Artificial Collective Intelligence Engineering: A Survey of Concepts and Perspectives.

Collectiveness is an important property of many systems-both natural and artificial. By exploiting a large number of individuals, it is often possible to produce effects that go far beyond the capabilities of the smartest individuals or even to produce intelligent collective behavior out of not-so-intelligent individuals. Indeed, collective intelligence, namely, the capability of a group to act collectively in a seemingly intelligent way, is increasingly often a design goal of engineered computational systems-motivated by recent technoscientific trends like the Internet of Things, swarm robotics, and crowd computing, to name only a few. For several years, the collective intelligence observed in natural and artificial systems has served as a source of inspiration for engineering ideas, models, and mechanisms. Today, artificial and computational collective intelligence are recognized research topics, spanning various techniques, kinds of target systems, and application domains. However, there is still a lot of fragmentation in the research panorama of the topic within computer science, and the verticality of most communities and contributions makes it difficult to extract the core underlying ideas and frames of reference. The challenge is to identify, place in a common structure, and ultimately connect the different areas and methods addressing intelligent collectives. To address this gap, this article considers a set of broad scoping questions providing a map of collective intelligence research, mostly by the point of view of computer scientists and engineers. Accordingly, it covers preliminary notions, fundamental concepts, and the main research perspectives, identifying opportunities and challenges for researchers on artificial and computational collective intelligence engineering.

Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need.

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50-60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification.

Ten-year experience of the multidisciplinary Osteoncology Center.

PURPOSE: Bone metastases (BMs) are responsible for high morbidity in patients. A multidisciplinary approach involving a team of specialists offers an effective therapeutic strategy based on disease characteristics, medical history, and performance status. We evaluated the impact of our 10-year multidisciplinary experience on the management of patients with BM. METHODS: We retrospectively analyzed 2194 medical reports of 1628 patients referred to our Osteoncology Center from 2005 to 2015. Cases were discussed weekly by a multidisciplinary team. RESULTS: Eight hundred thirty-eight (38.2%) of the 2194 visits were requested because of a risk of complications from BM. Antiblastic treatment and bone-targeted therapy were modified in 709 (66.3%) and 309 (31%) of cases, respectively. Radiotherapy was scheduled in 220 (20%) of the 1099 patients for whom information was recorded. Patients completed the Brief Pain Inventory (BPI) during their first visit, 1296 (59.1%) reporting pain (median intensity 4), and 537 (41.4%) experiencing a level that interfered substantially with daily activities. New ortheses and/or antalgic therapy was prescribed accordingly. After 7 days, 208 (16%) patients were re-evaluated and a new BPI administered. A significant improvement in the worst (p < 0.0001) and current pain (p = 0.03) was seen, together with a favorable impact on daily activities (p = 0.02). Two thousand fifty-one patients completed an anonymous questionnaire on the quality of the service, the majority (69.4%) expressing high satisfaction. CONCLUSIONS: Our 10-year osteoncology experience confirms the importance of a multidisciplinary approach to optimize BM management. Further evaluations are needed in relation to quality of life, outcome, and costs.

Primary Culture of Undifferentiated Pleomorphic Sarcoma: Molecular Characterization and Response to Anticancer Agents.

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal neoplasm with no specific line of differentiation. Eribulin, a novel synthetic microtubule inhibitor, has shown anticancer activity in several tumors, including soft tissue sarcomas (STS). We investigated the molecular biology of UPS, and the mechanisms of action of this innovative microtubule-depolymerizing drug. A primary culture from a patient with UPS was established and characterized in terms of gene expression. The activity of eribulin was also compared with that of other drugs currently used for STS treatment, including trabectedin. Finally, Western blot analysis was performed to better elucidate the activity of eribulin. Our results showed an upregulation of epithelial mesenchymal transition-related genes, and a downregulation of epithelial markers. Furthermore, genes involved in chemoresistance were upregulated. Pharmacological analysis confirmed limited sensitivity to chemotherapy. Interestingly, eribulin exhibited a similar activity to that of standard treatments. Molecular analysis revealed the expression of cell cycle arrest-related and pro-apoptotic-related proteins. These findings are suggestive of aggressive behavior in UPS. Furthermore, the identification of chemoresistance-related genes could facilitate the development of innovative drugs to improve patient outcome. Overall, the results from the present study furnish a rationale for elucidating the role of eribulin for the treatment of UPS.

Development of a Patient-Derived Xenograft (PDX) of Breast Cancer Bone Metastasis in a Zebrafish Model.

Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX) rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF) embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231). The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT), revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient's medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model.

Single bone metastasis from adenocarcinoma of the lacrimal gland: a case report.

Malignant tumors of the lacrimal gland are rare, and single bone metastases from lacrimal gland carcinoma are an exceptional event. We present the case of a 71-year-old man with a history of lumbar pain and left exophthalmos. Surgical resection of the lacrimal lesion and a bone biopsy gave a final histopathological diagnosis of primary ductal adenocarcinoma of the lacrimal gland with bone metastasis. The pathological tissue from both procedures was positive for androgen receptor expression. The patient underwent embolization and radiotherapy in association with total androgen blockade. After 20 months, the patient is still asymptomatic and has maintained the partial response at L1 with no progression to other sites. Our patient would appear to have a better prognosis and the disease a more indolent clinical course than the other cases of ductal adenocarcinoma of the lacrimal gland reported in the literature.

Two-stage, combined, three-level en bloc spondylectomy for a recurrent post-radiation sarcoma of the lumbar spine.

En bloc or extralesional resection means resection of the tumor in one piece together with a layer of healthy tissue: the margin is either marginal or wide. The prerequisite for an en bloc or extralesional spondylectomy is a tumor involvement of no more than one side of the posterior structures, so that a corridor can be created through which the spinal cord is released. This article presents a two-stage, combined anterior and posterolateral, three-level en bloc spondylectomy, and local flap wound coverage for a patient with a recurrent post-radiation sarcoma of the lumbar spine and infected wound after intralesional treatment. The patient had radiation therapy for an L4 Hodgkin's lymphoma 5 years before the development of the post-radiation sarcoma. Two-stage, three-level en bloc spondylectomy was done through a combined anterior and posterolateral approach. The resection margins were microscopically negative. Dural tear occurred intraoperatively because of tightly adherent dense scar tissue. Two years after spondylectomy, there was no evidence of tumor or infection recurrence; however, the patient died from her lymphoma. In surgically difficult spinal resections, we recommend the two-stage, combined anterior and posterolateral approach for en bloc spondylectomy. The staged procedure may provide for reduced perioperative complications and mortality, and meticulous dissection in the irradiated area, especially if infected. The combined approach provides for easier and safer dissection of the tumor and the spine from the anterior elements under direct visual control, and wide tumor resection.

One Step Double Augmentation with Human Dermis Allograft and Homologous PRP in Misdiagnosed and or Chronic Achilles Tendon Ruptures.

OBJECTIVE: Misdiagnosed/chronic Achilles tendon injuries are rare and disabling for patients. The surgical treatment of these rare injuries aims to ensure the tendon heals mechanically and biologically. This is the prerequisite for a good clinical and functional outcome and reduces recurrences. The main aim of the study is to present a surgical technique that has proven to be original, reproducible, and capable of guaranteeing solid tendon repair and optimal tissue regeneration. METHODS: We treated five patients, four males and one female, with the one-step double augmentation technique. All patients of this study complained of pain, but above all severe functional limitation that Achilles tendon injury had been causing for more than a month. In this study, we widely described the surgical technique, original and not found in the literature, which provides a biological graft (allograft of decellularized dermis) and homologous, thrombin-activated, platelet-rich plasma (H-PRP) in a single step. Surgical approach, always used by the first author, respected predefined steps: careful dissection and preparation of the peritendinous tissues from suture to the end of the procedure, tenorrhaphy, and augmentation with allopatch to obtain a mechanically effective repair to avoid recurrences, and finally "biological" augmentation with a unit of homologous, thrombin activated, PRP. We offered to all patients a regenerative rehabilitation program post-operatively. RESULTS: All patients were evaluated clinically (functional clinical tests and questionnaires) and instrumentally (elastic-sonography and perfusion MRI). The obtained results have been evaluated at a minimum follow-up of 18 months and a maximum of 24 months. In all patients pain was resolved, and district function and kinetic chains improved with resumption of daily activities, work, and sports. CONCLUSION: The present study confirmed the regenerative potential of decellularized dermis allograft and PRP (homologous and thrombin-activated). The same approach can also be exploited in cases of severe tendon destructuring and limited "intrinsic" regenerative potential at any age. The proposed one-step surgical technique of a double augmentation therefore appears useful, safe, reproducible, and applicable in all chronic tendon lesions with low regenerative potential.

Oligometastatic breast cancer and metastasis-directed treatment: an aggressive multimodal approach to reach the cure.

