MRI radiomics-based machine learning for classification of deep-seated lipoma and atypical lipomatous tumor of the extremities.

PURPOSE: To determine diagnostic performance of MRI radiomics-based machine learning for classification of deep-seated lipoma and atypical lipomatous tumor (ALT) of the extremities. MATERIAL AND METHODS: This retrospective study was performed at three tertiary sarcoma centers and included 150 patients with surgically treated and histology-proven lesions. The training-validation cohort consisted of 114 patients from centers 1 and 2 (n = 64 lipoma, n = 50 ALT). The external test cohort consisted of 36 patients from center 3 (n = 24 lipoma, n = 12 ALT). 3D segmentation was manually performed on T1- and T2-weighted MRI. After extraction and selection of radiomic features, three machine learning classifiers were trained and validated using nested fivefold cross-validation. The best-performing classifier according to previous analysis was evaluated and compared to an experienced musculoskeletal radiologist in the external test cohort. RESULTS: Eight features passed feature selection and were incorporated into the machine learning models. After training and validation (74% ROC-AUC), the best-performing classifier (Random Forest) showed 92% sensitivity and 33% specificity in the external test cohort with no statistical difference compared to the radiologist (p = 0.474). CONCLUSION: MRI radiomics-based machine learning may classify deep-seated lipoma and ALT of the extremities with high sensitivity and negative predictive value, thus potentially serving as a non-invasive screening tool to reduce unnecessary referral to tertiary tumor centers.

Malignant Transformation of Giant Cell Tumour of Bone: A Review of Literature and the Experience of a Referral Centre.

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.

Primary intraosseous solitary fibrous tumor: an extremely rare case report and brief review of the literature.

Solitary fibrous tumor (SFT), a rare mesenchymal neoplasm of fibroblastic origin, was initially discovered in the mediastinal pleura and then described in many extra-pleural sites.The reports of primary solitary fibrous tumor of bone are extremely rare and only a few cases have been previously mentioned in the literature, most of which in flat and short bones.Here we present the case of a 53-year-old female, who was referred to the emergency department of a peripheral hospital after an accidental fall. Imaging studies revealed an intertrochanteric fracture with an underlying intramedullary lytic lesion. A biopsy was performed and a diagnosis of Ewing sarcoma was initially suggested. She arrived at our hospital where we reevaluated the case. The biopsy was reviewed and a diagnosis of intraosseous SFT was proposed. She underwent en-block resection of the proximal right femur.Primary SFTs of the bone are, like in our case, easily misdiagnosed due to the low specificity of the imaging studies and the extreme rarity of the localization. An accurate diagnosis and early resection are very important and with careful long-term follow-up is essential, particularly in those who with malignant behavior, for the early detection of possible recurrence or metastasis.

The IlluminOss® photodynamic bone stabilization system for pathological osteolyses and fractures of the humerus: indications, advantages and limits in a series of 12 patients at 24 months of minimum follow-up.

BACKGROUND: Locked titanium nails are considered the reference treatment for metastatic bone lesions of the humerus in patients with aggressive histotypes, high risk of fracture or when estimated survival is lower than 6 months.Nevertheless, they are responsible for CT and MRI artifacts which interfere with postoperative radiotherapy and follow-up.The IlluminOss® is an intramedullary stabilization system which is introduced inside the humeral canal in a deflated state, and is then distended with a monomer which hardens after exposure to blue light,stabilizing the segment; it does not cause artifacts, allowing easier and more effective radiotherapy and follow-up. The aim of this study is to report our experience, indications, possible advantages and limitations of this stabilization system at 24 months of minimum follow-up in a series of 12 patients affected by pathological fractures or impending fractures of the humerus. METHODS: This is a retrospective case-series that included all patients who underwent surgery with the IlluminOss® Photodynamic Bone Stabilization System for pathological osteolyses and fractures of the humerus. Intraoperative and postoperative complications were valued. RESULTS: 12 patients and 13 procedures were included in the study. All surgeries were performed without intraoperative complications. No early postoperative complications were noted. The wounds healed in all cases and stitches were removed at two weeks from surgery, so the patients were able to perform chemotherapy after three weeks. All patients except one had a painless active range of motion which reached 90°.The VAS score was 7 preoperatively and 2.6 at one month from surgery. Pain relief was also associated to radiotherapy and chemotherapy. Unfortunately, two nail ruptures were reported at 4 and 12 months of follow-up. No artifacts were noted in the postoperative CT scans so the radiotherapy plans were easily performed without the need of dose compensation. CONCLUSIONS: The IlluminOss® intramedullary stabilization system can provide primary stability in humeral fractures and impending fractures;the surgical technique is easy and minimally invasive.Moreover,it does not present artifacts at postoperative imaging,probably giving a better chance to perform prompt radiotherapy and chemotherapy.However, randomized clinical studies are necessary to verify its potential strength and if precocious adjuvant radio- and chemotherapy are associated to a reduction of the local progression rate.

