selected miRNAs from a case of Giant Cell Tumor (GCT) apparently evolved into an OS. We found that most of modulated miRs were associated with pathways of bone resorption and osteogenesis. miRNA expression also revealed that GCT and OS were distinct tumors. Second, we validated the observed miRNA profile in two independent casuistries of ten GCT (not evolved into malignant tumors) and sixteen OS patients. Interestingly, we found that miR-181c and other three miRNAs identified in the first step of the study were also consistently de-regulated in all OS patients. Ectopic expression of miR-181c reduced cell viability and enhanced chemotherapeutic-induced cell death of U2OS and SAOS2 cells. These findings indicate that: i) miRNAs aberrantly modulated in GCT could be predictive of its development into OS and ii) miRNAs expression could be useful to monitor the OS therapeutic outcome.

Metastases are the most common malignancies involving bone; breast, prostate, lung and thyroid are the main sites of primary cancer. However, up to 30 % of patients present with bone metastases of unknown origin, where the site of the primary neoplasm cannot be identified at the time of diagnosis despite a thorough history, physical examination, appropriate laboratory testing and modern imaging technology (CT, MRI, PET). Sometimes only extensive histopathological investigations on bone specimens from biopsy can suggest the primary malignancy. At other times, a bone lesion can have such a highly undifferentiated histological appearance that a precise pathological classification on routine hematoxylin–eosin-stained section is not possible. The authors reviewed the relevant literature in an attempt to investigate the epidemiology of the histological primaries finally identified in patients with bone metastases from occult cancer, and a strategy of management and treatment of bone metastases from occult carcinomas is suggested. Lung, liver, pancreas and gastrointestinal tract are common sites for primary occult tumors. Adenocarcinoma is the main histological type, accounting for 70 % of all cases, while undifferentiated cancer accounts for 20 %. Over the past 30 years, lung cancer is the main causative occult primary for bone metastases and has a poor prognosis with an average survival of 4–8 months. Most relevant literature focuses on the need for standardized diagnostic workup, as surgery for bone lesions should be aggressive only when they are solitary and/or the occult primaries have a good prognosis; in these cases, identification of the primary tumor may be important and warrants special diagnostic efforts. However, in most cases, the primary site remains unknown, even after autopsy. Thus, orthopedic surgery has a mainly palliative role in preventing or stabilizing pathological fractures, relieving pain and facilitating the care of the patient in an attempt to provide the most appropriate therapy for the primary tumor as soon as possible. Level of evidence 5

Introduction Carbon fiber reinforced (CFR) implants have been proposed for the treatment of fractures or impending fractures of the long bones in the oncology patient. Aim of this study is to present the largest cohort of oncology patients operated by CFR nailing by the Italian Orthopaedic Society (SIOT) Bone Metastasis Study Group. Methods 53 adult oncology patients were operated on with a CFR-PEEK nail. All the data from adjuvants therapies were collected. Bone callus formation, response to radiotherapy, relapse or progression of the osteolysis were recorded. Hardware survival and failure, breakage and need for implant revision were also analysed. Results Anatomical implantation of nails include humerus (n = 35), femur (n =11) and tibia (n = 7). The most frequent tumors affecting the bone were myeloma (n = 13), breast (n = 11), lung (n = 8), and renal cell cancer (n = 7). Acrylic cement reinforcement was used in 2 patients. One patient was subjected to electrochemotherapy after nail insertion. Intraoperative and early postoperative complications occurred in 13.2% and 7.54% of patients respectively. Eight patients had local progression and one developed a stress fracture proximally to the distal static screw. Radiographic union occurred in 14 patients; one screw loosening was recorded. Discussion There is currently a lack of solid evidence on the clinical use of CFR nails in oncologic patients. This is the first and largest study of CFR nailing, with the longest available follow up. Conclusions Implant related complications and surgery-related morbidity should be taken into account in the decision-making process for the surgical management of these patients. These data can improve the surgeon-patient communication and guide further studies on patients’ survival and complications with respect to surgery.

