Technical and Functional Validation of a Teleoperated Multirobots Platform for Minimally Invasive Surgery

Nowadays Robotic assisted Minimally Invasive Surgeries (R-MIS) are the elective procedures for treating highly accurate and scarcely invasive pathologies, thanks to their abil- ity to empower surgeons\u2019 dexterity and skills. The research on new Multi-Robots Surgery (MRS) platform is cardinal to the development of a new SARAS surgical robotic platform, which aims at carrying out autonomously the assistants tasks during R- MIS procedures. In this work, we will present the SARAS MRS platform validation protocol, framed in order to assess: (i) its technical performances in purely dexterity exercises, and (ii) its functional performances. The results obtained show a prototype able to put the users in the condition of accomplishing the tasks requested (both dexterity- and surgical-related), even with rea- sonably lower performances respect to the industrial standard. The main aspects on which further improvements are needed result to be the stability of the end effectors, the depth per- ception and the vision systems, to be enriched with dedicated virtual fixtures. The SARAS\u2019 aim is to reduce the main surgeon\u2019s workload through the automation of assistive tasks which would benefit both surgeons and patients by facilitating the surgery and reducing the operation time

Differential Gene Expression Patterns of EBV Infected EBNA-3A Positive and Negative Human B Lymphocytes

The genome of Epstein-Barr virus (EBV) encodes 86 proteins, but only a limited set is expressed in EBV–growth transformed B cells, termed lymphoblastoid cell lines (LCLs). These cells proliferate via the concerted action of EBV nuclear antigens (EBNAs) and latent membrane proteins (LMPs), some of which are rate limiting to establish a stable homeostasis of growth promoting and anti-apoptotic activities. We show here that EBV mutants, which lack the EBNA-3A gene, are impaired but can still initiate cell cycle entry and proliferation of primary human B cells in contrast to an EBNA-2 deficient mutant virus. Surprisingly, and in contrast to previous reports, these viral mutants are attenuated in growth transformation assays but give rise to permanently growing EBNA-3A negative B cell lines which exhibit reduced proliferation rates and elevated levels of apoptosis. Expression profiles of EBNA-3A deficient LCLs are characterized by 129 down-regulated and 167 up-regulated genes, which are significantly enriched for genes involved in apoptotic processes or cell cycle progression like the tumor suppressor gene p16/INK4A, or might contribute to essential steps of the viral life cycle in the infected host. In addition, EBNA-3A cellular target genes remarkably overlap with previously identified targets of EBNA-2. This study comprises the first genome wide expression profiles of EBNA-3A target genes generated within the complex network of viral proteins of the growth transformed B cell and permits a more detailed understanding of EBNA-3A's function and contribution to viral pathogenesis

Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study

BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib. METHODS: This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination. RESULTS: Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs. CONCLUSIONS: Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST. TRIAL REGISTRATION NUMBER: NCT01468688.status: publishe

The STIMULUS Program: Clinical Trials Evaluating Sabatolimab (MBG453) Combination Therapy in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS) or Acute Myeloid Leukemia (AML)

