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BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status. ispartof: ANNALS OF ONCOLOGY vol:32 issue:9 pages:1127-1136 ispartof: location:England status: published

The reduction of CO2 and pollutant emissions of internal combustion engines (ICEs) keeping their performance close to the expectations is the main driver of the research in the transportation sector. To counteract the global warming issues international governments set strict emission limitations foreseeing severe penalties for exceeding them. The vehicle electrification surely helps to match these stringent requirements, but a net CO2 reduction can be achieved only if the electricity from the grid has low carbon content. This is not the case of most part of the Countries where the fossil fuels are still the main sources of electric energy production. Thus, considering also the still higher cost of the electric vehicles, the technological improvement of ICEs assumes a strategic importance in this transition period. Among the possible interventions ensuring to achieve this aim, the efficiency enhancement of ICE cooling pump is one of the most effective. As matter of fact, it is proven that the replacement of conventional centrifugal pump with Sliding Rotary Vane Pumps (SVRPs) lead to an interesting decrease of fuel consumption and CO2 emissions. Nevertheless, the design of this machines is not straightforward due to the complex thermo-fluid-dynamic phenomena taking place inside their chambers. This aspect is even more critical for wide operating range as in the case of heavy-duty vehicles. Here, high pump revolution speeds could be provided to satisfy the flow rate requirements thus involving efficiency deterioration due to friction losses enhancement. Therefore, to reduce the revolution speed needed by the pump to elaborate the required flow rate, a novel design strategy based on the enhancement of volumetric capability is presented. The pump resulting by this design approach was called Low Speed LS pump which was prototyped and experimentally characterized over a wide set of operating conditions. The indicated cycle was also measured to better assess the fluid-dynamic behaviour of the machine. The experimental results show a maximum efficiency close to 60% in accordance with the best literature results.

CO2 emissions related to the energy demand in commercial and residential buildings account for over 15% of worldwide greenhouse gases emissions. This issue requires the development of new solutions, technologies, and energy management strategies to reduce the environmental impact of this sector. Simultaneous heat and power production, namely cogeneration, is a proven method for this purpose. Among the different power systems, Organic Rankine Cycle (ORC) plants allow the production of mechanical and electric energy using hot sources at low temperature levels. This feature allows to combine this technology with solar collectors, making it possible to exploit the thermal energy exceeding the thermal needs when the solar irradiation is high. In this paper, an experimental characterization of a Solar Organic Rankine Cycle (SORC) is presented. The hot source of the power plant is reproduced by water heated up to 120 °C by two 12 kW electric resistances and stored in a buffer tank with a capacity of 200 L. The 1 kW ORC unit is equipped with a scroll volumetric expander operating off-grid. The main control variable of the unit is the pump speed which is varied in each operating condition to guarantee a superheating degree at the expander inlet. Since the variability of the solar source is a critical issue in these applications, off-design operating conditions have been tested, showing the capability of the plant to be also operated far from the design point. The maximum efficiency of the unit reached 4.7 % while the highest net power was 400 W. A further test conducted to evaluate the transient performances of the unit demonstrated its small inertia and the capability of the expander to produce power right after the unit activation.

Background: Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results. Patients and methods: We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged

Background The safety and efficacy outcome of elderly metastatic colorectal cancer (mCRC) patients fit enough to receive combination chemotherapy plus biological agents is an issue of growing interest. Also, gender-specific differential toxicity and efficacy of anti-epidermal growth factor receptor (EGFR)-based upfront treatments need to be explored. Patients and methods Valentino was a multicenter, randomized, phase II trial, investigating two panitumumab-based maintenance strategies following first-line panitumumab plus FOLFOX in RAS wild-type mCRC patients. We carried out a subgroup analysis, aimed at assessing the differences in efficacy, safety and quality of life (QoL) according to age (, Highlights • Anti-EGFR plus doublet chemotherapy followed by a maintenance strategy is a valuable upfront option in RAS wild-type mCRC. • Limited data are available on the safety and efficacy outcomes of elderly patients and according to patients’ gender. • In Valentino study, treatment efficacy was similar in patients aged