BACKGROUND Musculoskeletal sarcomas comprise 1% of all malignancies in adults. Unfortunately, sometimes they are addressed in non-appropriate way requiring a more invasive procedure to achieve radical surgery at a later date. Due to incomplete predictability of their extension, scheduled reconstruction cannot be performed at times, forcing plans to change or clogging up immediate reconstruction. In this paper, the authors provide an insight in the treatment of musculoskeletal sarcomas, particularly focusing on the preoperative planning of reconstructive strategies, which is crucial in order to prevent unpleasant surprises during reconstruction. METHODS Fifty-six consecutive patients requiring reconstructive procedures following the extirpation of tumors were recruited. All data collected during the diagnostic phase were analyzed collectively during a multi-disciplinary meeting where the surgical procedure was planned. A score system was created and results were then classified into "excellent", "good", "sufficient" and "poor". RESULTS After a minimum follow up of 12 months, we recorded the following results: excellent in 10 patients (17.9%), good in 28 patients (50%), sufficient in 12 cases (21.4%) and poor in 6 cases (10.7%). CONCLUSIONS The improvement of treatment and the long-lasting survival in musculoskeletal sarcoma have shifted the goal of therapeutic protocol to obtaining radical tumor removal and maximum functional restoration. When facing unpredictable extension of the resections, reconstruction may be a challenging or even impossible task to fulfil. Only meticulous preoperative planning can prevent surgeons from falling into all sorts of surgical traps following wide resections.

Two cases of chondrosarcoma involving the proximal femur and the soft tissues are reported. Both patients underwent subtotal femoral resection and quadriceps excision followed by reconstruction with a special prosthesis and arthrodesis of the knee. The tibial stem of the prosthesis was fixed with cement. The advantages of this method are discussed and compared with the use of total femoral prostheses.

Metastases to proximal femur are common and surgery is often suggested to prevent fractures; otherwise it is necessary in cases where this has already occurred. Adjuvant radiotherapy is necessary to reduce the risk of local progression. Nevertheless, the success or failure of radiation therapy treatments depends upon the accuracy in which target identification is correct and dose prescription is fulfilled. Unfortunately, the use of titanium nails consistently limits radiation dose; indeed, the presence of ferromagnetic artifacts interferes with target identification. We present the technique for implant a new carbon fiber nail useful to reduce the ferromagnetic artifacts which allows a better adjuvant radiotherapy.

Objective: Limb-sparing surgery is the mainstay treatment for musculoskeletal tumors thanks to advances in surgical techniques, imaging modalities and multimodal therapies. As patients survive longer, plastic reconstructive procedures and revision surgery are increasingly required after tumor excision. Infection rate is reported to be up to 20% after prosthetic replacement and 30-44% after pelvic resection. The purpose of this study was to investigate the incidence of surgical site infections (SSIs), identifying the causative microrganisms related to specific surgical procedures and significant risk factors for SSIs. Methods: We retrospectively reviewed 723 interventions performed between 2009 and 2015 for oncological conditions. Non neoplastic lesions, aseptic wound complications, non-skeletally mature patients were excluded. Standardised antibiotic prophylaxis was used for different surgical procedures and maintained until removal of surgical drains. Results: Without considering tumor types and surgical sites, the overall infection rate was 8.7% (63/724). Infection occurred in prosthetic reconstruction with an incidence rate of 7.8%, whereas almost half of patients having undergone pelvic surgery got infected and about 20% of patients with spinal surgery and amputations were infected. Pelvic location, malignancy and radiotherapy were related to a major risk of SSI. The causative pathogens were detected in all examined cases. The most frequent pathogens detected by culture included Staphylococcus aureus (27 cases, 47.4%) and S. epidermidis (10 cases, 17.5%). Among the S. aureus cases, 10/27 cases (37%) were methicillin-resistant S. aureus (MRSA). Sixty-three out of 130 microbial isolations (47.7%) were nosocomial ALERT organisms. Conclusion: Oncologic orthopedic surgery is burdened by frequent and challenging SSIs because of extensive soft tissues dissection, long operative times and poor skin conditions. Patients are immunosuppressed and often have concomitant comorbidities predisposing to SSIs. Monitoring of local bacterial aetiology of SSIs could help orthopedic oncologic specialized centres in achieving the optimisation of antibiotic prophylactic regimens.

