Search

Background: Metastatic Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors characterized by high morbidity and limited systemic treatment options, mainly based on radiometabolic treatments or chemotherapy. Based on the preclinical rationale that PGGLs carcinogenesis relies on angiogenesis, treatment with tyrosine kinase inhibitors (TKI) may represent another viable therapeutic option., Methods: We conducted a prospective phase II study in patients with metastatic or unresectable PGGLs. Patients received sunitinib (50 mg daily for 4 weeks, followed by a 2-week rest period) until progressive disease (PD), unacceptable toxicity or consent withdrawal. The primary endpoint was 12-month progression-free survival (PFS) rate; secondary endpoints were safety overall response rate (ORR) according to RECIST 1.1 criteria and overall survival (OS). EudraCT Number: 2011-002632-99., Results: Fifty patients were included. At a median follow-up of 71.7 months (IQR 35.4-100.1), the 1 year-PFS rate was 53.4 % (95 %CI 41.1-69.3) and median PFS was 14.1 months (95 % CI 8.9-25.7). ORR was 15.6 %, the median OS was 49.4 months (95 %CI 21.2-NA), and grade 3 or higher treatment-related adverse events were reported in 34 % patients. No significant correlation was found between specific genetic alterations or genomic clusters and sunitinib efficacy., Conclusion: Sunitinib is an active drug in patients with advanced PGGLs, capable of inducing prolonged disease control with a manageable toxicity profile., Competing Interests: Declaration of Competing Interest All other authors declared no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. The RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC., Patients and Methods: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment-naïve advanced TC. They received ramucirumab, carboplatin and paclitaxel for six cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was objective response rate (ORR) according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Centralized radiologic review was carried out., Results: From November 2018 to June 2023, 52 patients were screened and 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. The Eastern Cooperative Oncology Group performance status was 0 in 68.5% and 1 in 31.4% of patients. At the present analysis carried out some months after the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95% confidence interval (CI) 63.1% to 91.6%]. At the centralized radiological review of 33/35 assessable patients, ORR was 57.6% (95% CI 39.2% to 74.5%). After a median follow-up of 31.6 months, median PFS was 18.1 months (95% CI 10.8-52.3 months) and median OS was 43.8 months (95% CI 31.9 months-not reached). Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE ≥ grade 3., Conclusions: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To investigate the activity of regorafenib in advanced solitary fibrous tumour (SFT)., Methods: An Italian monocentric investigator-initiated exploratory single-arm Phase II trial was conducted of regorafenib in adult patients with advanced and progressive SFT, until progression or limiting toxicity. Prior treatment with antiangiogenics was allowed. Primary and secondary end-points were: overall response rate (ORR) by Choi criteria, and ORR by RECIST, progression-free survival (PFS), overall survival (OS)., Results: From January 2016 to February 2021, 18 patients were enroled [malignant-SFT = 13; dedifferentiated-SFT (D-SFT) = 4; typical-SFT (T-SFT) = 1]. Fourteen patients were pre-treated, in 12 cases with antiangiogenics (median [m-] lines of treatment = 3). Sixteen patients were evaluable for response (one screening failure; one early discontinuation). Six/16 (35.2%) required a definitive dose reduction. ORR by Choi was 37.5% (95% CI: 15.2-64.6), with 6/16 (37.5%) partial responses (PR), 6/16 (37.5%) stable disease (SD) and 4/16 (25%) progressions; 5/6 responses occurred in patients pre-treated with antiangiogenics. No responses were detected in D-SFT. Best RECIST responses were: 1/16 (6.2%) PR, 12/16 (75%) SD, 3/16 (18.8%) progressions. At 48.4 month m-FU, m-PFS by Choi was 4.7 (inter-quartile range: 2.4-13.1) months, with 31.2% patients progression-free at 1 year., Conclusion: Regorafenib showed activity in SFT, with 30% patients free-from-progression at one year. Responses were observed also in patients pretreated and refractory to another antiangiogenic agents. However, ORR and m-PFS were lower than reported with other antiangiogenics, and this was possibly due to discrepancies in the patient population and the high-rate of dose reductions., Competing Interests: Declaration of Competing Interest SS: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: personal financial interests (honoraria, consultancy or advisory role): Aadi, Astex Pharmaceuticals, Bavarian Nordic, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Deciphera, Epizyme, Gentili, GSK, Agenus, Ikena, MaxiVAX, Novartis, PharmaMar, Pharma Essentia, Rain Therapeutics, Servier. Support for attending meetings and/or travel Pharmamar; Institutional financial interests: Advenchen, Bayer, Blueprint, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, GSK, Hutchinson, Inhibrx, Karyopharm, Novartis, PharmaMar, Rain Therapeutics, SpringWorks; unpaid Member of the Scientifc Advisory Board of the Chordoma Foundation, Member of the Scientifc Advisory Board of the Desmoid Foundation, Member of the Scientifc Advisory Board of the Epithelioid Hemangioendothelioma Group, Member of the Scientifc Advisory Board of the Leiomyosarcoma Foundation. GGB: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: consulting fees from Eli Lilly, Pharmamar, AboutEvents; honoraria from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai, Istituto Gentili; support for attending meetings and/or travels from Novartis, Pharmamar, Eli Lilly; participation on advisory board from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai. AMF: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma. Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. CM: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: no COIs to declare. FGG: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: no COIs to declare. PC: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: no COIs to declare. MB: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: no COIs to declare. GPD: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: no COIs to declare. NZ: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: institutional research funding from Ikena Oncology, Astex therapeutics. SP: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: institutional research funding from Ikena Oncology, Pharmamar, Astex therapeutics. AG: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: compensations for advisory boards from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, Boehringer Ingelheim; Honoraria from Deciphera; Research grants from PharmaMar and Nanobiotix. PH: Patent patient stratification methods for antiangiogenic agents (Patent number: EPS3665307B1). MI: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. GT: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: no COIs to declare. RM: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: no COIs to declare. PGC: related to the submitted work: Bayer Institutional financial interest; outside the submitted work: institutional research funding from Advenchen Laboratories, Amgen Dompé , AROG Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Thymic malignancies are rare tumors with few therapeutic options. The STYLE trial was aimed to evaluate activity and safety of sunitinib in advanced or recurrent type B3 thymoma (T) and thymic carcinoma (TC)., Methods: In this multicenter, Simon 2 stages, phase 2 trial, patients with pretreated T or TC were enrolled in two cohorts and assessed separately. Sunitinib was administered 50 mg daily for 4 weeks, followed by a 2-week rest period (schedule 4/2), until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Progression-free survival, overall survival, disease control rate and safety were secondary endpoints., Results: From March 2017 to January 2022, 12 patients with T and 32 patients with TC were enrolled. At stage 1, ORR was 0% (90% confidence interval [CI]: 0.0-22.1) in T and 16.7% (90% CI: 3.1-43.8) in TC, so the T cohort was closed. At stage 2, the primary endpoint was met for TC with ORR of 21.7% (90% CI: 9.0%-40.4%). In the intention-to-treat analysis, disease control rate was 91.7% (95% CI: 61.5%-99.8%) in Ts and 89.3% (95% CI: 71.8%-97.7%) in TCs. Median progression-free survival was 7.7 months (95% CI: 2.4-45.5) in Ts and 8.8 months (95% CI: 5.3-11.1) in TCs; median overall survival was 47.9 months (95% CI: 4.5-not reached) in Ts and 27.8 months (95% CI: 13.2-53.2) in TCs. Adverse events occurred in 91.7% Ts and 93.5% TCs. Grade 3 or greater treatment-related adverse events were reported in 25.0% Ts and 51.6% TCs., Conclusions: This trial confirms the activity of sunitinib in patients with TC, supporting its use as a second-line treatment, albeit with potential toxicity that requires dose adjustment., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to investigate changes in volume and MRI T2-weighted intensity in desmoid-type fibromatosis (DF) receiving methotrexate plus vinca-alkaloids (MTX-VA) at Istituto Nazionale dei Tumori, Milan., Methods: All cases of sporadic DF treated with MTX-VA from 1999 to 2019 were reviewed. MRIs at baseline, 6 and 12 months of chemotherapy and at treatment withdrawal were retrospectively reviewed, contouring the tumor lesion and measuring diameters, volume, and mean T2-signal intensity (normalized to muscle) changes. These parameters were also evaluated according to clinical variables., Results: Thirty-two DF patients were identified. Best RECIST response was: 25% partial response, 69% stable disease, 6% progression. A ≥65% tumor volume reduction was observed in 38%, <65% reduction in 53%, an increase in 9%. 22% had RECIST stable disease with a ≥65% tumor volume reduction. T2-signal intensity decreased by ≥50% in 47%, <50% in 41% and increased in 12%. In patients with symptomatic improvement while on therapy and in patients maintaining symptomatic improvement during follow-up, median T2-signal intensity showed a reduction along the time points (3.0, 1.9, 1.2, 1.1; 2.9, 2.0, 1.2, 1.2, respectively); in patients without symptomatic improvement and in those clinically progressing during follow-up, a reduction was not observed. High T2-signal intensity at baseline was observed in patients showing RECIST progression during follow-up., Conclusions: In this series, RECIST detected a lower proportion of responses as compared to volumetric and T2-signal changes. T2-signal reduction seemed to better reflect symptomatic improvement. High T2-signal intensity at baseline was related to a higher proportion of further progression., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network., Methods: From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method., Results: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction., Conclusions: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup., (© 2020 American Cancer Society.)