Purpose Because the role of the primary tumour location in the adjuvant setting has not been clearly established in colon cancer, we analysed the clinical outcome according to the primary tumour location from three Italian trials assessing adjuvant therapy in colon cancer. Patients and methods Overall survival (OS) and disease-free survival (DFS) were assessed globally and in each trial, according to right-sided, transverse and left-sided primary colon cancer. Analysis was planned to provide overall and stage-specific results. Results Individual data of 5239 patients were included in this analysis. The right-sided tumours were 1540 (29%), tumours originating in the transverse were 815 (16%) and left-sided tumours were 2884 (55%). At the multivariate analysis, DFS findings from the comparison of the right-sided versus left-sided tumours (hazard ratio [HR] = 1.00; 95% confidence interval [CI] = 0.89–1.14) were not statistically associated with clinical outcomes in the overall population. On the contrary, OS findings, from the comparison of the right-sided versus left-sided tumours, were significantly associated with outcomes (HR = 1.20; 95% CI = 1.04–1.39). In stage II patients, there was no difference in terms of DFS and OS among the three different tumour locations, whereas in stage III patients, the left-sided tumours showed an improved prognosis in terms of OS (HR: 1.36 95% CI = 1.14–1.62, p Conclusion This is the largest analysis demonstrating a prognostic effect of the tumour location on patients with colon cancer receiving adjuvant chemotherapy. Nevertheless, the effect is limited to OS in stage III colon cancer. In stage II tumours, the primary location has a lesser impact. The transverse tumours should be prognostically considered in between the right-sided and left-sided tumours.

Sliding Rotary Vane Expanders (SVRE) are widely used in ORC-based power units for waste heat recovery in internal combustion engine (ICE) thanks to the capability to handle off-design conditions and their lower speed. In particular, SVRE revolution speed is usually varied together with the pump one to regulate the recovery unit. Nevertheless, this parameter affects SVRE performance and such effects should be taken into account. Thus, in order to reach this goal, in this paper a control strategy based on revolution speed variation was developed for SVRE. Its suitability and effects on expander performance were analyzed through a SVRE model developed in GT-Suite™ environment. The model was experimentally validated thanks to an extensive experimental campaign carried out on a 1.5 kW SVRE installed on an ORC-based power unit fed by the exhaust gases of a 3 liters supercharged Diesel engine. The results confirm the regulation strategy effectiveness as the maximum deviation between the intake-end pressure (object of regulation) and the set-point is 4% of its value for a wide range of operating conditions. Moreover, the numerical results show that the increase of revolution speed until a certain value leads to the expander global efficiency increase and mechanical power too.

Background Several post hoc analyses of randomized controlled trials (RCTs) suggested the importance of microsatellite instability (MSI) as a positive predictive factor to immunotherapy in patients with advanced gastric cancer (GC); however, individually these have low statistical power. Methods RCTs investigating treatment with or without an anti-programmed cell death protein 1 (PD-1) agent for advanced GC and providing outcome according to MSI status were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for anti-PD-1-based therapy compared with standard therapy. Evidence for treatment effect by MSI status was evaluated by a test of interaction. Results The phase III KEYNOTE-062, CheckMate-649, JAVELIN Gastric 100 and KEYNOTE-061 trials were included. A total of 2545 patients with evaluable MSI status were included and 123 (4.8%) had MSI-high cancers. The HR for overall survival benefit with anti-PD-1-based regimens was 0.34 (95% CI: 0.21-0.54) for MSI-high cancers versus 0.85 [95% confidence interval (CI): 0.71-1.00] for microsatellite stable. The treatment effect was significantly different in the two subgroups (P for interaction 0.003). In the MSI-high subgroup, the HR for progression-free survival was 0.57 (95% CI: 0.33-0.97; P = 0.04) and the odds ratio for response was 1.76 (95% CI: 1.10-2.83; P = 0.02). Conclusions Patients with MSI-high GC should be regarded as a specific and highly immunosensitive population worthy of dedicated clinical trials., Highlights • A meta-analysis on the predictive role of MSI in RCTs of anti-PD-1-based therapy versus chemotherapy in advanced GC. • HR for overall survival with anti-PD-1-based therapy was 0.34 (95% CI: 0.21-0.54) in MSI subgroup (P for interaction in MSI versus microsatellite stable = 0.003). • The HRs for OS were similar in the analysis restricted to first-line and to anti-PD-1 monotherapy versus chemoimmunotherapy. • In the MSI subgroup, the HR for progression-free survival was 0.57 (95% CI: 0.33-0.97) and the odd ratio for response was 1.76 (95% CI: 1.10-2.83).