This is a retrospective review of 49 cases of giant cell tumor (GCT) of the mobile spine treated surgically.Our goal was to determine which factors influenced local recurrence.GCT is a benign, locally aggressive tumor that rarely occurs in the spine. The management of local recurrence can be challenging.We performed a retrospective analysis of GCTs of the mobile spine managed between 1970 and 2005. Median follow-up was 145 months with a minimum of 2 years or until death. We used the Kaplan-Meier method to test whether Enneking stage, surgery type, and surgical margin had statistically significant impact on local recurrence. The log rank test was used for comparison, and a P value of less than 0.05 was deemed significant.Of the 49 patients, 11 (22%) local recurrences occurred. The latest recurrence occurred at 60 months. Age less than 25 years was associated with a worse relapse-free survival (P = 0.03). En bloc resection was associated with better local control with Enneking stage III tumors (P = 0.01); however, intralesional resection provided adequate control of Enneking stage II tumors. There were 6 (12%) cases of metastasis, and 2 patients died from the progression of their disease. One patient died from the complications of the surgery.En bloc resection should be considered for Enneking stage III GCTs of the mobile spine. The choice of en bloc resection must be balanced with the inherent risks of the procedure. Intralesional resection of Enneking stage II tumors provides adequate local control. Patients should be followed for at least 5 years because local relapse can occur late.

Purpose Standardized indications for treatment of tumor-related spinal instability are hampered by the lack of a valid and reliable classification system. The objective of this study was to determine the interobserver reliability, intraobserver reliability, and predictive validity of the Spinal Instability Neoplastic Score (SINS). Methods Clinical and radiographic data from 30 patients with spinal tumors were classified as stable, potentially unstable, and unstable by members of the Spine Oncology Study Group. The median category for each patient case (consensus opinion) was used as the gold standard for predictive validity testing. On two occasions at least 6 weeks apart, each rater also scored each patient using SINS. Each total score was converted into a three-category data field, with 0 to 6 as stable, 7 to 12 as potentially unstable, and 13 to 18 as unstable. Results The κ statistics for interobserver reliability were 0.790, 0.841, 0.244, 0.456, 0.462, and 0.492 for the fields of location, pain, bone quality, alignment, vertebral body collapse, and posterolateral involvement, respectively. The κ statistics for intraobserver reliability were 0.806, 0.859, 0.528, 0.614, 0.590, and 0.662 for the same respective fields. Intraclass correlation coefficients for inter- and intraobserver reliability of total SINS score were 0.846 (95% CI, 0.773 to 0.911) and 0.886 (95% CI, 0.868 to 0.902), respectively. The κ statistic for predictive validity was 0.712 (95% CI, 0.676 to 0.766). Conclusion SINS demonstrated near-perfect inter- and intraobserver reliability in determining three clinically relevant categories of stability. The sensitivity and specificity of SINS for potentially unstable or unstable lesions were 95.7% and 79.5%, respectively.

Sarcomas are rare malignancies with generally poor prognosis, for which current therapies have shown limited efficacy. In order to improve the prognosis of patients, there is an urgent medical need to identify new molecular targets that can be exploited for the development of innovative treatment approaches. Inhibition of histone deacetylases (HDACs) has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and HDAC inhibitors (HDACi) have been reported as potent and specific anticancer molecules in preclinical and clinical studies. Here we investigated the molecular and functional effects of a new generation HDACi, ITF2357, in preclinical models of soft tissue and bone sarcomas. A wide panel of sarcomas cells, both established and patient derived cell lines, were used. For in vitro experiments Western Blot, RT-PCR, flow cytometry and conservative isobologram analysis have been performed. In vivo efficacy of ITF2357/doxorubucin combination was evaluated in nude mice bearing sarcoma xenografts. Using in vitro and in vivo sarcoma models, we demonstrate that ITF2357 decreases cell viability, activates apoptosis and increases the growth inhibitory efficacy of doxorubicin. The molecular mechanisms of action of ITF2357-mediated cell death implied the activation of mitochondrial apoptosis, as attested by the increase of pro-apoptotic BH3-only proteins, and both caspase and bcl-2 dependent cell death. We also found that ITF2357 transcriptionally upregulated the pro-apoptotic BH3-only genes Bax, Puma, Noxa and BIM in cells harbouring mutant or wild type p53, thus indicating a p53 independent mechanism. Both bcl-2 overexpression and caspases inhibition strongly reduced apoptosis, corroborating the evidence that activation of mitochondrial pathway occurs upstream and before caspases activation. We also found that ITF2357 induces a canonical autophagic process, and that inhibition of autophagy increased apoptosis induced by ITF2357, indicating that in our models autophagy shows a prosurvival effect. We also reported that ITF2357 induced FOXO1/3a up-regulation, FOXO proteins nuclear accumulation, and transcriptional activation of FOXO-target genes, such as BH3-only proteins Puma, Noxa and Bim. Knockdown experiments demonstrated that reduction of both FOXO1 and 3a did not inhibit the induction of Bim expression in response to ITF2357, and consequently did not protect sarcoma cells against ITF2357-induced apoptosis, independently from p53 status. Notably, ITF2357 synergized with doxorubicin to induce in vitro cell death and to reduce in vivo tumor growth. Therefore ITF2357 may represent an important therapeutic agent against human sarcoma regardless p53 status, and the pharmacological combination of ITF2357 with doxorubicin has the potential to enhance sensitization in different preclinical models of sarcoma. Citation Format: Maria Grazia Tupone, Marta Di Martile, Marianna Desideri, Simonetta Buglioni, Barbara Antoniani, Carlotta Mastroiorio, Rita Falcioni, Virginia Ferraresi, Nicola Baldini, Roberto Biagini, Michele Milella, Daniela Trisciuoglio, Donatella Del Bufalo. Histone deacetylase inhibitor ITF2357 induces apoptosis and increases doxorubicin cytotoxicity in preclinical models of human sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3699.