Background: In patients with metastatic colorectal cancer (mCRC) receiving highly active first-line combination treatments, early tumor shrinkage (ETS) and depth of response (DoR) are associated with survival, but their influence on outcomes during maintenance therapy is unknown. The Valentino study showed inferior PFS in 229 RAS wild-type mCRC patients randomized to panitumumab plus FOLFOX followed by maintenance with panitumumab vs. panitumumab + 5-FU/LV., Patients and Methods: After blinded independent central review of ETS (≥20% reduction of the sum of target lesions) and DoR in patients enrolled in Valentino, the prognostic and predictive role of such parameters was investigated, along with their combination with PRESSING panel (uncommon genomic alterations associated with anti-EGFRs resistance beyond RAS and BRAF)., Results: One hundred and ninety-six patients were included (ETS in 132 [67.3%], median DoR: 44.1%). Both ETS and DoR ≥34% were associated with longer mPFS (p = 0.010 and p < 0.001) and mOS (p = 0.006 and p < 0.001). The PFS benefit of 5-FU/LV added to panitumumab maintenance, reported in the study, was independent from ETS and DoR status (interaction tests NS for both PFS and OS). However, outcomes were extremely poor in patients who received single-agent panitumumab and had no-ETS (mPFS and mOS: 7.7 and 18.7 months) or DoR < 34% (mPFS and mOS: 6.5 and 18 months). Combining PRESSING panel ('molecular hyperselection') and response dynamics allowed to stratify both PFS (p < 0.001 and p < 0.001 for ETS and DoR, respectively) and OS (p < 0.001 and p = 0.017 for ETS and DoR, respectively)., Conclusions: ETS and DoR allow on-treatment anticipation of outcomes following an anti-EGFR-based strategy planning de-escalation, and poor radiological response may guide enrolment in crossover strategy trials. As in vivo markers of drug sensitivity, ETS and DoR may be integrated with several patient- and tumor-related factors to wisely drive decision-making on upfront treatment duration and intensity., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Declaration of interests: FP has received honoraria for speaker activities and participation in advisory boards from Sanofi, Amgen, Bayer, Merck-Serono, Lilly, Roche, Servier, and research grants from BMS. SL has received honoraria for speaker activities and participation in advisory boards from Amgen, Bayer, Merck-Serono, Roche, Servier, Bristol-Myers Squibb. CC has received honoraria for speaker activities and participation in advisory boards from Roche, Amgen, Bayer, Servier, Merck-Serono and research grants from Merck Serono. LR has received honoraria for speaker activities and participation in advisory boards from AstraZeneca, AbbVie, Amgen, ArQule, Basilea, Bayer, Celgene, Eisai, Exelixis, Gilead, Hengrui Therapeutics, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Nerviano Medical Sciences, Roche, Sanofi, and research grants to her Institution from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Lilly, Exelixis, FibroGen, Incyte, Ipsen, Merck Sharp & Dohme. AZ has received honoraria for speaker activities and participation in advisory boards from Sanofi, Amgen, Bayer, Merck-Serono, Roche. PR has received honoraria for speaker activities and participation in advisory boards from Servier, Amgen, Roche and Merck. MDB has received honoraria for speaker activities and participation in advisory boards from Amgen, Roche, Lilly, Servier, MSD. FM has received honoraria for speaker activities from Servier. FDB has received honoraria for speaker activities and participation in advisory boards from Amgen, Roche, Novartis, Incyte, Celgene. All other authors declared no disclosures., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

