Clinical and translational implications of immunotherapy in sarcomas.

Immunotherapy has emerged as promising treatment in sarcomas, but the high variability in terms of histology, clinical behavior and response to treatments determines a particular challenge for its role in these neoplasms. Tumor immune microenvironment (TiME) of sarcomas reflects the heterogeneity of these tumors originating from mesenchymal cells and encompassing more than 100 histologies. Advances in the understanding of the complexity of TiME have led to an improvement of the immunotherapeutic responsiveness in sarcomas, that at first showed disappointing results. The proposed immune-classification of sarcomas based on the interaction between immune cell populations and tumor cells showed to have a prognostic and potential predictive role for immunotherapies. Several studies have explored the clinical impact of immune therapies in the management of these histotypes leading to controversial results. The presence of Tumor Infiltrating Lymphocytes (TIL) seems to correlate with an improvement in the survival of patients and with a higher responsiveness to immunotherapy. In this context, it is important to consider that also immune-related genes (IRGs) have been demonstrated to have a key role in tumorigenesis and in the building of tumor immune microenvironment. The IRGs landscape in soft tissue and bone sarcomas is characterized by the connection between several tumor-related genes that can assume a potential prognostic and predictive therapeutic role. In this paper, we reviewed the state of art of the principal immune strategies in the management of sarcomas including their clinical and translational relevance.

A randomized phase II trial of Captem or Folfiri as second-line therapy in neuroendocrine carcinomas.

BACKGROUND: Neuroendocrine Carcinomas (NECs) prognosis is poor.No standard second-line therapy is currently recognized after failure of platinum-based first-line treatment. FOLFIRI and CAPTEM regimens have shown promising activity in preliminary studies. We aimed to evaluate these regimens in metastatic NEC patients. METHODS: This is an open-label, multicenter, randomized non-comparative phase II trial to evaluate the activity and safety of FOLFIRI or CAPTEM in metastatic NEC patients. Primary endpoints were the 12 weeks-Disease Control Rate (12w-DCR) by investigator assessment per RECIST v1.1 and safety per CTCAE v5.0. Additional endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients' serum samples were subject to NGS miRNome profiling in comparison with healthy donors to reveal differentially expressed miRNAs as candidate circulating biomarkers. RESULTS: The study was halted for futility at interim analysis, as the minimum 12w-DCR threshold of 10 out of 25 patients required for the first step was not reached. From 06/03/2017 to 18/01/2021, 53 out of 112 patients were enrolled. Median follow-up was 22.6 months (range: 1.4-60.4). The 12w-DCR was 39.1 % in the FOLFIRI arm and 28.0 % in the CAPTEM arm. In the FOLFIRI subgroup the 12-months OS rate was 28.4 % (95 % CI: 12.7-46.5) while in the CAPTEM subgroup it was 32.4 % (95 % CI: 14.9-51.3). The most common G3-G4 side effects were neutropenia (n = 5, 18.5 %) and anemia (n = 2, 7.4 %) for FOLFIRI and G3-G4 thrombocytopenia (n = 2, 8.0 %), G4 nausea/vomiting (n = 1, 4.0 %) for CAPTEM. Three microRNAs emerged as NEC independent predictors. High expression values were found to be significantly associated with decreased PFS and OS. CONCLUSION: The safety profile of FOLFIRI and CAPTEM was manageable. FOLFIRI and CAPTEM chemotherapy showed comparable activity in the second-line setting after progression on etoposide/platinum. GOV IDENTIFIER: NCT03387592.

A novel patient-derived immortalised cell line of myxofibrosarcoma: a tool for preclinical drugs testing and the generation of near-patient models.

BACKGROUND: Myxofibrosarcoma is a rare malignant soft tissue sarcoma characterised by multiple local recurrence and can become of higher grade with each recurrence. Consequently, myxofibrosarcoma represents a burden for patients, a challenge for clinicians, and an interesting disease to study tumour progression. Currently, few myxofibrosarcoma preclinical models are available. METHODS: In this paper, we present a spontaneously immortalised myxofibrosarcoma patient-derived cell line (MF-R 3). We performed phenotypic characterization through multiple biological assays and analyses: proliferation, clonogenic potential, anchorage-independent growth and colony formation, migration, invasion, AgNOR staining, and ultrastructural evaluation. RESULTS: MF-R 3 cells match morphologic and phenotypic characteristics of the original tumour as 2D cultures, 3D aggregates, and on the chorioallantoic membrane of chick embryos. Overall results show a clear neoplastic potential of this cell line. Finally, we tested MF-R 3 sensitivity to anthracyclines in 2D and 3D conditions finding a good response to these drugs. CONCLUSIONS: In conclusion, we established a novel patient-derived myxofibrosarcoma cell line that, together with the few others available, could serve as an important model for studying the molecular pathogenesis of myxofibrosarcoma and for testing new drugs and therapeutic strategies in diverse experimental settings.