A Rare Case of First Metatarsal Extrusion: Results of Treatment After 12 Months.

We present the case of a 21-year-old male with 12 months' follow-up after reimplantation of a completely extruded first metatarsal. The patient had a motorcycle accident involving his right foot and ankle, with multiple lesser metatarsal fractures, lateral malleolus fracture, and a total first metatarsal extrusion (without fracture) through a large dorso-medial forefoot wound. The extruded bone was recovered at the site of the motor vehicle accident and was transported to the hospital with the patient. Before the reimplantation surgery was undertaken, the first metatarsal was immersed in a chlorhexidine solution for 20 minutes and then washed in an antibiotic solution. Metatarsal fixation was performed with Kirschner wires; the lateral malleolus fracture was fixed with plate and screws. An external fixator was then applied. Throughout the 12-month follow-up period, there was no evidence of infection. At the present time, this case suggests that, after antiseptic cleansing and prompt surgery, extruded first metatarsal reimplantation is possible with a reasonable degree of clinical success.

Sarcoma patients' quality of life from diagnosis to yearly follow-up: experience from an Italian tertiary care center.

Aim: To investigate sarcoma patients' perception of quality of life and psychosocial distress across the different disease's stages. Patients & methods: Total 329 sarcoma patients were monitored from diagnosis up to a maximum of six consecutive follow-up visits. Results: Functional status worsened over time with the lowest value after surgery and a full recovery not earlier than the second follow-up visit. Married and single patients exhibited similar quality of life pattern. High levels of psychological distress were observed from diagnosis to active treatment periods with a progressive improvement during follow-up. Psychological distress pattern over time varied by marital status and age. Conclusion: Our study suggests the importance of integrating psychosocial care to medical therapy across the entire sarcoma journey.

En bloc spondylectomy in patients older than 60 years: indications, results and complications in a series of 37 patients.

PURPOSE: To review a series of patients > 60 years affected by primary spine bone tumors, who have undergone surgery, and to describe their clinical presentation, results and complications associated with surgical treatment. METHODS: A review of all patients > 60 years affected by primary spine bone tumor surgically treated with en bloc spondylectomy from 1993 to 2015 was performed. Thirty-seven cases were identified, and clinical and radiological characteristics, therapy, complications and survival were evaluated. RESULTS: Only 14/37 cases were not previously treated. Complications were quite frequent: 64% of patients experienced almost one early complication; 48% and 27% experienced 2 and ≥ 3 early complications, respectively; 37% of patients experienced almost one late complication; and 10% and 8% experienced 2 and ≥ 3 late complications, respectively. Massive blood loss and dural tear were the more frequent surgical complications; no deaths were reported during surgeries; one patient died during the first postoperative day due to hemorrhage and cardiac complications, one during the third postoperative day for the same cause despite of a savage surgery, and another one died at 7 days from index surgery due to myocardial infarction. The 5-year disease-related survival and global survival were 62.8% and 52.1%, respectively. Nineteen patients are still alive, 15 of whom without any evidence of disease. CONCLUSIONS: Primary malignant or locally aggressive bone tumors of the spine should be treated with wide surgery also in the older age, although the complications rate and the risk of patient survival can be considered high. These slides can be retrieved under Electronic Supplementary Material.

Intralesional vs. extralesional procedures for low-grade central chondrosarcoma: a systematic review of the literature.