The outstanding thermo-mechanical and tribological properties of C/C materials make them suitable in a wide range of industrial applications, where high performance at harsh temperature conditions are required. The great interest for their frictional properties points out the need to comprehend and characterize the dynamical phenomena occurring during frictional contact. Within this framework, this work offers an overview of their prevailing frictional and dynamic contact response taking place under different temperatures. The tests reveal a strong relationship between the C/C frictional response, the material propensity to destabilize the system dynamics and the working temperature, providing a glimpse into the occurrence of thermally-driven instabilities for C/C materials and offering information in terms of dynamical response in a broad range of temperature.

Mechanisms of acquired resistance to trastuzumab-based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post-progression in patients receiving chemotherapy and trastuzumab for advanced HER2-positive [immunohistochemistry (IHC) 3+ or 2+ with in-situ hybridization (ISH) amplification] gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over-expression were defined as post-trastuzumab IHC score

Purpose Adjuvant chemotherapy improves survival of patients with gastric cancer. Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) was a phase III study comparing sequential FOLFIRI followed by docetaxel/cisplatin versus 5-fluorouracil monotherapy. The intensive regimen was not superior in terms of disease-free survival (DFS) and overall survival (OS). Methods The treatment was to be started within 8 weeks from surgery. This analysis evaluates the impact of time from surgery to chemotherapy start (TSC) on outcomes. Results Out of 1,106 randomized, 1,072 patients without major violations of eligibility criteria and receiving at least one treatment cycle were analyzed. Median TSC was 50 days. Chemotherapy was interrupted in 201 (18.8%) cases, whereas it was completed without or with modifications in 277 (25.8%) and 594 (55.4%), respectively. At a median follow-up of 56.9 months, 513 progressions and 472 deaths occurred. A longer TSC was significantly associated with longer DFS (hazard ratio [HR] 0.95; 95% confidence interval [CI] 0.89-1.00; p = 0.05) and OS (HR 0.91; 95% CI 0.86-0.97; p = 0.004), after adjustment for treatment arm, age, sex, primary tumor site, number of resected nodes, and tumor stage. Better treatment compliance was associated with improved survival. Conclusions Our findings suggest that longer TSC had at least no detrimental effect on DFS and OS, whereas treatment completion had a protective effect. Our findings need to be confirmed prospectively.

Background Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methods Key inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3months. TEMIRI (TMZ 150mg/m2 on days 1–5 plus irinotecan 100mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0months; hazard ratio=0.29, 95% CI 0.02–0.41; P=0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. Conclusions TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

International audience; Friction-induced vibrations are a complex phenomenon, arising when two surfaces undergo relative sliding. During the last decades many studies on friction-induced vibrations have been carried out, where the simulation of the contact dynamic excitation has always been a challenge to face. This work proposes a new method to reproduce the local dynamic excitation from the contact and its effect on the vibrational response of the system. A friction law including a perturbative term of the friction coefficient is introduced. The evolution of the perturbative term, recovered by dedicated experiments, allows for simulating and analysing the contact excitation mechanisms. The comparisons between numerical and experimental results show good correlation between the measured vibrations and the ones simulated numerically, validating the proposed friction law.

Background Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P

Charge air cooling is the typical technique to reduce temperature of the engine intake air, increasing air density and improving cylinder filling and engine volumetric efficiency in present turbocharged diesel engines. Usually, charge air is cooled by environmental air that crosses a heat exchanger placed in front of the vehicle: its cooling capacity is related to the vehicle speed and other constraints (presence of the main radiator). This leads to an intake air temperature from 30 to 80 °C, depending on engine load, external air conditions and vehicle speed again. If the intake air was more cooled down, the engine volumetric efficiency would be further increased. This can only be done by the use of a dedicated cooling fluid, operating at lower temperature with respect to external air. In this paper, therefore, an evaporator, mounted in parallel with the one of the refrigeration unit used for cabin cooling, was placed on the intake line of a turbocharged diesel engine (F1C IVECO engine), tested on a high speed dynamometer bench: the air refrigeration unit is also composed by a compressor, a condenser and a thermostatic expansion valve. The effects of the undercooling of the charge air have been experimental assessed in terms of fuel consumption and regulated emission reduction, evaluated on the most common engine operating points. Mechanical power demand of the compressor has obviously taken into account in order to assess overall benefits. Achieved net fuel consumption is in the order of 1% at fixed conditions operating the engine as a light duty type, when the intake air sub-cooling is turned on. A benefit on the regulated emissions has been observed (Nitrogen Oxides, Soot) regardless of the setup of the engine combustion processes (injection time, fuel distribution for each injection, Exhaust Gas Recirculated rate). Unburned hydrocarbon and Carbon monoxide behavior, on the other hand, deserves some more attention and call for the re-calibration of the previously cited combustion control parameters.