Metastatic breast cancer (BC) is considered an incurable disease and is usually treated with palliative intent. However, about 50% of metastatic BCs present with only a few metastatic lesions and are characterized by longer overall survival. These patients, defined as oligometastatic, could benefit from a multimodal approach, which combines systemic therapy with metastasis-directed treatment (stereotactic ablative therapy or surgery). The current definition of oligometastatic seems incomplete since it is based only on imaging findings and does not include biological features, and the majority of relevant data supporting this strategy comes from retrospective or non-randomized studies. However, the chance of reaching long-term complete remission or even a cure has led to the development of randomized trials investigating the impact of combined treatment in oligometastatic BC (OMBC). The SABR-COMET trial, the first randomized study to include BC patients, showed promising results from a combination of stereotactic ablative radiotherapy and systemic therapy. Considering the randomized trial's results, multidisciplinary teams should be set up to select OMBC patients who could achieve long-term survival with aggressive multimodal treatment.

Systemic Inflammatory Indices in Second-Line Soft Tissue Sarcoma Patients: Focus on Lymphocyte/Monocyte Ratio and Trabectedin.

A second-line standard of treatment has not yet been identified in patients with soft tissue sarcomas (STS), so identifying predictive markers could be a valuable tool. Recent studies have shown that the intratumoral and inflammatory systems significantly influence tumor aggressiveness. We aimed to investigate prognostic values of pre-therapy neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory index (SII), progression-free survival (PFS), and overall survival (OS) of STS patients receiving second-line treatment. In this single-center retrospective analysis, ninety-nine patients with STS were enrolled. All patients received second-line treatment after progressing to anthracycline. PFS and OS curves were calculated using the Kaplan-Meier method of RNA sequencing, and CIBERSORT analysis was performed on six surgical specimens of liposarcoma patients. A high NLR, PLR, and SII were significantly associated with worse PFS (p = 0.019; p = 0.004; p = 0.006). Low LMR was significantly associated with worse OS (p = 0.006). Patients treated with Trabectedin showed a better PFS when the LMR was low, while patients treated with other regimens showed a worse PFS when the LMR was low (p = 0.0154). The intratumoral immune infiltrates analysis seems to show a correlation between intratumoral macrophages and LMR. PS ECOG. The metastatic onset and tumor burden showed prognostic significance for PFS (p = 0.004; p = 0.041; p = 0.0086). According to the histologies, PFS was: 5.7 mo in liposarcoma patients vs. 3.8 mo in leiomyosarcoma patients vs. 3.1 months in patients with other histologies (p = 0.053). Our results confirm the prognostic role of systemic inflammatory markers in patients with STS. Moreover, we demonstrated that LMR is a specific predictor of Trabectedin efficacy and could be useful in daily clinical practice. We also highlighted a possible correlation between LMR levels and the percentage of intratumoral macrophages.

Myxofibrosarcoma landscape: diagnostic pitfalls, clinical management and future perspectives.

Myxofibrosarcoma (MFS) is a common entity of adult soft tissue sarcomas (STS) characterized by a predilection of the extremities and a high local recurrence rate. Originally classified as a myxoid variant of malignant fibrous histiocytoma, this musculoskeletal tumor has been recognized since 2002 as a distinct histotype showing a spectrum of malignant fibroblastic lesions with myxoid stroma, pleomorphism and curvilinear vessels. Currently, the molecular pathogenesis of MFS is still poorly understood and its genomic profile exhibits a complex karyotype with a number of aberrations including amplifications, deletions and loss of function. The diagnosis is challenging due to the unavailability of specific immunohistochemical markers and is based on the analysis of cytomorphologic features. The mainstay of treatment for localized disease is represented by surgical resection, with (neo)-adjuvant radio- and chemotherapy. In the metastatic setting, chemotherapy represents the backbone of treatments, however its role is still controversial and the outcome is very poor. Recent advent of genomic profiling, targeted therapies and larger enrollment of patients in translational and clinical studies, have improved the understanding of biological behavior and clinical outcome of such a disease. This review will provide an overview of current diagnostic pitfalls and clinical management of MFS. Finally, a look at future directions will be discussed.

A Rationale for the Activity of Bone Target Therapy and Tyrosine Kinase Inhibitor Combination in Giant Cell Tumor of Bone and Desmoplastic Fibroma: Translational Evidences.