To solve the problem of vascular access failure, a novel semi-degradable hybrid vascular graft, manufactured by electrospinning using silk fibroin and polyurethane (Silkothane), has been previously developed and characterized in vitro. This proof-of-concept animal study aims at evaluating the performances of Silkothane grafts in a sheep model of arteriovenous shunt, in terms of patency and short-term remodeling. Nine Silkothane grafts are implanted between the common carotid artery and the external jugular vein of nine sheep, examined by palpation three times per week, by echo-color Doppler every two weeks, and euthanized at 30, 60, and 90 days (N = 3 per group). At sacrifice, grafts are harvested and submitted for histopathology and/or scanning electron microcopy (SEM). No cases of graft-related complications are recorded. Eight of nine sheep (89%) show 100% primary unassisted patency at the respective time of sacrifice (flow rate 1.76 ± 0.61 L min -1 , one case of surgery-related thrombosis excluded). Histopathology and SEM analysis evidence signs of inflammation and pseudointima inside the graft lumen, especially at the venous anastomosis; however, endoluminal stenosis never impairs the functionality of the shunt and coverage by endothelial cells is observed. In this model, Silkothane grafts grant safety and 100% patency up to 90 days., (© 2020 Wiley-VCH GmbH.)

Objectives: Giant cell tumour of bone (GCTB) is a rare tumour, generally managed with surgery. Treatment of the very rare unresectable advanced/metastatic GCTB is challenging and denosumab is the only current available medical option, an anti-RANKL monoclonal antibody inhibiting osteolysis. An uncommon but severe and treatment-limiting adverse event of denosumab is the osteonecrosis of the jaw (ONJ). The clinical management of GCTB patients stopping denosumab for medication-related (MR)-ONJ and the possible reintroduction of denosumab after MR-ONJ resolution is matter of debate. We performed a retrospective study to describe the incidence, clinical features and outcome of MR-ONJ in unresectable GCTB patients treated with denosumab at our Institution., Design and Setting: Retrospective, single-institutional study., Participants: Adult patients receiving denosumab as antineoplastic therapy for GCTB and experiencing MR-ONJ at Fondazione IRCCS Istituto Nazionale Tumori of Milan between January 2008 and July 2019., Main Outcome Measures: Incidence, time of onset and clinical features of MR-ONJ., Results: 29 patients with locally advanced and/or metastatic GCTB treated with denosumab were identified. At a median follow-up of 70 months (range 1-125), 4 (13.8%) patients experienced MR-ONJ while on treatment, after 125, 119, 85 and 41 months of denosumab, respectively. All patients showed an ongoing tumour stabilisation with denosumab at the MR-ONJ onset and in all cases denosumab was stopped. All four patients were treated with ozone therapy. Two are waiting for surgery, two were already operated on. Both of them experienced disease progression and were thus rechallenged with denosumab. One is still on therapy after 25 months. The other had an MR-ONJ relapse after 39 months and was treated again with ozone therapy and surgery. She is under surveillance, GCTB being currently stable., Conclusion: A clinical algorithm of denosumab rechallenge after complete resolution of MR-ONJ in progressing GCTB patients should be prospectively validated., Competing Interests: Competing interests: SS, AMF, AR, NS: institutional research funding from Pfizer, Novartis, Glaxo. PGC: grants and personal fees from Bayer, Glaxo, Novartis., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: Age, sex, stage, histotype, and surgery are the most recognized prognostic factors for malignant pleural mesothelioma (MPM). Tumor volume (TV) was suggested as an alternative prognostic evaluation. We aimed to assess the prognostic role of Tumor, Node, Metastases (TNM) versus TV and number of pleural sites (NPS)., Patients and Methods: Information on stage, TV, and NPS was collected for 52 MPM patients (pts) at our institution from 2009 to 2012. Baseline computed tomography imaging was performed to define TNM, TV, and NPS. Pts were divided in 3 stage groups: early (I-II), III, and IV. A dedicated computer system calculated TV. Pts were divided in 2 groups according to mean baseline TV (483 cm 3 ). NPS was defined on the basis of the NPS macroscopically involved by disease (1-3). The association between TNM, tumor size (T), TV, NPS, TV and NPS, and overall survival was assessed using Cox models adjusted for age, sex, histology, and treatment., Results: Most pts were male; mean age was 62 years. We showed an association between TV, TNM, and T. Stage III (hazard ratio [HR], 4.71; P = .02) and IV (HR, 7.40; P < .01), T3 (HR, 5.07; P < .01) and T4 (HR, 5.09; P < .01), TV > 483 cm 3 (HR, 3.47; P < .01) and NPS 2 (HR, 3.00; P = .08) and 3 (HR, 6.05; P < .01) were predictive of worse survival. However, the TV and NPS combination performed better than TV, NPS, and TNM alone as a prognostic classifier., Conclusion: We showed that TV is related to TNM staging and T, in particular. Improved prognostic performance might be achievable using quantitative clinical staging combining TV and NPS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Several attempts made so far to combine silk fibroin and polyurethane, in order to prepare scaffolds encompassing the bioactivity of the former with the elasticity of the latter, suffer from critical drawbacks concerning industrial and clinical applicability (e.g., separation of phases upon processing, use of solvents unaddressed by the European Pharmacopoeia, and use of degradable polyurethanes). Overcoming these limitations, in this study, we report the successful blending of regenerated silk fibroin with a medical-grade, non-degradable polyurethane using formic acid and dichloromethane, and the manufacturing of hybrid, semi-degradable electrospun tubular meshes with different ratios of the two materials. Physicochemical analyses demonstrated the maintenance of the characteristic features of fibroin and polyurethane upon solubilization, blending, electrospinning, and postprocessing with ethanol or methanol. Envisioning their possible application as semidegradable substrates for haemodialysis arteriovenous grafts, tubular meshes were further characterized, showing submicrometric fibrous morphologies, tunable mechanical properties, permeability before and after puncture in the same order of magnitude as commercial grafts currently used in the clinics. Results demonstrate the potential of this material for the development of hybrid, new-generation vascular grafts with disruptive potential in the field of in situ tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 807-817, 2019., (© 2018 Wiley Periodicals, Inc.)