Background EOX (EPI + oxaliplatin-OHP + capecitabine-CAPE) is still one of the standard regimens for M or LA GC, but the role of EPI is today widely questioned and DOC replaced it in many institutions. A new DOC-based combination was developed with attempt at increasing efficacy/activity vs EOX without the heavy toxicity of the “classic” DOC regimen. Methods From 1/2013 to 11/2018, 169 previously untreated patients (pts) with M (87,6%) or LA GC were randomized by 23 centers between low-TOX (arm A) and EOX (arm B): Arm A: DOC: 35 mg/m2 iv, d 1 and 8 + OHP: 80 mg/m2 iv, d 1 + CAPE: 750 mg/ m2 x2 daily p.o. for 2 weeks Arm B: EPI: 50 mg/m2 iv, d 1 +OHP: 130 mg/m2 iv, d 1 +CAPE: 625 mg/m2 x2 daily p.o. for 3 weeks Both regimens recycled q 3 weeks If no PD or heavy toxicity, pts were programmed on therapy for a maximum of 5 (if CR) or 6 courses (if PR or SD). The primary endpoint was PFS, the secondary OS, ORR, DCR and tolerability. The study was designed to detect a 35% (80% power at a two side 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events (75% of expected). Results At the cut-off date of interim analysis, 164 pts (median age 62 y; 63,9% male; ECOG PS: 0 in 75,7%) have available data for evaluation of primary efficacy analysis. The median PFS (KM) was 5.8 months (95% CI: 5.0 – 7.8) in arm A vs 6.5 months (95% CI: 5.0 – 8.9) in arm B, without statistical difference (NS). Also OS was comparable in the two arms: 12.2 (95% CI: 8.6 -16.0) vs 12.8 months (95% CI: 9.1-21.0). ORR were 22% and 35.4% and DCR 59.8% and 65.9%, respectively, again NS. The median number of courses per patient was 6 and treatment modification was higher in arm A (90,2% vs 78%) with a weakly higher number of AE with CTC ≥ 3 in arm A (54 vs 41). Conclusions These results indicate that, on the basis of the planned futility analysis, it is unlikely that low-TOX regimen is able to reach the target of improvement against EOX, both in efficacy/activity and in tolerability. Therefore, if the clinician’s choice is in favour of a triplet (i.e. in aggressive or very symptomatic disease), EOX could remain a standard option. Clinical trial identification NCT02076594. Legal entity responsible for the study GISCAD. Funding Study carried out within the Rete Oncologica Lombarda-ROL project and founded as per the Deliberazioni di Giunta Regionale (DGR) di Regione Lombardia n° VIII/010761 dell’11-12-2009 e DGR IX/1485 del 30-03-2011”. Disclosure All authors have declared no conflicts of interest.