Giant cell tumor of bone (GCTB) and desmoplastic fibroma (DF) are bone sarcomas with intermediate malignant behavior and unpredictable prognosis. These locally aggressive neoplasms exhibit a predilection for the long bone or mandible of young adults, causing a severe bone resorption. In particular, the tumor stromal cells of these lesions are responsible for the recruiting of multinucleated giant cells which ultimately lead to bone disruption. In this regard, the underlying pathological mechanism of osteoclastogenesis processes in GCTB and DF is still poorly understood. Although current therapeutic strategy involves surgery, radiotherapy and chemotherapy, the benefit of the latter is still debated. Thus, in order to shed light on these poorly investigated diseases, we focused on the molecular biology of GCTB and DF. The expression of bone-vicious-cycle- and neoangiogenesis-related genes was investigated. Moreover, combining patient-derived primary cultures with 2D and 3D culture platforms, we investigated the role of denosumab and levantinib in these diseases. The results showed the upregulation of RANK-L, RANK, OPN, CXCR4, RUNX2 and FLT1 and the downregulation of OPG and CXCL12 genes, underlining their involvement and promising role in these neoplasms. Furthermore, in vitro analyses provided evidence for suggesting the combination of denosumab and lenvatinib as a promising therapeutic strategy in GCTB and DF compared to monoregimen chemotherapy. Furthermore, in vivo zebrafish analyses corroborated the obtained data. Finally, the clinical observation of retrospectively enrolled patients confirmed the usefulness of the reported results. In conclusion, here we report for the first time a molecular and pharmacological investigation of GCTB and DF combining the use of translational and clinical data. Taken together, these results represent a starting point for further analyses aimed at improving GCTB and DF management.

Radiation-induced sarcomas.

Radiation-induced sarcomas are rare, high-grade sarcomas that may arise within the radiation volume at a mean latency period of 3-55 years after radiation therapy, doses of which range from 45 to 60 Gy. Radiation-induced osteosarcomas, fibrosarcomas, and malignant fibrous histiocytomas are the most common. Extensive surgery with microscopically negative-margin resection, or amputation is recommended for improved survival. Adjuvant radiation therapy and chemotherapy have not been shown to improve survival rates significantly. The prognosis is poor.

Case Report: Adult NTRK-Rearranged Spindle Cell Neoplasm: Early Tumor Shrinkage in a Case With Bone and Visceral Metastases Treated With Targeted Therapy.

BACKGROUND: NTRK (neurotrophic tyrosine receptor kinase)-rearranged spindle cell neoplasms are a new group of tumors included in the new 5th edition of the World Health Organization (WHO) classification of soft Tissue and Bone Sarcomas. These tumors are characterized by NTRK gene fusions and show a wide spectrum of histologies and clinical behavior. Several targeted therapies have recently been approved for tumors harboring NTRK fusions, including STS. CASE PRESENTATION: A 26-year-old male with advanced, pretreated NTRK rearranged spindle cell neoplasm and liver, lung and bone metastases was treated with larotrectinib on a continuous 28-day schedule, at a dose of 100 mg twice daily. An 18FDG-PET/CT scan performed after 7 days of treatment showed tumor shrinkage in both visceral and bone lesions. There was no drug-related toxicity. Subsequent evaluations confirmed continued tumor regression in disease sites. The patient is well and continues treatment. CONCLUSION: The clinical and radiological response of our patient with an uncommon TPM4 (exon 7)-NTRK1 (exon 12) gene fusion tumor treated with a first-generation TRK inhibitor could contribute to a better understanding of the biology of this new STS entity and help to improve patient management.

The potential role of the extracellular matrix in the activity of trabectedin in UPS and L-sarcoma: evidences from a patient-derived primary culture case series in tridimensional and zebrafish models.

BACKGROUND: Soft tissue sarcomas (STS) are a rare group of solid neoplasm including among others liposarcoma, leiomyosarcoma (L-sarcoma) and undifferentiated pleomorphic sarcoma (UPS) entities. The current first-line treatment is represented by anthracycline based- regimens, second-line may include trabectedin. Currently the activity of trabectedin and its mechanism of action is not completely elucidated. METHODS: Taking the advantages of our 3D patient-derived primary culture translational model we performed genomic-, chemobiogram, proteomic- and in vivo analysis in a UPS culture (S1). Furthermore pharmacological profiling of a UPS and L-sarcoma patient-derived case series and in silico analysis were carried out. RESULTS: Trabectedin exhibited an increased activity in 3D respect to 2D cultures suggesting an extracellular matrix (ECM) and timp1 involvement in its mechanism of action. Moreover 3D S1 xenotranspanted zebrafish model showed an increased sensitivity to trabectedin. Finally the results were further validated in a UPS and L-sarcoma case series. CONCLUSIONS: Taken together these results confirmed the activity of trabectedin in these STS histotypes. Moreover the data underline the ECM involvement in the cytotoxic effect mediated by trabectedin and could open the door for researches aimed to focus on the patient setting that could benefit from this agent.