Background: Therapy options for pts with HR-MDS or AML who are not candidates for intensive chemotherapy (IC) or hematopoietic stem cell transplantation (HSCT) are limited, and clinical outcomes are poor. Novel, effective and tolerable therapies are urgently needed. TIM-3 is an inhibitory receptor that regulates both adaptive and innate immune responses. It is expressed on immune cells and on leukemic stem cells (LSCs) and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS and AML. Sabatolimab is a high-affinity, humanized, anti-TIM-3 IgG4 (S228P) antibody that simultaneously targets TIM-3 on immune and myeloid cells; this may restore immune function while also directly targeting LSCs and blasts. In preclinical studies, sabatolimab enhanced immune cell-mediated killing of AML cells in vitro. In early results from a ph 1b study (NCT03066648), sabatolimab + hypomethylating agents (HMAs; decitabine [Dec] or azacitidine [Aza]) demonstrated encouraging overall response rates in pts with high-/very high-risk MDS (+ Dec, 61%; + Aza, 57%) and newly diagnosed AML (+ Dec, 47%; + Aza, 29%), and a favorable safety profile. Study Design and Methods: The STIMULUS clinical trial program currently includes 3 trials evaluating the efficacy and safety of sabatolimab combination therapy in pts with HR-MDS or AML who are ineligible for IC or HSCT: STIMULUS-MDS1 (NCT03946670; ph 2) in pts with HR-MDS, STIMULUS-MDS2 (NCT04266301; ph 3) in pts with HR-MDS or chronic myelomonocytic leukemia-2 (CMML-2), and STIMULUS-AML1 (NCT04150029; ph 2) in pts with AML. STIMULUS-MDS1 is a randomized, double-blind, placebo-controlled ph 2 study evaluating the addition of sabatolimab to HMA in pts with HR-MDS. The 2 primary endpoints are complete remission (CR) rate and/or progression-free survival. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival, duration of CR, transfusion independence, safety, pharmacokinetics (PK), and immunogenicity. Approximately 120 pts will be randomized 1:1 to receive sabatolimab 400 mg or placebo IV Q2W (D8 and D22 of each 28-d cycle), + Dec 20 mg/m2 IV on D1-D5 or Aza 75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9, of each 28-d cycle. STIMULUS-MDS2 is a randomized, double-blind, placebo-controlled ph 3 study of sabatolimab in combination with Aza in pts with HR-MDS or CMML-2; the primary endpoint is OS. Secondary endpoints include measures related to pt quality of life, such as time to definitive deterioration of fatigue, improvement of fatigue, transfusion-free intervals, and physical/emotional functioning, as well as additional efficacy and safety parameters. Approximately 500 pts will be randomized 1:1 to sabatolimab 800 mg or placebo IV Q4W at D8 of each 28-d cycle + Aza using the same Aza dosing schedule as in STIMULUS-MDS1. Eligible pts for STIMULUS-MDS1 or -MDS2 are treatment-naïve adults with HR-MDS (Revised International Prognostic Scoring System [IPSS-R] intermediate-/high-/very high-risk MDS). Pts with intermediate-risk MDS enrolling in STIMULUS-MDS1 are also required to have ≥5% bone marrow blasts at baseline. Pts with CMML-2 are eligible for STIMULUS-MDS2 only. STIMULUS-AML1 is a single-arm ph 2 study evaluating the safety and efficacy of sabatolimab in combination with Aza and venetoclax in pts with AML who are not candidates for IC or HSCT. Primary endpoints are incidence of dose-limiting toxicities (safety run-in) and CR rate. Secondary endpoints include safety and tolerability, CR/CRi rate, measurable residual disease-negative rate, durability of CR, relapse-free survival, EFS, OS, PK, transfusion independence, and immunogenicity. Eligible pts for STIMULUS-AML1 are adults with newly diagnosed AML who are not candidates for IC or HSCT, based on comorbidities (including renal and hepatic impairments, cardiac and pulmonary comorbidities), age (≥75 years old), or Eastern Cooperative Oncology Group performance status of 2 or 3. STIMULUS-AML1 will enroll approximately 86 pts. Part 1 consists of a safety run-in (≈18 pts) across 2 escalating sabatolimab dose levels (400/800 mg IV Q4W on D8 of each 28-d cycle) in combination with Aza (75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9) and venetoclax 400 mg PO QD. If this triple combination is assessed to be safe, part 2 (expansion) will open and enroll approximately 68 additional pts who will receive sabatolimab 800 mg Q4W in combination with Aza and venetoclax. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kim:SL VaxiGen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; BL&H: Research Funding; Sanofi Genzyme: Honoraria; Abbvie: Honoraria. Miyazaki:Novartis Pharma KK: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Platzbecker:Amgen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Malek:Novartis: Current Employment. Scott:Novartis: Current Employment. Niolat:Novartis: Current Employment. Peyrard:Novartis: Current Employment. Ma:Novartis: Current Employment. Kiertsman:Novartis: Current Employment. Stegert:Novartis AG: Current Employment, Current equity holder in publicly-traded company. Hertle:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria

Effect of Hospital and Surgeon Case Volume on Perioperative Quality of Care and Short-term Outcomes After Radical Cystectomy for Muscle-invasive Bladder Cancer: Results From a European Tertiary Care Center Cohort

This prospective multicenter study analyzed the effect of hospital and surgeon case volume on perioperative quality of care and short-term complications and mortality in 479 patients undergoing radical cystectomy for bladder cancer. We found that hospital volume might represent an at least equally important factor regarding postoperative complications as the surgeon case volume itself at European tertiary care centers. Background Case volume has been suggested to affect surgical outcomes in different arrays of procedures. We aimed to delineate the relationship between case volume and surgical outcomes and quality of care criteria of radical cystectomy (RC) in a prospectively collected multicenter cohort. Patients and Methods This was a retrospective analysis of a prospectively collected European cohort of patients with bladder cancer treated with RC in 2011. We relied on 479 and 459 eligible patients with available information on hospital case volume and surgeon case volume, respectively. Hospital case volume was divided into tertiles, and surgeon volume was dichotomized according to the median annual number of surgeries performed. Binomial generalized estimating equations controlling for potential known confounders and inter-hospital clustering assessed the independent association of case volume with short-term complications and mortality, as well as the fulfillment of quality of care criteria. Results The high-volume threshold for hospitals was 45 RCs and, for high-volume surgeons, was > 15 cases annually. In adjusted analyses, high hospital volume remained an independent predictor of fewer 30-day (odds ratio, 0.34; P = .002) and 60- to 90-day (odds ratio, 0.41; P = .03) major complications but not of fulfilling quality of care criteria or mortality. No difference between surgeon volume groups was noted for complications, quality of care criteria, or mortality after adjustments. Conclusion The coordination of care at high-volume hospitals might confer a similar important factor in postoperative outcomes as surgeon case volume in RC. This points to organizational elements in high-volume hospitals that enable them to react more appropriately to adverse events after surgery. (C) 2017 Elsevier Inc. All rights reserved