Background Metastatic pancreatic cancer (mPAC) is a devastating disease with few therapeutic options. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene and there are reports of MGMT alterations in various gastrointestinal cancers, including colorectal cancer and mPAC. Low MGMT expression by immunohistochemistry (IHC) and MGMT promoter methylation ultimately result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This report presents data on MGMT testing mPAC pts admitted at our center. Methods Formalin-fixed paraffin-embedded (FFPE) tissue samples were examined via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), to assess MGMT promoter methylation, and IHC, to assess protein expression. Furthermore, Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®” and “Oncomine BRCA Research Assay”) and PCR analysis of microsatellite instability (MSI) were performed. Results Archived FFPE tissue sections obtained from 90 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to April 2019 were analyzed. At the time of this report, 60 samples (66%) had adequate tissue for extended analyses. As expected, 55 (92%) pts had KRAS mutations, while ATM, CDKN2A mutations and microsatellite instability (MSI) were found in 3 (5%), 4( 6%) and 2 (3%) pts, respectively. MGMT promoter methylation was found in 21 pts (35%), of which 13 (61%) had low/negative MGMT protein expression. Of note, amongst MGMT methylated pts, there were 5 (23%) BRCA1/2 somatic mutant and 2 (9%) MSI, suggesting possible genomic instability. Conclusions MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in metastatic CRC, with phase II studies showing a response rate of 10% in chemorefractory pts with MGMT methylation treated with TMZ. In our single center experience, MGMT methylation was found in 35% of patients with mPAC. This data warrant further prospective confirmation; nevertheless, considering the growing interest in the role of DNA-damage response genes in mPAC, there is definitely a rationale in investigating MGMT methylation as a predictive and prognostic biomarker in mPAC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Morano: Honoraria (self): Servier. F. Pietrantonio: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy: Servier; Research grant / Funding (institution): BMS. F.G.M. De Braud: Advisory / Consultancy: TizianaLife Sciences; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy: Amgen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Octimet Oncology; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: AstraZeneca. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Background Rivoceranib is an oral, selective tyrosine kinase inhibitor of VEGFR-2 with demonstrated efficacy for gastric cancer in China. ANGEL was a global phase III study to evaluate the efficacy and safety of rivoceranib in gastric cancer. Methods Main eligibility criteria included advanced/metastatic adenocarcinoma of the stomach or gastroesophageal junction after failure of ≥ 2 prior lines of chemotherapy; ECOG PS ≤ 1. Patients were stratified by geographic region (Asia vs North America/Europe), disease measurability, prior ramucirumab use, and treatment therapy line (3rd or ≥ 4th), and randomized (2:1 ratio) to rivoceranib 700 mg qd po or matched placebo with BSC until disease progression, intolerable toxicity or withdrawal of consent. Primary endpoint: overall survival (OS, ITT population). Secondary endpoints: progression-free survival (PFS); objective response rate (ORR); disease control rate (DCR); quality of life (QoL); safety. Clinical trial registration: NCT03042611. Results Overall, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled from Feb 2017 – Oct 2018. Baseline demographics were balanced. While mOS in ≥ 3rd-line patients did not show statistical difference for rivoceranib vs placebo (5.78 vs 5.13 mo; HR = 0.93; 95% CI 0.74–1.15; p = 0.4850), mPFS was significantly improved with rivoceranib (2.83 vs 1.77 mo; HR = 0.57; 95% CI 0.46–0.79; p Conclusions While OS was not significantly improved in the overall population, most other efficacy endpoints including OS in ≥ 4th-line suggest that rivoceranib has a benefit and is well tolerated in patients with gastric cancer. Clinical trial identification NCT03042611. Editorial acknowledgement Lee Miller, Miller Medical Communications Ltd. Legal entity responsible for the study LSK BioPharma. Funding LSK BioPharma. Disclosure Y. Kang: Advisory / Consultancy: ONO; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSK Biopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Roche. M. Di Bartolomeo: Honoraria (self), Speaker Bureau / Expert testimony: Lilly spa; Honoraria (self), Speaker Bureau / Expert testimony: Servier; Honoraria (self), Speaker Bureau / Expert testimony: Merck-Serono; Honoraria (self), Speaker Bureau / Expert testimony: MSD; Travel / Accommodation / Expenses: Roche spa; Travel / Accommodation / Expenses: Sanofi. I. Chau: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli-Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Bayer; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck-Serono; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Oncologie International; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): Janssen-Cilag; Research grant / Funding (institution): Sanofi Oncology. H.H. Yoon: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): LSK; Honoraria (institution), Advisory / Consultancy: BeiGene; Advisory / Consultancy: FivePrime Therapeutics; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merrimack; Research grant / Funding (institution): Genetech/Roche; Research grant / Funding (institution): Boston Biomedical. S. Cascinu: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly. M. Ryu: Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Daehwa. K. Lee: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): Eli Lilly; Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): ASLAN Pharmaceuticals; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp.; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics. A. McGinn: Shareholder / Stockholder / Stock options, Full / Part-time employment: LSK BioPharma. N. Sankar: Shareholder / Stockholder / Stock options, Full / Part-time employment: LSK BioPharma. N. Boku: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Eli Lilly; Honoraria (self): Chugai. All other authors have declared no conflicts of interest.

