Role of CDK4 as prognostic biomarker in Soft Tissue Sarcoma and synergistic effect of its inhibition in dedifferentiated liposarcoma sequential treatment.

Soft tissue sarcomas represent an heterogeneous group of rare mesenchymal tumors comprising 1% of all solid malignancies. Among them, liposarcoma is one of the most common histotypes with atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma (ALT/WDLPS and DDLPS) as the major sub-entities. The unavailability of predictive, prognostic and druggable biomarkers makes the management of these lesions challenging. In recent years CDK4 and its inhibitors have emerged as potential agents for these lesions especially for ALT/WDLPS and DDLPS but the results are not conclusive and need to be elucidated. This study involved 21 ALT/WDLPS and DDLPS patients. Histological analyses of MDM2 and CDK4 were carried out. Moreover, a DDLPS patient-derived cancer model was established in vitro and in vivo assessing the efficacy of palbociclib in combination and sequential treatment. Finally, in silico analyses on CDK4 expression were carried out. The results showed a higher expression of CDK4 and MDM2 in DDLPS compared to ALT/WDLPS. Moreover, no correlation between MDM2 expression and CDK4 was observed. Next, in vitro analysis of CDK4 inhibitor palbociclib showed an antagonistic effect when combined to other chemotherapeutics, while it exhibited a significant synergy when administered in sequential schedule with lenvatinib. Next, in vivo analysis on DDLPS xenotransplanted embryos assessing the efficacy and safety profile of the in vitro tested schedules confirmed the observed data. This proof-of-concept study sheds light on the natural history of ALT/WDLPS and DDLPS and provides the rationale for the clinical applicability of sequential treatment with palbociclib in the management of DDLPS.

First step results from a phase II study of a dendritic cell vaccine in glioblastoma patients (CombiG-vax).

Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes. Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test). Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery. Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT).

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.

Immuno markers in newly diagnosed glioblastoma patients underwent Stupp protocol after neurosurgery: a retrospective series.

PURPOSE: The aims of our retrospective study investigated the role of immune system in glioblastoma (GBM), which is the most aggressive primary brain tumor in adults characterized by a poor prognosis. The recurrence rate remains high, probably due to "immune-desert" tumor microenvironment (TME) making GBM hidden from the anti-tumoral immune clearance. Considering this, we aimed to create a panel of prognostic markers from blood and tumor tissue correlating with overall survival (OS) and progression-free survival (PFS). METHODS: Firstly, we analyzed the inflammatory markers NLR and PLR as the ratio of the absolute neutrophil count and absolute platelet count by the absolute lymphocyte count respectively, collected at different time points in the peripheral blood of 95 patients. Furthermore, in 31 patients of the same cohort, we analyzed the formalin-fixed paraffin embedded samples to further compare the impact of circulating and inflammatory markers within the TME. RESULTS: Patients aged < 60 years and with methylated MGMT showed better OS. While, pre-chemotherapy Systemic Inflammatory Index (SII) < 480 was related to a better OS and PFS, we observed that only CD68+macrophage and CD66b+neutrophils expressed in vascular/perivascular area (V) showed a statistically significant prognostic role in median OS and PFS. CONCLUSIONS: Thus, we underscored a role of SII as predictive value of response to STUPP protocol. Regarding the TME-related markers, we suggested to take into consideration for future studies with new immunotherapy combinations, each component relating to expression of immune infiltrating subsets.

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.

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.

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.

Immune Checkpoint Inhibitors With or Without Bone-Targeted Therapy in NSCLC Patients With Bone Metastases and Prognostic Significance of Neutrophil-to-Lymphocyte Ratio.

Introduction: Bone metastases (BMs) are a negative prognostic factor in patients with non-small cell lung cancer (NSCLC). Although immune-checkpoint inhibitors (ICIs) have dramatically changed the therapeutic landscape of NSCLC, little information is available on BMs from NSCLC treated with ICIs alone or in association with bone-targeted therapy (BTT) such as zoledronate or denosumab. Methods: From 2014 to 2020, 111 of the 142 patients with BMs secondary to NSCLC extrapolated from the prospective multicenter Italian BM Database were eligible for analysis. Information on blood count, comorbidities, and toxicity was retrospectively collected. The neutrophil-to-lymphocyte ratio (NLR) pre- and post-treatment was calculated. Survival was analyzed using the Kaplan-Meier method, with statistical significance of survival differences assessed using the log-rank test. Results: Median age was 66 (range, 42-84) years. Performance status (PS) Eastern Cooperative Oncology Group (ECOG) was 0-1 in 79/111 patients. The majority of patients (89.2%) had adenocarcinoma histology. At a median follow-up of 47.4 months, median progression-free (mPFS) and overall survival (mOS) was 4.9 (95%CI, 2.8-10.0) and 11.9 (95%CI, 8.2-14.4) months, respectively. Forty-six (43.4%) patients with BM NSCLC underwent first- or further-line therapy with ICIs: 28 (60.8%) received nivolumab, 9 (19.6%) pembrolizumab, and 9 (19.6%) atezolizumab. Of the 46 patients treated with ICIs, 30 (65.2%) underwent BTT: 24 (80.0%) with zoledronate and 6 (20.0%) with denosumab. The ICI-alone group had an mOS of 15.8 months [95%CI, 8.2-not evaluable (NE)] vs. 21.8 months (95%CI, 14.5-not evaluable) for the ICI plus BTT group and 7.5 (95%CI, 6.1-10.9) months for the group receiving other treatments (p < 0.001). NLR ≤5 had a positive impact on OS. Conclusion: BTT appears to have a synergistic effect when used in combination with ICIs, improving patient survival.