Modeling Myxofibrosarcoma: Where Do We Stand and What Is Missing?

Myxofibrosarcoma (MFS) is a malignant soft tissue sarcoma (STS) that originates in the body's connective tissues. It is characterized by the presence of myxoid (gel-like) and fibrous components and typically affects patients after the fifth decade of life. Considering the ongoing trend of increasing lifespans across many nations, MFS is likely to become the most common musculoskeletal sarcoma in the future. Although MFS patients have a lower risk of developing distant metastases compared with other STS cases, MFS is characterized by a high frequency of local recurrence. Notably, in 40-60% of the patients where the tumor recurs, it does so multiple times. Consequently, patients may undergo multiple local surgeries, removing the risk of potential amputation. Furthermore, because the tumor relapses generally have a higher grade, they exhibit a decreased response to radio and chemotherapy and an increased tendency to form metastases. Thus, a better understanding of MFS is required, and improved therapeutic options must be developed. Historically, preclinical models for other types of tumors have been instrumental in obtaining a better understanding of tumor development and in testing new therapeutic approaches. However, few MFS models are currently available. In this review, we will describe the MFS models available and will provide insights into the advantages and constraints of each model.

High-grade transformation of a polymorphous adenocarcinoma of the salivary gland: a case report and review of the literature.

Background: Polymorphous adenocarcinoma (PAC) represents the second most widespread neoplasm of the minor salivary glands. These tumors rarely develop a histological progression from low-grade to high-grade malignancy, named "high-grade transformation" (HGT). Only nine cases are described in literature. Case description: Here, we describe the case of a 76-year-old male patient with a PAC recurrence of the oral floor displaying HGT, and we explore the tumor cytomorphological features, genomic profiling, and the patient's clinical management. The tumor mass was characterized by poorly atypical cellular elements with vesicular nuclei and comedonecrosis foci. The growth pattern was predominantly solid, tubular, and cribriform. The lesion did not show microsatellite instability or targeted molecular alterations. The case was successfully treated with radical surgery followed by radiotherapy. Conclusion: We report for the first time the recurrence of a PAC with HGT arising in the oral floor after 20 years from the primary lesion. These preliminary data and the literature analysis enhance the knowledge of this extremely rare disease.

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.

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.

Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models.

Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four-step route, and a representative member was confirmed to have native fluorescence, including a band in the near-infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cell lines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrPC levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain-independent anti-prion compounds.

The emerging role of cancer nanotechnology in the panorama of sarcoma.

In the field of nanomedicine a multitude of nanovectors have been developed for cancer application. In this regard, a less exploited target is represented by connective tissue. Sarcoma lesions encompass a wide range of rare entities of mesenchymal origin affecting connective tissues. The extraordinary diversity and rarity of these mesenchymal tumors is reflected in their classification, grading and management which are still challenging. Although they include more than 70 histologic subtypes, the first line-treatment for advanced and metastatic sarcoma has remained unchanged in the last fifty years, excluding specific histotypes in which targeted therapy has emerged. The role of chemotherapy has not been completely elucidated and the outcomes are still very limited. At the beginning of the century, nano-sized particles clinically approved for other solid lesions were tested in these neoplasms but the results were anecdotal and the clinical benefit was not substantial. Recently, a new nanosystem formulation NBTXR3 for the treatment of sarcoma has landed in a phase 2-3 trial. The preliminary results are encouraging and could open new avenues for research in nanotechnology. This review provides an update on the recent advancements in the field of nanomedicine for sarcoma. In this regard, preclinical evidence especially focusing on the development of smart materials and drug delivery systems will be summarized. Moreover, the sarcoma patient management exploiting nanotechnology products will be summed up. Finally, an overlook on future perspectives will be provided.

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.

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches.

Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.

Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance.

Prion diseases are a group of neurodegenerative disorders characterized by the accumulation of misfolded prion protein (called PrPSc). Although conversion of the cellular prion protein (PrPC) to PrPSc is still not completely understood, most of the therapies developed until now are based on blocking this process. Here, we propose a new drug strategy aimed at clearing prions without any direct interaction with neither PrPC nor PrPSc. Starting from the recent discovery of SERPINA3/SerpinA3n upregulation during prion diseases, we have identified a small molecule, named compound 5 (ARN1468), inhibiting the function of these serpins and effectively reducing prion load in chronically infected cells. Although the low bioavailability of this compound does not allow in vivo studies in prion-infected mice, our strategy emerges as a novel and effective approach to the treatment of prion disease.

Serpin Signatures in Prion and Alzheimer's Diseases.

Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alteration of the serpin-protease equilibrium can lead to severe consequences. SERPINA3 dysregulation has been associated with Alzheimer's disease (AD) and prion diseases. In this study, we investigated the differential expression of serpin superfamily members in neurodegenerative diseases. SERPIN expression was analyzed in human frontal cortex samples from cases of sporadic Creutzfeldt-Jakob disease (sCJD), patients at early stages of AD-related pathology, and age-matched controls not affected by neurodegenerative disorders. In addition, we studied whether Serpin expression was dysregulated in two animal models of prion disease and AD.Our analysis revealed that, besides the already observed upregulation of SERPINA3 in patients with prion disease and AD, SERPINB1, SERPINB6, SERPING1, SERPINH1, and SERPINI1 were dysregulated in sCJD individuals compared to controls, while only SERPINB1 was upregulated in AD patients. Furthermore, we analyzed whether other serpin members were differentially expressed in prion-infected mice compared to controls and, together with SerpinA3n, SerpinF2 increased levels were observed. Interestingly, SerpinA3n transcript and protein were upregulated in a mouse model of AD. The SERPINA3/SerpinA3nincreased anti-protease activity found in post-mortem brain tissue of AD and prion disease samples suggest its involvement in the neurodegenerative processes. A SERPINA3/SerpinA3n role in neurodegenerative disease-related protein aggregation was further corroborated by in vitro SerpinA3n-dependent prion accumulation changes. Our results indicate SERPINA3/SerpinA3n is a potential therapeutic target for the treatment of prion and prion-like neurodegenerative diseases.

3-T magnetic resonance-guided high-intensity focused ultrasound (3 T-MR-HIFU) for the treatment of pain from bone metastases of solid tumors.

INTRODUCTION: Bone metastases (BM) are still the main cause of morbidity and mortality in cancer patients, not only because of their complications, defined as skeletal-related events (SREs), but also because of the negative impact bone pain has on quality of life (QoL) and survival, especially when opioid analgesics and locoregional treatments fail. MATERIALS AND METHODS: A single-center prospective study was carried out on 12 patients with symptomatic BM treated with MRI-guided focused ultrasound (MR-HIFU). The primary endpoint was the effectiveness of MR-HIFU in reducing current and breakthrough cancer pain (BTCP) scores. The main secondary aims were the evaluation of circulating markers at different time-points and their relation to pain and procedure efficacy. Other secondary objectives included temporal evolution of pain response, evaluation of QoL, and side effects of the treatment. Descriptive statistics were used to evaluate primary and secondary endpoints. Questionnaires on pain and QoL completed at baseline and at 30 days were compared using appropriate statistical tests with exploratory intent. RESULTS: MR-HIFU was successfully completed in all 12 patients enrolled between September 2015 and December 2018. On day 30, 6 (50.0%) patients showed a complete response of current pain and 6 a partial response, while 5 (41.7%) obtained a complete BTCP response. A partial response of BM evaluated by MD Anderson criteria was obtained in 9 (81.8%) patients. Only one patient progressed in the target lesion after MR-HIFU. No treatment-related adverse events were recorded. Bone turnover markers CTX/RANK-L (P) do not demonstrate any significant change with the pain or BM response. CONCLUSION: In our patients, targeted therapy of painful BM with MRI-guided focused ultrasound ablation was safe and showed encouraging early-onset and functional results.

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.

Expression pattern of perilipins in human brain during aging and in Alzheimer's disease.

AIMS: Perilipins are conserved proteins that decorate intracellular lipid droplets and are essential for lipid metabolism. To date, there is limited knowledge on their expression in human brain or their involvement in brain aging and neurodegeneration. The aim of this study was to characterise the expression levels of perilipins (Plin1-Plin5) in different cerebral areas from subjects of different age, with or without signs of neurodegeneration. METHODS: We performed real-time RT-PCR, western blotting, immunohistochemistry and confocal microscopy analyses in autoptic brain samples of frontal and temporal cortex, cerebellum and hippocampus from subjects ranging from 33 to 104 years of age, with or without histological signs of neurodegeneration. To test the possible relationship between Plins and inflammation, correlation analysis with IL-6 expression was also performed. RESULTS: Plin2, Plin3 and Plin5, but not Plin1 and Plin4, are expressed in the considered brain areas with different intensities. Plin2 appears to be expressed more in grey matter, particularly in neurons in all the areas analysed, whereas Plin3 and Plin5 appear to be expressed more in white matter. Plin3 seems to be expressed more in astrocytes. Only Plin2 expression is higher in old subjects and patients with early tauopathy or Alzheimer's disease and is associated with IL-6 expression. CONCLUSIONS: Perilipins are expressed in human brain but only Plin2 appears to be modulated with age and neurodegeneration and linked to an inflammatory state. We propose that the accumulation of lipid droplets decorated with Plin2 occurs during brain aging and that this accumulation may be an early marker and initial step of inflammation and neurodegeneration.