International audience; This paper presents an experimental and numerical analysis on friction-induced vibrations arising from the frictional contact between two bodies in relative motion. The sliding contact has been reproduced within a mechanical system characterized by a simple dynamics, in order to better distinguish between the dynamic response of the system and the broadband excitation coming from the contact. The effects of some parameters, mainly relative velocity, roughness and normal load, on the magnitude and frequency content of the induced vibrations are investigated, also by comparing results from experimental measurements and simulations. A distinction between weak and strong coupling is recovered by the experimental results. Finally, accounting for the contribution of the roughness to the contact-induced vibrations, a conceptually innovative method to implement the effect of the roughness in the numerical simulation is proposed.

Background No evidence-based treatment options are available for patients with advanced colorectal cancer (CRC) progressing after standard therapies. MGMT is involved in repair of DNA damage and MGMT promoter methylation may predict benefit from alkylating agents such as temozolomide. The aim of our study was to evaluate the activity of temozolomide in terms of response rate in patients with metastatic CRC and MGMT methylation, after failure of approved treatments. Patients and methods Patients were enrolled in a monocentre, open-label, phase II study and treated with temozolomide at a dose of 150 mg/m2/day for 5 consecutive days in 4-weekly cycles. The treatment was continued for at least six cycles or until progressive disease. Results Thirty-two patients were enrolled from August 2012 to July 2013. Treatment was well tolerated with one grade 4 thrombocytopenia and no other grade ≥3 toxicities. No complete response occurred. The objective response rate was 12%, reaching the pre-specified level for promising activity. Median progression-free survival and overall survival were 1.8 and 8.4 months, respectively. Patients with KRAS, BRAF and NRAS wild-type CRC showed significantly higher response when compared with those with any RAS or BRAF mutation (44% versus 0%; P = 0.004). TP53 status had no influence on the primary end point. Conclusions Temozolomide is tolerable and active in heavily pre-treated patients with advanced CRC and MGMT promoter methylation. Further studies in biomolecularly enriched populations or in a randomized setting are necessary to demonstrate the efficacy of temozolomide after failure of standard treatments.

Background Biliary Tract Cancers (BTC) are a devastating and molecularly heterogeneous group of diseases, with significant differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and Gall bladder (GB) cancer. O6-methylguanine-DNA methyltransferase (MGMT) is a key DNA repair gene, responsible of alkyl groups’ elimination from the O6-position of guanine. Reductions in MGMT expression and MGMT promoter methylation result in diminished DNA-repair of O6-alkylguanine adducts and enhanced sensitivity to alkylating agents, such as temozolomide (TMZ). This alterations have been described in BTC in small reports with variable frequencies. Here we present data on MGMT methylation tested in BTC pts admitted at our center. Methods MGMT promoter methylation was studied via methyl specific PCR (EZ DNA Methylation-Gold™ KIT), while protein expression was assessed with immunohistochemistry (IHC). Formalin-fixed paraffin-embedded (FFPE) tissue samples were also examined using Next Generation Sequencing (50 genes “Hotspot Cancer Panel, Ion Torrent®”). Results Archived FFPE tissue sections from 100 pts admitted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from October 2017 to February 2019 were analyzed. Amongst the 89 samples with adequate tissue, 73% were ICC, 16% were ECC and 8 % were GC. 34 pts (38%) had MGMT promoter methylation, while low/negative MGMT protein expression was found in 45 pts (50%). MGMT methylation was identified in 38% of ICC, 26% of ECC and 62% of GC. As expected, we identified IDH1/2 mutations in 15%, all affected by ICC. Of note, amongst MGMT methylated pts, there were 4 pts (11%) with concomitant IDH1/2 mutations, which are reported to be associated with CpG Island Methylator Phenotype. Conclusions MGMT is a prognostic and predictive marker in glioblastomas and there is an increasing evidence in its role in gastrointestinal cancer, with phase II studies showing a response rate of 10% in chemorefractory MGMT- methylated colorectal cancer treated with TMZ. In our single center experience, MGMT methylation was found in 38% of patients with BTC. This data warrant further confirmation, but there is a growing interest in novel targeted therapies exploiting the role of MGMT methylation as a predictive and prognostic biomarker in BTC. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure F. Morano: Honoraria (institution): Servier. F. Pietrantonio: Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: EMD Serono; Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Servier; Research grant / Funding (self): BMS. M. Di Bartolomeo: Honoraria (institution), Advisory / Consultancy: Eli Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pharm Research Associated; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: ACCMED; Advisory / Consultancy: Incyte; Advisory / Consultancy: Teofarma; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Fondazione Menarini; Speaker Bureau / Expert testimony: MSD. All other authors have declared no conflicts of interest.