Background: Limited information is available on the applicative value of liquid biopsy (LB) in rare tumors, including Ewing’s sarcoma (ES). The accepted precision diagnostics standards would greatly benefit from a non-invasive LB test monitoring pathognomonic gene rearrangements in the bloodstream. Methods: Tissue and blood samples were collected from six and four ES patients, respectively. Plasma was cleared by two successive rounds of centrifugation and stored frozen until RNA extraction by the QIAmp CNA kit. RNA was retro-transcribed and subjected to real-time quantitative polymerase chain reaction (RT-qPCR) and digital polymerase chain reaction (dPCR). Reactions were set up using two custom primer sets identifying types 1 and 2 EWS-FLI1 fusion transcripts. Results: The two prevalent types of EWS-FLI1 rearrangements could be identified using only two sets of polymerase chain reaction primers, regardless of patient-specific EWS-FLI1 DNA breakpoints. RT-qPCR and dPCR discriminated the two variants in five tumor tissue RNAs and in four circulating tumor RNAs (ctRNAs). Of note, EWS-FLI1 molecular diagnosis was possible using blood samples even when tumor tissue was not available. ctRNA levels correlated ( p < 0.05) with volume-based positron emission tomography (PET) parameters (metabolic tumor volume and total lesion glycolysis), and allowed the fine tracking of disease course after surgery, during adjuvant as well as neoadjuvant chemotherapy, and at follow up in one patient. Conclusions: To our knowledge, this is one of the few single-marker LB assays in solid tumors specifically designed to detect rearranged RNAs in blood, and the first study describing EWS circulating tumor RNAs in ES patients. Altogether, our results support the idea that LB may have a considerable impact on ES patient monitoring and management.

Study Design. Reliability analysis based on expert panel case series review and grading per the Enneking and Weinstein-Boriani-Biagini classification systems. Objective. To assess the reliability of the Enneking and Weinstein-Boriani-Biagini classification systems. Summary of Background Data. The Enneking and Weinstein-Boriani-Biagini (WBB) classifications were developed to stage and facilitate treatment planning in patients with primary spine tumors. To date, their interobserver and intraobserver reliability has not been assessed‐a fundamental step in facilitating broader clinical and research use. Methods. Clinical information, imaging studies, and biopsy results were compiled from 15 selected patients with primary spinal tumors. Eighteen spine surgeons independently estimated and scored the cases for Enneking grade, tumor and metastasis categories, Enneking stage, Enneking-recommended surgical margin, WBB zones and layers, and WBB-recommended surgical procedures, with a second assessment performed after random resorting of cases. Interobserver and intraobserver reliability of each category were assessed by percent agreement or proportional overlap. The Fleiss, Cohen, and Mezzich statistics () were then applied, determined by the type of variable analyzed. Results. The statistics for interobserver reliability were 0.82, 0.22, 0.00, 0.57, 0.47, 0.31, 0.58, and 0.54 for the fields of Enneking grade, tumor and metastasis categories, Enneking stage, Enneking-recommended surgical margin, WBB zones and layers, and WBB-recommended surgical procedures, respectively. The statistics for intraobserver reliability were 0.97, 0.53, 0.47, 0.82, 0.67, 0.63, 0.79, and 0.79 for the same respective fields. According to Landis and Koch, the ranges of values of 0.00 to 0.20, 0.21 to 0.40, 0.41 to 0.60, 0.61 to 0.80, and 0.80 imply slight, fair, moderate, substantial, and near-perfect agreement, respectively. Conclusion. Results indicate moderate interobserver reliability and substantial and near-perfect intraobserver reliability for both the Enneking and WBB classification in terms of staging and guidance for treatment, despite a less than moderate interobserver reliability in interpreting the Enneking local tumor extension and WBB sector. Before incorporating the classifications in the clinical practice and research studies, further work is required to investigate the validity of the classifications.