INTRODUCTION: Chondroid lesions are very common bone tumors. In most cases, they are benign enchondromas (EC) and, in a minor percentage, chondrosarcomas (CSs), the malignant counterpart. In the latter cases, surgery is the mainstay treatment, because they are chemo- and radio-resistant unless dedifferentiation occurs. If resection is recognized as the gold standard for intermediate-, high-grade tumors, and for low-grade chondrosarcoma (LG-CS) located in the spine and pelvis to reduce the risk of local recurrence, there is still no consensus in literature on the treatment of central low-grade chondrosarcoma (cLG-CS) located in the limbs. Our aim is to perform a review of literature on evidence supporting this approach or not. MATERIALS AND METHODS: An electronic research of the medical archives was carried out in March 2017 seeking papers evaluating the results of curettage and resection in cLG-CS. RESULTS: We selected 13 studies corresponding to our criteria. Unfortunately, they were descriptive, retrospective, non-randomized studies. We identified a population of 471 patients for a total of 473 low-grade chondrosarcomas. Two hundred and ninety-nine lesions were treated with curettage and 174 with wide surgery. The two groups were not homogeneous for diagnosis, size and staging, so no comparison between resection and curettage was possible. The global weighted average percentage of local recurrence was 6.7% (20 cases) and 10.9% (19 cases) after curettage and resection, respectively. No cases of metastasis were reported in the group treated with intralesional surgery, compared to five cases reported in the group treated with resection. Indications for surgery were given in most cases based on symptoms and imaging. CONCLUSIONS: The absence of a preoperative histological diagnosis and the lack of a scientific method to conduct the studies do not sufficiently support curettage for low-grade chondrosarcomas. In the absence of this, resection must be considered a general rule for every malignancy. In our opinion, based on the low biological growth rate of low-grade chondrosarcoma, every chondromatous lesion can be followed-up. Biopsies must be performed based on clinical and radiological suspicions such as pain, scalloping or increase in size, rather than on performing a PET scan to evidence more informative high metabolic areas.

Sarcopenia: a histological and immunohistochemical study on age-related muscle impairment.

BACKGROUND: Sarcopenia and osteoporosis increase the risk of bone fracture in the elderly due to the loss of muscle mass and the decrease in bone mineral density. Myostatin and Bone Morphogenetic Proteins (BMPs) are important molecules involved in muscle mass homeostasis. AIM: In this study, we investigated the role of BMP4 and myostatin in the pathophysiogenesis of sarcopenia related to osteoporosis and osteoarthritis. METHODS: Muscle atrophy, BMP4 and myostatin expression were evaluated in 27 biopsies of osteoarthritic (OA) women and 27 biopsies from osteoporotic (OP) group by immunohistochemical reaction. Muscle stem cell niches were investigated by transmission electron microscopy analysis. RESULTS: Myostatin and BMP4 expression was evaluated by counting the number of positive fibers on 25 high-power field. We found that OA muscle biopsies showed a significantly higher number of BMP4-positive fibers (37.35 ± 5.63) as compared with muscle of OP patients (9.60 ± 1.57). Unlike BMP4 expression, the number of myostatin-positive fibers in OP patients (33.95 ± 4.10) was significantly higher compared to OA group (13.86 ± 1.68). The ultrastructural analysis of BMP4-positive tissues displayed the presence of a high rate of satellite cells both single or as syncytium giving proof of muscle regeneration capability. DISCUSSION: Our results indicated that sarcopenia and osteoporosis shared an impairment of metabolic activity. Conversely, the molecular mechanisms of OA seem to inhibit the onset of an age-related sarcopenia. CONCLUSION: The characterization of molecular mechanisms underlying the bone-muscle crosstalk could open new therapeutic perspectives in elderly diseases.

Conservative surgery for the treatment of osteonecrosis of the femoral head: current options.

The prevention of femoral head collapse and the maintenance of hip function would represent a substantial achievement in the treatment of osteonecrosis of the femoral head; however it is difficult to identify appropriate treatment protocols to manage patients with pre-collapse avascular necrosis in order to obtain a successful outcome in joint preserving procedures. Conservative treatments, including pharmacological management and biophysical modalities, are not supported by any evidence and require further investigation. The appropriate therapeutic approach has not been identified. The choice of surgical procedures is based on patient clinical conditions and anatomopathological features; preservation of the femoral head by core decompression may be attempted in younger patients without head collapse. Biological factors, such as bone morphogenetic proteins and bone marrow stem cells, would improve the outcome of core decompression. Another surgical procedure proposed for the treatment of avascular necrosis consists of large vascularized cortical bone grafts, but its use is not yet common due to surgical technical issues. Use of other surgical technique, such as osteotomies, is controversial, since arthroplasty is considered as the first option in case of severe femoral head collapse without previous intervention.