Clinically available alternatives of vascular access for long-term haemodialysis-currently limited to native arteriovenous fistulae and synthetic grafts-suffer from several drawbacks and are associated to high failure rates. Bioprosthetic grafts and tissue-engineered blood vessels are costly alternatives without clearly demonstrated increased performance. In situ tissue engineering could be the ideal approach to provide a vascular access that profits from the advantages of vascular grafts in the short-term (e.g. early cannulation) and of fistulae in the long-term (e.g. high success rates driven by biointegration). Hence, in this study a three-layered silk fibroin/polyurethane vascular graft was developed by electrospinning to be applied as long-term haemodialysis vascular access pursuing a 'hybrid' in situ engineering approach (i.e. based on a semi-degradable scaffold). This Silkothane ® graft was characterized concerning morphology, mechanics, physical properties, blood contact and vascular cell adhesion/viability. The full three-layered graft structure, influenced by the polyurethane presence, ensured mechanical properties that are a determinant factor for the success of a vascular access (e.g. vein-graft compliance matching). The Silkothane ® graft demonstrated early cannulation potential in line with self-sealing commercial synthetic arteriovenous grafts, and a degradability driven by enzymatic activity. Moreover, the fibroin-only layers and extracellular matrix-like morphology, presented by the graft, revealed to be crucial in providing a non-haemolytic character, long clotting time, and favourable adhesion of human umbilical vein endothelial cells with increasing viability after 3 and 7 d. Accordingly, the proposed approach may represent a step forward towards an in situ engineered hybrid vascular access with potentialities for vein-graft anastomosis stability, early cannulation, and biointegration.