Achilles tendon reconstruction with peroneus tendon transfer following epithelioid sarcoma resection: a rare case report at 5 years follow-up.

BACKGROUND: Soft-tissue sarcomas (STS) are rare in hand and foot. In this paper we present a case of reconstruction of Achilles tendon defect with peroneus brevis transfer reinforced with medial gastrocnemius fascia and plantaris tendon after excision of a local recurrence of epithelioid sarcoma. CASE PRESENTATION: Fifty-five years-old female. MRI showed a lump of 5 × 2,5 × 2 cm into Achille's tendon with invasion of the anterior fat tissue but no invasion of the surrounding bones. The patient underwent excision of the tumour and reconstruction of the tendinous defect with peroneus brevis transfer. Surgical technique has been widely described. DISCUSSION AND CONCLUSIONS: Epithelioid sarcoma arising from the Achilles tendon is an extremely rare malignant tumour in an atypical site and may easily be confused with other soft tissue masses. It presents a technical challenge because of the large tendon defect remaining following wide resection. Reconstruction with peroneus brevis transfer, reinforced with medial gastrocnemius fascia and plantaris tendon, restore appropriate structural continuity and resistance. Functional results are satisfactory.

MR imaging of bone metastases and choice of sequence: spin echo, in-phase gradient echo, diffusion, and contrast medium.

Magnetic resonance imaging (MRI) is the only imaging technique allowing the direct visualization of the bone marrow and is the most sensitive to detect bone metastases. Sensitivity is high, but a good understanding and an informed choice of acquisition sequences can easily improve specificity. Fat and water distribution (spin echo), indirect visualization of bone trabeculae (in-phase gradient echo), evaluation of bone edema and cell density (diffusion), and the study of vascularization (contrast medium) should be cleverly combined to enable good detection and lesion characterization.

Multidisciplinary approach to the treatment of bone metastases: Osteo-Oncology Center, a new organizational model.

AIMS AND BACKGROUND: Bone metastases are responsible for high morbidity in cancer patients. The frequency of pain and other serious complications associated with such metastases depends on the site and type of lesions and preventive therapy. The present paper aims to inform the scientific community about a new organizational health care model specifically designed for patients with bone metastases, in the hope of stimulating the creation of similar initiatives whose goals are to decrease the high morbidity of this pathology, reduce the frequency of complications, limit psychophysical distress of patients, and improve quality of life. METHODS: In January 2005, an Osteo-Oncology Center was opened in our institute to provide multidisciplinary care (19 specialists involved) for patients with bone metastases, to train physicians, and to conduct research in the field. RESULTS: In its first three years of activity, 601 multidisciplinary team consultations were made and a total of 425 patients were seen. The most frequent primary tumor site was the lung in males and the breast in females. Upon presentation at the Center, 79% of patients reported experiencing a level of pain (median pain intensity, 3.69) that interfered with normal daily activities. An anonymous questionnaire was also completed on the quality of the service provided: 75% of patients were very satisfied, 23% were satisfied, 1% responded "I don't know", and only 1% expressed dissatisfaction. CONCLUSIONS: Our preliminary results confirm the usefulness of a multidisciplinary center for the management of patients with bone metastases, especially in terms of decreasing psychophysical suffering.

Percutaneous CT-guided biopsy of the spine: results of 430 biopsies.

Biopsies of lesions in the spine are often challenging procedures with significant risk of complications. CT-guided needle biopsies could lower these risks but uncertainties still exist about the diagnostic accuracy. Aim of this retrospective study was to evaluate the diagnostic accuracy of CT-guided needle biopsies for bone lesions of the spine. We retrieved the results of 430 core needle biopsies carried out over the past fifteen years at the authors' institute and examined the results obtained. Of the 430 biopsies performed, in 401 cases the right diagnosis was made with the first CT-guided needle biopsy (93.3% accuracy rate). Highest accuracy rates were obtained in primary and secondary malignant lesions. Most false negative results were found in cervical lesions and in benign, pseudotumoral, inflammatory, and systemic pathologies. There were only 9 complications (5 transient paresis, 4 haematomas that resolved spontaneously) that had no influence on the treatment strategy, nor on the patient's outcome. In conclusion we can assert that this technique is reliable and safe and should be considered the gold standard in biopsies of the spine.