Social neuroscience: Primate research goes wireless.

A new study leads the way to a more ethical and ethologically meaningful way of investigating brain functions of complex behaviors in social animals.

X-rays radiomics-based machine learning classification of atypical cartilaginous tumour and high-grade chondrosarcoma of long bones.

BACKGROUND: Atypical cartilaginous tumour (ACT) and high-grade chondrosarcoma (CS) of long bones are respectively managed with active surveillance or curettage and wide resection. Our aim was to determine diagnostic performance of X-rays radiomics-based machine learning for classification of ACT and high-grade CS of long bones. METHODS: This retrospective, IRB-approved study included 150 patients with surgically treated and histology-proven lesions at two tertiary bone sarcoma centres. At centre 1, the dataset was split into training (n = 71 ACT, n = 24 high-grade CS) and internal test (n = 19 ACT, n = 6 high-grade CS) cohorts, respectively, based on the date of surgery. At centre 2, the dataset constituted the external test cohort (n = 12 ACT, n = 18 high-grade CS). Manual segmentation was performed on frontal view X-rays, using MRI or CT for preliminary identification of lesion margins. After image pre-processing, radiomic features were extracted. Dimensionality reduction included stability, coefficient of variation, and mutual information analyses. In the training cohort, after class balancing, a machine learning classifier (Support Vector Machine) was automatically tuned using nested 10-fold cross-validation. Then, it was tested on both the test cohorts and compared to two musculoskeletal radiologists' performance using McNemar's test. FINDINGS: Five radiomic features (3 morphology, 2 texture) passed dimensionality reduction. After tuning on the training cohort (AUC = 0.75), the classifier had 80%, 83%, 79% and 80%, 89%, 67% accuracy, sensitivity, and specificity in the internal (temporally independent) and external (geographically independent) test cohorts, respectively, with no difference compared to the radiologists (p ≥ 0.617). INTERPRETATION: X-rays radiomics-based machine learning accurately differentiates between ACT and high-grade CS of long bones. FUNDING: AIRC Investigator Grant.

Osteoporosis and sarcopenia: the connections.

Osteoporosis and sarcopenia are the most frequent musculoskeletal disorders affecting older people. Osteoporosis is a widespread disorder affecting millions of individuals of all ethnic backgrounds worldwide, particularly among older women. It is characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in the risk of fracture. Sarcopenia is considered to be one of the major factors responsible for functional limitations and motor dependency in elderly persons. In age-related muscle atrophy, a decrease in muscle fiber size and number, and a preferential loss of type II fibers have been reported. A decrease in the circulating levels of specific hormones (e.g., estrogen, testosterone, growth hormone, and insulin-like growth factor-1) has been shown to be associated with sarcopenia and this appears to play an important role in its pathogenesis.

Long-term longitudinal study on swine VML model.

BACKGROUND: Volumetric Muscle Loss (VML), resulting from severe trauma or surgical ablation, is a pathological condition preventing myofibers regeneration, since skeletal muscle owns the remarkable ability to restore tissue damage, but only when limited in size. The current surgical therapies employed in the treatment of this pathology, which particularly affects military personnel, do not yet provide satisfactory results. For this reason, more innovative approaches must be sought, specifically skeletal muscle tissue engineering seems to highlight promising results obtained from preclinical studies in VML mouse model. Despite the great results obtained in rodents, translation into human needs a comparable animal model in terms of size, in order to validate the efficacy of the tissue engineering approach reconstructing larger muscle mass (human-like). In this work we aim to demonstrate the validity of a porcine model, that has underwent a surgical ablation of a large muscle area, as a VML damage model. RESULTS: For this purpose, morphological, ultrasound, histological and fluorescence analyses were carried out on the scar tissue formed following the surgical ablation of the peroneus tertius muscle of Sus scrofa domesticus commonly called mini-pig. In particular, the replenishment of the damaged area, the macrophage infiltration and the vascularization at different time-points were evaluated up to the harvesting of the scar upon six months. CONCLUSION: Here we demonstrated that following VML damage, there is an extremely poor regenerative process in the swine muscle tissue, while the formation of fibrotic, scar tissue occurs. The analyses performed up to 180 days after the injury revealed the development of a stable, structured and cellularized tissue, provided with vessels and extracellular matrix acquiring the status of granulation tissue like in human.