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.

Activity and Safety of Immune Checkpoint Inhibitors in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis.

Immune-checkpoint inhibitors (ICIs) have widened the therapeutic scenario of different cancer types. Phase I/II trials have been designed to evaluate the role of ICIs both as single agents and in combination in neuroendocrine neoplasms (NENs), but as yet no randomized controlled phase III trials have been carried out. A systematic review and meta-analysis of studies published could help to reduce the biases of single-phase II trials. Efficacy data were obtained on 636 patients. Pooled percentages of the overall response rate (ORR) and disease control rate (DCR) were 10% (95% CI: 6-15%, I2 = 67%, p < 0.1) and 42% (95% CI: 28-56%, I2 = 93%, p < 0.1), respectively. Median progression-free survival (mPFS) was 4.1 months (95% CI 2.6-5.4; I2 = 96%, p < 0.1) and median overall survival (mOS) was 11 months (95% CI 4.8-21.1; I2 = 98%, p < 0.1). Among the ICIs used as single agents, the anti-PD1 toripalimab achieved the highest ORR. Combination regimens were superior to monotherapy, e.g., the ICI combination nivolumab + ipilimumab, and the ICI + anti-angiogenetic combination atezolizumab + bevacizumab, both of which warrant further investigation. Promising efficacy and a good safety profile of ICIs represent a valid opportunity for expanding the therapeutic landscape of NENs. Predictive biomarkers are needed to identify the most suitable candidates for these regimens.

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.

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.

Is it possible to conduct clinical trials during a pandemic? The example of a trial of hydroxychloroquine.

OBJECTIVES: to examine the factors that, in the context of the current pandemic, have influenced the conduct of a randomized clinical trial on hydroxychloroquine in Italy. DESIGN: the trend of enrolment in the PROTECT study, "A randomized study with Hydroxychloroquine versus observational support for prevention or early phase treatment of Coronavirus disease (COVID-19)" (Eudract number: 2020-001501-24, NCT04363827), conducted in the period from May to September 2020, was analysed to evaluate the possible association of the enrolment rate with the amount of information published in the national and local press on hydroxychloroquine. SETTING AND PARTICIPANTS: the PROTECT clinical study is an Italian interventional superiority study, open label, with cluster randomization, aimed at evaluating whether treatment with hydroxychloroquine can reduce the percentage of symptomatic subjects compared to observation only in a population of subjects exposed to SARS-CoV-2 virus consisting of cohabitants/contacts of COVID-19 patients and asymptomatic or paucisymptomatic subjects diagnosed with COVID-19. MAIN OUTCOME MEASURES: the number of asymptomatic or paucisymptomatic COVID-19 patients and the number of contacts/cohabitants of COVID-19 patients enrolled in the Protect study from May to September 2020. RESULTS: from May to September 2020, the number of patients diagnosed with COVID-19 enrolled in the PROTECT clinical trial showed a decrease consistent with the number of news on hydroxychloroquine appearing in the national and local press, starting from the time when the first criticisms of the efficacy of hydroxychloroquine were made known; the number of contacts/cohabitants of COVID-19 patients showed a more marked and more timely decrease. CONCLUSIONS: in the context determined by the current COVID-19 pandemic, conducting a controlled clinical trial is strongly influenced by public opinion on scientific issues. Adherence to a clinical study can become highly problematic and invalidate the possibility of answering a scientific question and the validity of a project. In the current pandemic situation, randomized controlled trials may not always be the optimal tool to reach the expected scientific evidence, due to a number of problems. It is preferable to use a sequential or adaptive design. Furthermore, study protocols should implement innovative approaches that also include the involvement of participants in the decision-making process. In any case, the influence of public information on scientific issues is an extremely important factor to consider in the design of clinical trials in exceptional situations such as a pandemic.