Background: To explore the activity of axitinib in advanced solitary fibrous tumour (SFT)., Patients and Methods: In this investigator-driven phase II study on axitinib in advanced and progressive SFT, patients received axitinib, 5 mg bis in day (BID), until progression or limiting toxicity. Pathologic diagnosis was centrally reviewed, distinguishing malignant SFT (M-SFT) and high-grade/dedifferentiated SFT (HG/D-SFT) subtypes. The primary end-point was the overall response rate (ORR) by Choi criteria (Choi). Secondary end-points were response by Response Evaluation Criteria in Solid Tumours (RECIST), progression-free survival (PFS) and overall survival (OS)., Results: From April 2015 and October 2017, 17 eligible patients entered the study (metastatic: 17; SFT subtype: 13 M-SFT, 4 HG/D-SFT; prior treatment: 9 antiangiogenics, 5 cytotoxics). All patients were evaluable for response. The best Choi response was seven partial response (PR) (ORR, 41.2%), six stable disease (SD) and four progressions. Choi-ORR was 54% (7/13) when only M-SFTs were considered. Four of seven responsive patients were pretreated with pazopanib. No responses were detected in HG/D-SFT. Best RECIST response was one PR (5.9%), 14 SD and two progressions. Toxicity was as expected. Median Choi-PFS was 5.1 (interquartile range [IQR]: 2.5-14.8) months. Median Choi-PFS was 14.8 (IQR: 5.1-18.0) and 2.8 (IQR: 2.0-5.9) months for patients responsive and non-responsive by Choi, respectively (p = 0.0416). At a 14.4-month median follow-up, median OS was 25.3 months., Conclusion: This study showed that axitinib is active in progressive advanced SFT. One-half of patients carrying the malignant variant of the disease responded, with a >12-month median progression arrest. Responses were better detected with Choi and seen even in patients resistant to other antiangiogenics. Tolerability was good., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The objectives of the study are to develop a new way to assess stability and discrimination capacity of radiomic features without the need of test-retest or multiple delineations and to use information obtained to perform a preliminary feature selection. Apparent diffusion coefficient (ADC) maps were computed from diffusion-weighted magnetic resonance images (DW-MRI) of two groups of patients: 18 with soft tissue sarcomas (STS) and 18 with oropharyngeal cancers (OPC). Sixty-nine radiomic features were computed, using three different histogram discretizations (16, 32, and 64 bins). Geometrical transformations (translations) of increasing entity were applied to the regions of interest (ROIs), and the intra-class correlation coefficient (ICC) was used to compare the features computed on the original and modified ROIs. The distribution of ICC values for minimal and maximal entity translations (ICC 10 and ICC 100 , respectively) was used to adjust thresholds of ICC (ICC min and ICC max ) used to discriminate between good, unstable (ICC 10 < ICC min ), and non-discriminative features (ICC 100 > ICC max ). Fifty-four and 59 radiomic features passed the stability-based selection for all the three histogram discretizations for the OPC and STS datasets, respectively. The excluded features were similar across the different histogram discretizations (Jaccard's index 0.77 ± 0.13 and 0.9 ± 0.1 for OPC and STS, respectively) but different between datasets (Jaccard's index 0.19 ± 0.02). The results suggest that the observed radiomic features are mainly stable and discriminative, but the stability depends on the region of the body under observation. The method provides a way to assess stability without the need of test-retest or multiple delineations.

Aim: To evaluate the effects of display pixel pitch and maximum luminance on intra- and inter-observer reproducibility and observer performance when evaluating chest lesions and bone fractures., Materials and Methods: This was a multi-institutional study for a retrospective interpretation of selected digital radiography images. Overall, 82 images were selected by senior radiologists, including 50 cases of chest lesions and 32 cases of bone fractures. These images were displayed at two pixel pitches (0.212 and 0.165 mm size pixels) and two maximum luminance values (250 and 500 cd/m 2 ) and reviewed twice by senior and junior radiologists. All the observers had to indicate the likelihood of the presence of the lesions and to rate the relative confidence of their assessment. Cohen Kappa statistic was computed to estimate the reproducibility in correctly identifying lesions; for multi-reader-multi-case (MRMC) analysis, weighted Jackknife Alternative Free-response Receiver Operating Characteristic (wJAFROC) statistical tools was applied., Results: The intra-radiologist and inter-observer reproducibility values were the highest for the 0.165 mm size pixel at 500 cd/m 2 display, for both chest lesions and bone fractures evaluations. As regards chest lesions, observer performances were significantly greater with 0.165 mm size pixel display at 500 cd/m 2 than with lower maximum luminance and/or larger pixel pitch displays. Concerning bone fractures, the performance obtained with 0.212 mm size pixel display at 250 cd/m 2 was statistically lower than that obtained with 0.165 mm sixe pixel display at 500 cd/m 2 ., Conclusion: Our results indicate that an increased maximum luminance level and a decreased pixel pitch of medical-grade display improve the accuracy of detecting both chest lesions and bone fractures.

Introduction: Bacterial resistance burden has increased in the past years, mainly due to inappropriate antibiotic use. Recently it has become an urgent public health concern due to its impact on the prolongation of hospitalization, an increase of total cost of treatment and mortality associated with infectious disease. Almost half of the antimicrobial prescriptions in outpatient care visits are prescribed for acute upper respiratory infections, especially rhinosinusitis, otitis media, and pharyngotonsillitis. In this context, otorhinolaryngologists play an important role in orienting patients and non-specialists in the utilization of antibiotics rationally and properly in these infections., Objectives: To review the most recent recommendations and guidelines for the use of antibiotics in acute otitis media, acute rhinosinusitis, and pharyngotonsillitis, adapted to our national reality., Methods: A literature review on PubMed database including the medical management in acute otitis media, acute rhinosinusitis, and pharyngotonsillitis, followed by a discussion with a panel of specialists., Results: Antibiotics must be judiciously prescribed in uncomplicated acute upper respiratory tract infections. The severity of clinical presentation and the potential risks for evolution to suppurative and non-suppurative complications must be taken into 'consideration'., Conclusions: Periodic revisions on guidelines and recommendations for treatment of the main acute infections are necessary to orient rationale and appropriate use of antibiotics. Continuous medical education and changes in physicians' and patients' behavior are required to modify the paradigm that all upper respiratory infection needs antibiotic therapy, minimizing the consequences of its inadequate and inappropriate use., (Copyright © 2018 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