Prognostic Value of Pre-Treatment [18F]FDG PET/CT Texture Analysis in Undifferentiated Soft-Tissue Sarcoma.

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.

Narrative Medicine: A Digital Diary in the Management of Bone and Soft Tissue Sarcoma Patients. Preliminary Results of a Multidisciplinary Pilot Study.

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.

The role of minimally invasive plate osteosynthesis (MIPO) technique for treating 3- and 4-part proximal humerus fractures in the elderly - a case study.

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 We included n=42 unilateral 3- and 4-parts proximal humeral fractures treated with MIPO: 20 4-part fractures and 22 were 3-parts fractures were included. 17 patients 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.

Wide Surgery in the Cervical Spine: Indications, Results, and Complications in a Series of 30 Patients Affected by Primary Bone Tumors.

BACKGROUND: En bloc surgery is the mainstay treatment for primary malignant bone tumors, as well as in the cervical spine. Unfortunately, literature on the topic is limited to case reports and small series. METHODS: We reviewed all patients affected by primary cervical spine bone tumors treated with en bloc surgeries from 1996 to 2016 and identified 30 eligible cases. We evaluated the clinical presentation and tumor characteristics and reported surgical results, complications, recurrence, and survival rates. RESULTS: Only 17 of 30 patients had not been previously treated at presentation. Osteosarcoma and chordoma were the most frequent tumors, and pain was reported in all cases. En bloc spondylectomy, hemispondylectomy, and posterior arch en bloc resection were performed in 16, 12, and 2 patients, respectively. The obtained margin was adequate (wide and marginal) in 60% of cases and intralesional in the remaining cases. Two deaths occurred in the immediate postoperative period. Neurological deterioration, dural tear, and dysphagia were the most frequent complications. The 5-year local recurrence-free survival was 70.4%. The recurrence rate was 38.5% and 11.7% in previously and non-previously treated patients, respectively (χ2: 2.94; P = 0.086). Overall survival at 5 years was 58% and 47% for all series and malignant tumors, respectively. CONCLUSION: Primary cervical spine bone tumors present a difficult approach. Findings suggest that patients treated with en bloc surgery show recurrence and survival rates comparable to the same tumors located in the thoracolumbar spine.

3D-Printed Titanium Custom-Made Prostheses in Reconstruction after Pelvic Tumor Resection: Indications and Results in a Series of 14 Patients at 42 Months of Average Follow-Up.

Wide resection is currently considered the mainstay treatment for primary bone tumors. When the tumor is located in anatomically complex segments, 3D-Printed Titanium Custom-Made Prostheses (3DPTCMP) are possible reconstructive solutions. The aim of the present paper is to analyze indications, results and complications of a series of 14 patients who underwent pelvis reconstruction with 3DPTCMP after tumor removal from January 2015 to December 2019. Chondrosarcoma was the main histology; indications were tumors located in the acetabular area without enough residual bone to support a cup with an iliac stem, and tumors located near the sacrum-iliac joint. The margins were wide in 12 cases, and marginal and intralesional in one case each. In three cases, resection also included the sacrum-iliac joint, so a spine stabilization was performed and linked to the pelvic prosthesis; The average MSTS score was 46.3%; the 5-year local recurrence-free survival was 85.7%. Wound dehiscences were the main complication, resolved with multiple debridements; nevertheless, prosthesis removal was necessary in one case. Currently, the 3DPTCMP is an effective resource for reconstruction after resection of tumors located in the pelvis. Further studies are necessary to value long-term results; more strategies are necessary to try to reduce the infection rate and improve osteointegration.

Biofabricating murine and human myo-substitutes for rapid volumetric muscle loss restoration.

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.