Background In non-randomized trials, temozolomide (TMZ) has shown activity in about 10% of pts with chemorefractory mCRC bearing MGMT methylation. Methods This multicenter, randomized phase II trial investigated PFS superiority of second-line CAPTEM (Arm A) vs FOLFIRI (arm B) in RAS mutated mCRC pts with MGMT methylation centrally confirmed by MSP. Eligible pts had ECOG PS 0-1, measurable disease, and failed prior oxaliplatin-based therapy. Randomization to arm A (capecitabine 750 mg/sqm b.i.d. days 1-14 plus TMZ 75 mg/sqm b.i.d. days 10-14 q28) or B was stratified according to time elapsed from the start of oxaliplatin-based therapy and PD ( Results A total of 86 pts were randomized (43 per arm). After a median follow-up of 30.5 months (IQR 12.2-36.3), 79 disease PFS events occurred. PFS and OS were 3.5 (2.0-5.0) and 9.5 (8.2-25.8) months in arm A vs 3.5 (2.3-6.1) and 10.6 (8.5-20.8) in arm B (HR = 1.86 [0.82-1.72] and HR = 0.97 [0.58-1.61]), respectively. ORR and DCR were 11.6% and 53.5% in both arms. Grade ≥3 treatment-related adverse events had higher incidence in arm B versus A (47.6% vs 16.3%), and quality of life was significantly worse in arm B. In the subgroup with negative MGMT IHC expression, there were no significant differences between the two arms in terms of activity and efficacy endpoints, whereas in pts with positive MGMT IHC expression CAPTEM regimen was associated with significantly inferior outcomes in terms of PFS (2.0 vs 3.5 mos; HR = 2.08 [1.02-4.21]), OS (5.7 vs 10.6 mos; OR = 1.07 [0.39-2.93]) and DCR (15.4 vs 56.5%; OR = 0.23 [0.04-0.99]), interaction test p = 0.125, 0.732, 0.028. Predicting outcomes with MB was more accurate when using ctDNA vs tumor DNA. Conclusions TMZ-based treatment should be investigated by a phase III trial, ideally conducted in patients with MGMT methylated/MGMT IHC negative tumors. Clinical trial identification NCT02414009. Legal entity responsible for the study Fondazione IRCCS Istituto Nazionale Tumori di Milano. Funding Fondazione IRCCS Istituto Nazionale Tumori di Milano. Disclosure F. Pietrantonio: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merck-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier. F. Morano: Honoraria (self): Servier Italia SpA . S. Lonardi: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Bristol-Mayers-Squibb. L. Rimassa: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Sirtex Medical; Honoraria (self), Advisory / Consultancy: Italfarmaco; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Baxter; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: ArQule; Honoraria (self), Advisory / Consultancy: Xelixis; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Eisai. A. Sartore-Bianchi: Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Merk-Serono; Honoraria (self), Advisory / Consultancy: Roche. M. Di Bartolomeo: Advisory / Consultancy: Lilly; Advisory / Consultancy: Servier; Travel / Accommodation / Expenses: Roche. F.G.M. De Braud: Honoraria (self), Advisory / Consultancy: TizianaLife Sciences; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Pharm Research Associated; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Octimet Oncology; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: Teofarma; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy: EMD Serono; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Gentili; Speaker Bureau / Expert testimony: Fondazione Menarini. All other authors have declared no conflicts of interest.