Three-dimensional collagen-based scaffold model to study the microenvironment and drug-resistance mechanisms of oropharyngeal squamous cell carcinomas.

OBJECTIVE: Squamous cell carcinoma (SCC) represents the most common histotype of all head and neck malignancies and includes oropharyngeal squamous cell carcinoma (OSCC), a tumor associated with different clinical outcomes and linked to human papilloma virus (HPV) status. Translational research has few available in vitro models with which to study the different pathophysiological behavior of OSCCs. The present study proposes a 3-dimensional (3D) biomimetic collagen-based scaffold to mimic the tumor microenvironment and the crosstalk between the extracellular matrix (ECM) and cancer cells. METHODS: We compared the phenotypic and genetic features of HPV-positive and HPV-negative OSCC cell lines cultured on common monolayer supports and on scaffolds. We also explored cancer cell adaptation to the 3D microenvironment and its impact on the efficacy of drugs tested on cell lines and primary cultures. RESULTS: HPV-positive and HPV-negative cell lines were successfully grown in the 3D model and displayed different collagen fiber organization. The 3D cultures induced an increased expression of markers related to epithelial-mesenchymal transition (EMT) and to matrix interactions and showed different migration behavior, as confirmed by zebrafish embryo xenografts. The expression of hypoxia-inducible factor 1α (1α) and glycolysis markers were indicative of the development of a hypoxic microenvironment inside the scaffold area. Furthermore, the 3D cultures activated drug-resistance signaling pathways in both cell lines and primary cultures. CONCLUSIONS: Our results suggest that collagen-based scaffolds could be a suitable model for the reproduction of the pathophysiological features of OSCCs. Moreover, 3D architecture appears capable of inducing drug-resistance processes that can be studied to better our understanding of the different clinical outcomes of HPV-positive and HPV-negative patients with OSCCs.

First prospective data on breast cancer patients from the multicentre italian bone metastasis database.

Bone metastases (BM) are still the main cause of morbidity in cancer patients because of skeletal-related events (SREs) that reduce quality of life. They have also led to increased social and healthcare costs. At present, data available on BM are insufficient. This was a multicentre prospective observational study of patients with BM from breast cancer (BC) with at least 6 months' follow-up. Information on patients at the first diagnosis of BM, including demographics and characteristics of the primary tumor and BM. Data were periodically updated by participating centres and reviewed by the coordinator centre. From October 2014 to July 2019, 618 patients with BM from solid tumors were enrolled and 220 were eligible for the present study. Median age was 62 years (range 26-86). Median follow-up was 34 months (range 6-149). At the time of enrolment, 109 (50%) had only BM (BOM) and 109 (50%) had concomitant visceral lesions and BM (BVM). Median time-to-first BM was 47 months (range 0-312) in BOM and 78.6 months in BVM patients. Disease-free interval differed on the basis of BC molecular subtype and stage. Ninety-eight BM patients had at least on SRE. Zoledronate was used in 69.1% of cases and denosumab in 28.3%. First-line treatment was hormone-based (50.7%), chemotherapy-based (38.7%) or chemotherapy- + hormone therapy-based (9.7%). Median progression-free and overall survival were 15.1 months (95% CI 12.6-18.4) and 66.8 months (95% CI 52.1-79.2), respectively. Our prospective study could substantially help to better understand the natural history of BM from BC.

Induction chemotherapy plus concomitant chemoradiotherapy in nasopharyngeal carcinoma: An updated network meta-analysis.

BACKGROUND: Induction chemotherapy (IC) added to concurrent chemoradiotherapy (CCRT) appears to be superior to CCRT alone for locally-advanced nasopharyngeal carcinoma (NPC). The main objective of this network meta-analysis (NMA) was to assess the impact of different IC regimens on patient outcome. PATIENTS AND METHODS: We systematically searched and extracted data from randomized, controlled trials involving stage III-IV NPC patients randomly assigned to receive IC + CCRT vs. CCRT alone. Overall survival (OS), locoregional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) in the two arms were compared using hazard ratios (HRs). RESULTS: Eight clinical trials were identified including 2362 patients. OS-benefit from doublet IC regimens, in particular platinum-docetaxel and platinum-gemcitabine regimens, was seen. With regard to LRFS, docetaxel-platinum-5FU regimen showed a greater impact than the others. An indirect comparison between taxane- and gemcitabine-based IC regimens showed a benefit of the latter in terms of OS and DMFS. CONCLUSIONS: Although CCRT with cisplatin has been the gold standard of treatment in NPC for several years. Docetaxel + cisplatin-IC and cisplatin + gemcitabine-IC regimens have a positive impact on survival in locally-advanced NPC and should be considered the new standard option.