The objective response is an important endpoint to evaluate clinical activity of new anticancer drugs. Standardized criteria for evaluating response are needed for comparing results of different trials and represent the basis for advances in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 are the most used in clinical practice and in clinical trials; however, they are not able to capture atypical responses seen with immunotherapy drugs. We describe the evolution of response criteria with a special focus on the immune-related criteria.

Purpose: To evaluate the diagnostic yield and complication rate of 2 different biopsy techniques (fine-needle aspiration, FNA, and core-needle biopsy, CNB) in the diagnosis of pulmonary lesions in 2 distinct periods, 2010-2012 and 2013-2015., Methods: We retrospectively analyzed the results of 691 CT-guided lung biopsies in 665 patients who were divided into 2 groups: cohort 1 (January 2010 to December 2012) was composed of 271 consecutive patients with 284 procedures either by FNA or CNB; cohort 2 (January 2013 to December 2015) was composed of 394 patients with 407 CNBs. Univariate and multivariate logistic regression modeling was used for selected outcomes including diagnostic yield, bleeding and pneumothorax., Results: Cohort 1 comprised 165 men and 106 women (mean age 68.5 years) with 180 FNAs and 104 CNBs; cohort 2 comprised 229 men and 165 women (mean age 66.4 years) with 407 CNBs. The diagnostic yield increased in cohort 2 with respect to cohort 1. There was a slight increase in CT procedure complications (pneumothorax and bleeding) from cohort 1 to cohort 2. The overall risk of complications was greater for lesions ≤20 mm and for lesions at >20 mm distance from the pleura., Conclusions: CT-guided CNB had a higher diagnostic yield than discretional use of either FNA or CNB; there was a slight but acceptable increase in complication rates.

Electrical Impedance Tomography (EIT) is an image reconstruction technique applied in medicine for the electrical imaging of living tissues. In literature there is the evidence that a large resistivity variation related to the differences of the human tissues exists. As a result of this interest for the electrical characterization of the biological samples, recently the attention is also focused on the identification and characterization of the human tissue, by studying the homogeneity of its structure. An 8 electrodes needle-probe device has been developed with the intent of identifying the structural inhomogeneities under the surface layers. Ex-vivo impeditivity measurements, by placing the needle-probe in 5 different patterns of fat and lean porcine tissue, were performed, and impeditivity maps were obtained by EIDORS open source software for image reconstruction in electrical impedance. The values composing the maps have been analyzed, pointing out a good tissue discrimination, and the conformity with the real images. We conclude that this device is able to perform impeditivity maps matching to reality for position and orientation. In all the five patterns presented is possible to identify and replicate correctly the heterogeneous tissue under test. This new procedure can be helpful to the medical staff to completely characterize the biological sample, in different unclear situations.

Aim: To assess the safety and efficacy of transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) using a new generation of 40 μm drug eluting beads in patients not eligible for curative treatment., Methods: Drug eluting bead TACE (DEB-TACE) using a new generation of microspheres (embozene tandem, 40 μm) preloaded with 100 mg of doxorubicin was performed on 48 early or intermediate HCC patients with compensated cirrhosis. Response to therapy was assessed with Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST) guidelines applied to computed tomography or magnetic resonance imaging. Eleven out of the 48 treated patients treated progressed on to receive liver orthotopic transplantation (OLT). This allowed for histological analysis on the treated explanted nodules., Results: DEB-TACE with 40 μm showed a good safety profile without major complications or 30-d mortality. The objective response rate of treated tumors was 72.6% and 26.7% according to mRECIST and RECIST respectively. Histological examination in 11 patients assigned to OLT showed a necrosis degree > 90% in 78.6% of cases. The overall time to progression was 13 mo (11-21)., Conclusion: DEB-TACE with 40 μm particles is an effective treatment for the treatment of HCC in early-intermediate patients (Barcelona Clinic Liver Cancer stage A/B) with a good safety profile and good results in term of objective response rate and necrosis., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose.