We report a case of ABC in a child where, after resection of the posterior spinal column of L1, we did a biological reconstruction using a posterior tension band with a segment of fascia lata allograft in tension between T12 and L2. After the long term follow up, X-ray and MRI controls showed a satisfactory alignment of the spine and no local recurrence. The patient now has no sign of spinal instability or deviation, with no kind of discomfort or pain, and has a normal life. In our experience this biological tension band interferes minimally with the growth of the spine, and has a less number of complications in comparison with other more aggressive methods and so is a good option for restoring the stability in young patients with benign spinal tumors that arises on the posterior column without having any kind of potential deviations.

BACKGROUND: We recently developed a clinical decision support tool, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases. After making it publicly available on www.PATHFx.org , we attempted to externally validate it using independent, international data. METHODS: We collected data from patients treated at 13 Italian orthopaedic oncology referral centers between 2010 and 2013, then applied to PATHFx, which generated a probability of survival at three and 12-months for each patient. We assessed accuracy using the area under the receiver-operating characteristic curve (AUC), clinical utility using Decision Curve Analysis (DCA), and compared the Italian patient data to the training set (United States) and first external validation set (Scandinavia). RESULTS: The Italian dataset contained 287 records with at least 12 months follow-up information. The AUCs for the three-month and 12-month estimates was 0.80 and 0.77, respectively. There were missing data, including the surgeon's estimate of survival that was missing in the majority of records. Physiologically, Italian patients were similar to patients in the training and first validation sets. However notable differences were observed in the proportion of those surviving three and 12-months, suggesting differences in referral patterns and perhaps indications for surgery. CONCLUSIONS: PATHFx was successfully validated in an Italian dataset containing missing data. This study demonstrates its broad applicability to European patients, even in centers with differing treatment philosophies from those previously studied.

BACKGROUND In primary central high-grade osteosarcoma, a number of distinct subtypes have been identified, but little is known about the response to chemotherapy. METHODS The authors investigated whether the subtypes correlated with histologic response to chemotherapy in 1058 patients with osteosarcoma of the extremities who were treated with neoadjuvant chemotherapy over the last 20 years. The tumors were classified as osteoblastic (70%), chondroblastic (13%), fibroblastic (9%), and telangiectatic (6%). At diagnosis, 911 patients had localized disease and 147 had resectable lung metastases. RESULTS The response to preoperative chemotherapy was good (90% or more tumor necrosis) in 59% of patients and poor (< 90% tumor necrosis) in 41% of patients. The rate of good responses was significantly higher (P = 0.0001) in the fibroblastic (83%) and telangiectatic (80%) tumors and significantly lower in chondroblastic tumors (43%). Prognosis was significantly correlated with the histologic subtypes. The 5-year overall survival rate was significantly higher (P = 0.0001) in fibroblastic (83%) and telangiectatic (75%) tumors than in osteoblastic (62%) and chondroblastic (60%) tumors. In all subtypes, except for the chondroblastic subtype, the 5-year overall survival rate was significantly higher (P = 0.0001) in good responders P = 0.0001 (68%) than in poor responders (52%). CONCLUSIONS The authors concluded that the histologic subtype of primary central high-grade osteosarcoma of the extremity was strictly correlated with histologic response to chemotherapy and probably, as a consequence, also with prognosis. Further studies are needed to establish whether these results justify a specific therapeutic approach based on the histologic subtype of the tumor. Cancer 2003;97:3068–75. © 2003 American Cancer Society. DOI 10.1002/cncr.11456

The authors present a case of mesenchymal chondrosarcoma located in the sacrum of a 23-year-old patient treated with radiotherapy and chemotherapy. A review of the literature on the topic is also reported.