Background We aimed to investigate the association between blood cell count-based immuno-inflammatory parameters, clinico-pathological characteristics and clinical outcomes in patients (pts) with RAS wt, metastatic colorectal cancer (mCRC) randomized to panitumumab (pani) plus FOLFOX4 induction followed by maintenance with pani +/- 5FU/LV in the phase 2 Valentino study. Methods Pts in the intention-to-treat population (n = 229) were screened for the availability of pre-treatment complete blood cell count. We focused on neutrophil-to-lymphocyte ratio (NLR), absolute monocyte count (AMC) and platelet count (PC). NLR and AMC were defined high if ≥ 4 and 900/mcl, respectively, based on literature data. PC was defined high if > of the median value of the study population. The Kaplan-Meier method and Cox proportional hazards regression model were used for survival analyses. Results A total of 215 pts were included. NLR and AMC were significantly associated with ECOG PS. AMC and PC were associated with the presence of synchronous metastases and primary tumor resection. After a median follow-up of 26.7 months, high NLR was associated with worse progression-free survival [PFS] (HR 1.51, p = 0.015) and overall survival [OS] (HR 2.18, p Conclusions In pts with RAS wt, mCRC randomized in the Valentino study, baseline PC showed and independent association with OS and PFS and baseline AMC was independently associated with PFS. Pts with high PC did not derive any PFS benefit from the addiction of 5-FU/LV to pani in the maintenance setting. Clinical trial identification NCT02476045. Legal entity responsible for the study The authors. Funding Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Amgen. Disclosure S. Lonardi: Honoraria (self): Roche; Honoraria (self): Amgen; Honoraria (self): Bayer; Honoraria (self): Merck-Serono; Honoraria (self): Servier; Honoraria (self): Bristol-Myers Squibb. L. Rimassa: Honoraria (self): AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Lilly; Honoraria (self): Bayer; Honoraria (self): Sirtex Medical; Honoraria (self): Italfarmaco; Honoraria (self): Sanofi; Honoraria (self): ArQule; Honoraria (self): Baxter; Honoraria (self): Ipsen; Honoraria (self): Exelixis; Honoraria (self): Amgen; Honoraria (self): Incyte; Honoraria (self): Celgene. A. Zaniboni: Honoraria (self): Sanofi; Honoraria (self): Amgen; Honoraria (self): Bayer; Honoraria (self): Merck-Serono; Honoraria (self): Roche. A. Sartore-Bianchi: Honoraria (self): Sanofi; Honoraria (self): Amgen; Honoraria (self): Bayer; Honoraria (self): Merck-Serono; Honoraria (self): Roche. M. Di Bartolomeo: Honoraria (self): Amgen; Honoraria (self): Roche; Honoraria (self): Lilly; Honoraria (self): Servier; Honoraria (self): Incyte; Honoraria (self): Celgene. F.G.M. De Braud: Honoraria (self): Amgen; Honoraria (self): Roche; Honoraria (self): Novartis. F. Pietrantonio: Honoraria (self): Sanofi; Honoraria (self): Amgen; Honoraria (self): Bayer; Honoraria (self): Merck-Serono; Honoraria (self): Roche; Honoraria (self): Servier. All other authors have declared no conflicts of interest.

Background ASCO and ESMO guidelines have identified inadequate sampling of lymph nodes, pT4 primary tumors, obstruction or perforation, lymphovascular and perineural invasion, and poorly differentiated tumors as negative prognostic factors supporting the clinicians in treating their patients with stage II colon cancer (CC). However, the influence of histological subtypes on the risk of death or disease recurrence remains controversial. Methods The phase III, multicenter, randomized TOSCA trial compared 3 vs. 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. Objective of this sub-study was to investigate the role of the histological subtype [(mucinous adenocarcinoma (MUC) or non-mucinous adenocarcinoma (NMUC)] on the impact of the treatment duration in terms of relapse-free survival (RFS) and overall survival (OS) in the subgroup of patients with high-risk stage II, grade 3 CC. Results Out of 3,614 patients from 130 centres enrolled in the per-protocol population defined in the TOSCA trial, 85 MUC and 389 NMUC patients were included in this analysis. No statistical differences were found between 3 vs. 6 months groups in both histological subgroups in terms of baseline characteristics, except for tumor side. The proportion of patients with right-sided cancer was higher for patients with MUC than NMUC. A significant interaction between treatment duration and histology was observed on both RFS (p = 0.027) and OS (p = 0.017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p = 0.045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p = 0.037) were detected for patients treated in the 3 months arm. No statistically significant differences were detected in the subgroup of patients with NMUC. Conclusions Both MUC and poorly differentiated subtypes have unfavorable clinical characteristics. Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to clarify the possible negative effect of the histological subtype to improve the prognosis of these patients. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.