Lung cancer is one of the major causes of cancer related mortality worldwide. Brain metastases (BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 25-40% of cases, adversely influencing quality of life (QoL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. Nevertheless, the blood-brain barrier (BBB) makes central nervous system (CNS) a sanctuary site. To date, the combination of chemotherapy with whole brain radiation therapy (WBRT), surgery and/or stereotactic radiosurgery (SRS) represents the most used treatment for patients (pts) with intracranial involvement. However, due to their clinical conditions, many pts are not able to undergo local treatments. Targeted therapies directed against epidermal growth factor receptor (EGFR), such as gefitinib, erlotinib and afatinib, achieved important improvements in EGFR mutated NSCLC with favorable toxicity profile. Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC pts with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as osimertinib and rociletinib, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review we want to highlight literature data about the use and the effectiveness of EGFR-TKIs in pts with BM from NSCLC., Competing Interests: MC Garassino declares consultancies from AstraZeneca, Roche, Boehringer. The other authors have no conflicts of interest to declare.

Imaging makes a significant contribution to the diagnosis, prognosis and follow-up in sarcoidosis. Despite its increasing use, the role of computed tomography (CT) scanning in patients with known or suspected pulmonary sarcoidosis is still undefined. This review aims to compare the utility and limitations of chest radiograph and CT in patients with pulmonary sarcoidosis, with regards to the most critical clinical issues such as the diagnostic sensitivity, the differential diagnosis, and the prediction of the disease reversibility.

Introduction: The Tailgut cyst (cystic hamartoma) is an uncommon congenital disease of presacral retrorectal space and is embryologically part of some forms of enteric cysts. It is a benign malformation, although cases have been described in neoplastic degeneration., Presentation of Case: A caucasian 24 year old female presented shortly after childbirth with hypogastric abdominal discomfort associated with rectal tenderness, bleeding and moderate urinary symptoms for about three weeks. No previous similar episodes were reported. The patient was not suffering from haemorrhoids or inflammatory disease of the gastrointestinal tract. Clinical examination revealed no significant abnormalities or in the perianal area and gluteal surface. Digital rectal examination was suspicious of the presence of a presacral retrorectal mass. However, it could not exclude a trans-sphinteric perianal fistula. There was no fistulous communication with the exterior and the pain seemed to be more pronounced in the rectum. MRI, which has a diagnostic accuracy of 76-100% for the detection of any perianal fistulae, was performed and demonstrated the presence of a retrorectal cystic hamartoma (Tailgut cyst)., Discussion: The most common retrorectal space cystic lesions includes epidermoid cysts, dermoid cysts and enteric cysts. It presents with pelvic pain, and sometimes with local abscess, secondary to a sinus cyst. There can also be a communication between Tailgut cyst and fistula; in the absence of primary infection may develop postinflammatory fibrosis. Radiological investigation is carried out by TRUS, CT and MRI. During MRI, on T1-weighted images, the signal intensity may change from hypointense to hyperintense as protein concentration increases, as well as in the case of bleeding. On T2-weighted images, signal intensity of mucinous fluids can decrease from highly hyperintense to hypointense with increasing protein concentration and viscosity., Conclusion: MRI is a non-invasive useful imaging investigation with high diagnostic accuracy when a retrorectal cyst is suspected. Despite its rarity, Tailgut cyst should be considered, both for acute complications, like infection or bleeding, and for the risk, however infrequent, of neoplastic degeneration., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The article describes the epidemiologic profile of dengue cases in Vitória, the capital of Espírito Santo, Brazil, from 2000 to 2009, aimed at identifying risk groups regarding the incidence and severity of the disease., Methods: Confirmed cases of dengue among city residents during ten years were classified as dengue fever, dengue hemorrhagic fever, dengue shock syndrome and dengue with complications, and analyzed according to sex, age, race-color and education., Results: The proportion of dengue cases was highest among women aged 20 to 29 years-old and similar between whites and blacks. A gradual decrease occurred in the percentage of dengue cases in the population aged 15 years-old or more, in the historical series of 10 years, and a growing increase in individuals less than 15 years-old, showing statistical significance. The fatality rate ranged from zero to 0.3% for all forms of dengue and from 0.2% to 18.2% for severe forms., Conclusions: The profile of those affected by the disease in the municipality is similar to those affected in Brazil. The increasing number of cases in individuals under 15 years-old corroborates the results of recent studies in other Brazilian municipalities.