HRAS overexpression predicts response to Lenvatinib treatment in gastroenteropancreatic neuroendocrine tumors.

Introduction: Neuroendocrine neoplasms (NENs) are a rare group of tumors exceptionally heterogeneous, with clinical presentation ranging from well differentiated more indolent tumors to poorly differentiated very aggressive forms. Both are often diagnosed after the metastatic spread and require appropriate medical treatment. A high priority need in the management of this disease is the identification of effective therapeutic strategies for advanced and metastatic patients. The recent TALENT trial demonstrated the efficacy of lenvatinib, a multi-tyrosine kinase inhibitor, in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) with no other treatment indication. Further development of this drug in advanced NETs is warranted. Methods: We investigated potential clinical and molecular determinants of lenvatinib response in human primary cultures derived from patients with GEP-NET of different grades and sites of origin. We correlated response to treatment with patient clinical characteristics, with the mutational status of 161-cancer associated genes and with the expression levels of MKI-related genes. Results: Lenvatinib exerted a significant antitumor activity in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard frontline treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder showing a significant survival inhibition, and 5 as non-responder. We observed that the overexpression of HRAS in the original tumor tissue compared to the matched healthy tissue significantly correlated with responsiveness of primary cells to lenvatinib (p=.048). All 5 non-responder cultures showed normal HRAS expression, while of the 6 responder cultures, 4 had HRAS overexpression. Overexpression of HRAS was not associated with gene mutation. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) or molecular markers correlated with response. Discussion: Lenvatinib appears to be a highly effective drug for the treatment of NETs. The evaluation of HRAS expression in the tumor tissue might improve patient selection and optimize therapeutic outcome.

Deciphering the Genomic Landscape and Pharmacological Profile of Uncommon Entities of Adult Rhabdomyosarcomas.

Adult rhabdomyosarcoma (RMS) represents an uncommon entity with an incidence of less than 3% of all soft tissue sarcomas (STS). Consequently, the natural history and the clinical management of this disease are infrequently reported. In order to fill this gap, we investigated the molecular biology of an adult RMS case series. The expression of epithelial mesenchymal transition-related gene and chemoresistance-related gene panels were evaluated. Moreover, taking advantage of our STS translational model combining patient-derived primary culture and 3D-scaffold, the pharmacological profile of an adult head and neck sclerosing RMS was assessed. Furthermore, NGS, microsatellite instability, and in silico analyses were carried out. RT-PCR identified the upregulation of CDH1, SLUG, MMP9, RAB22a, S100P, and LAPTM4b, representing promising biomarkers for this disease. Pharmacological profiling showed the highest sensitivity with anthracycline-based regimen in both 2D and 3D culture systems. NGS analysis detected RAB3IP-HMGA2 in frame gene rearrangement and FGFR4 mutation; microsatellite instability analysis did not detect any alteration. In silico analysis confirmed the mutation of FGFR4 as a promising marker for poor prognosis and a potential therapeutic target. We report for the first time the molecular and pharmacological characterization of rare entities of adult head and neck and posterior trunk RMS. These preliminary data could shed light on this poorly understood disease.

ALK-negative lung inflammatory myofibroblastic tumor in a young adult: A case report and literature review of molecular alterations.

RATIONALE: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that is prevalent among children and adolescents. Surgery is the most important therapeutic approach for IMT and complete resection is recommended. Although 50% of IMTs show anaplastic lymphoma kinase (ALK) rearrangements, crizotinib has proven an effective therapeutic approach. However, the genetic landscape of this tumor is still not fully understood and treatment options are limited, especially in the majority of ALK-negative tumors. PATIENT CONCERNS: We describe the clinical case of a healthy 18-year-old female in whom a pulmonary nodule was incidentally detected. DIAGNOSES: Following a small increase in the size of the nodule, the patient underwent both 18FDG-PET/CT and 68Ga-PET/CT, resulting in a suspicion of bronchial hamartoma. INTERVENTIONS: The patient underwent surgery and a salivary gland-like lung tumor was diagnosed. OUTCOMES: After surgery, the patient was referred to our cancer center, where a review of the histology slides gave a final diagnosis of ALK-negative lung IMT. Given the histology, it was decided not to administer adjuvant therapy and the patient was placed in a 3-monthly follow-up program. The patient is still disease-free 2 years post-surgery. LESSONS: Although there is no standard of care for the treatment of IMT, identifying genomic alterations could help to redefine the management of patients with negative-ALK disease. Our review of the literature on IMT and other kinase fusions revealed, in addition to ALK rearrangements, the potential association of ROS1, NTRK, RET, or PDGFR beta alterations with the tumor.