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 <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post‐progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over‐expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over‐expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab‐based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti‐HER2 second‐line strategies in initially HER2‐positive disease.
What's new?
Patients with cancers positive for human epidermal growth factor receptor 2 (HER2) generally fail to respond to second‐line treatments, particularly when first‐line therapy included use of the HER2‐targeted agent trastuzumab. Post‐progression changes in HER2 expression, however, have not been studied extensively, and as a consequence, their therapeutic relevance is unclear. In this study, HER2 loss was associated with acquired resistance to trastuzumab in almost one‐third of patients with gastric or gastroesophageal cancers that initially were HER2‐positive. The findings suggest that after failure of trastuzumab, HER2 status should be reassessed prior to inclusion in clinical trials with targeted agents.
Due to the aging of population, materials able to repair damaged tissues are needed. Among others, bioactive glasses (BGs) have attracted a lot of interest due to their outstanding properties both ...for hard and soft tissues. Here, for the first time, two new BGs, which gave very promising results in preliminary in vitro‐tests, were implanted in animals in order to evaluate their regenerative potential. The new BGs, named BGMS10 and Bio_MS and containing specific therapeutic ions, were produced in granules and implanted in rabbits' femurs for up to 60 days, to test their biocompatibility and osteoconduction. Additionally, granules of 45S5 Bioglass® were employed and used as a standard reference for comparison. The results showed that, after 30 days, the two novel BGs and 45S5 displayed a similar behavior, in terms of bone amount, thickness of new bone trabeculae and affinity index. On the contrary, after 60 days, 45S5 granules were mainly surrounded by wide and scattered bone trabeculae, separated by large amounts of soft tissue, while in BGMS10 and Bio_MS the trabeculae were thin and uniformly distributed around the BG granules. This latter scenario could be considered as more advantageous, since the features of the two novel BG granules allowed for the neo‐formation of a uniformly distributed bony trabeculae, predictive of more favorable mechanical behavior, compared to the less uniform coarse trabeculae, separated by large areas of soft tissue in 45S5 granules. Thus, BGMS10 and Bio_MS could be considered suitable products for tissue regeneration in the orthopedic and dental fields.
•Novel engine intake air under-cooling system with air conditioning evaporator.•Indicated cylinder pressure and temperature reconstruction and analysis.•Comprehensive engine efficiencies evaluation ...and comparison.•Exhaust Gas Recirculation strategy optimization for emissions control.•About 1% fuel consumption reduction with cooling power considered.
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: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) ...mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear.
Patients and methods: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing.
Results: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not nonresponder (NR). EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs.
Conclusion: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.
While the negative prognostic role of BRAF V600E mutation in metastatic colorectal cancer (mCRC) is well established, the impact of BRAF codons 594 and 596 mutations, occurring in <1% of CRCs, is ...completely unknown. The present work aims to describe clinical, pathological and molecular features and prognosis of BRAF codons 594 and 596 mutant mCRCs, compared with BRAF V600E mutant and wild-type ones.
Patients treated for mCRC at three Italian Institutions between October 2006 and October 2014, with available KRAS and NRAS codon 12, 13, 59, 61, 117 and 146 and BRAF codon 594, 596 and 600 mutational status, as detected by means of direct sequencing or matrix assisted laser desorption ionization time-of-flight MassArray, were included.
Ten patients bearing BRAF codons 594 or 596 mutated tumors were identified and compared with 77 and 542 patients bearing BRAF V600E mutated and BRAF wild-type tumors, respectively. While BRAF V600E mutated tumors were more frequently right-sided, mucinous and with peritoneal spread, BRAF 594 or 596 mutated were more frequently rectal, nonmucinous and with no peritoneal spread. All BRAF 594 or 596 mutated tumors were microsatellite stable. Patients with BRAF codons 594 or 596 mutated tumors had markedly longer overall survival (OS) when compared with BRAF V600E mutated median OS: 62.0 versus 12.6 months; hazard ratio: 0.36 (95% confidence interval 0.20–0.64), P = 0.002, both at univariate and multivariate analyses.
BRAF codon 594 or 596 mutated mCRCs are different from BRAF V600E ones in terms of molecular features, pathological characteristics and clinical outcome. This is consistent with preclinical evidences of a kinase inactivating effect of these mutations. The role of CRAF in transducing the intracellular signal downstream BRAF 594 or 596 mutated proteins opens the way to further preclinical investigation.
Outcome of pseudomyxoma peritonei (PMP) after cytoreductive surgery (CRS) and hypertermic intraperitoneal chemotherapy (HIPEC) is heterogeneous even after adjusting for clinico-pathological ...prognostic variables. The identification of additional prognostic or even predictive biomarkers is an unmet clinical need.
Forty patients with mucinous appendiceal tumors and PMP were clinically eligible and had evaluable tumor samples obtained after CRS and HIPEC. We carried out next-generations sequencing (NGS) of 50 gene's hotspot regions contained in the Hotspot Cancer Panel v2 using the Ion Torrent Personal Genome Machine platform (Life Technologies).
KRAS and GNAS mutations were found in 72% and 52%, and their allelic frequency was below 10% in 55% and 43% of samples, respectively. KRAS and GNAS mutations were associated with worse progression-free survival (PFS) at univariate analysis (P = 0.006 and 0.011, respectively). At multivariate analysis, only KRAS mutations were independently associated with PFS (P = 0.012); GNAS mutations were not—being significantly associated with other poor prognostic features such as incomplete cytoreduction or KRAS mutations. Validation of results was carried out in an independent bi-institutional cohort of 25 patients and the prognostic effect of KRAS mutations was again confirmed in the multivariate model (P = 0.029). NGS approach allowed the discovery of other potentially druggable mutations such as those in PI3K, AKT, LKB1, FGFR3 and PDGFRA.
Given the homogeneity of this series and the sensitivity of NGS in this low-cellularity tumor, we demonstrated for the first time a poor prognostic role of KRAS mutations.
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.
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.
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).
Patients with MSI-high GC should be regarded as a specific and highly immunosensitive population worthy of dedicated clinical trials.
•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).
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.
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.
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).
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.
•Second-line pembrolizumab showed a strong association between tTMB and efficacy in gastric and gastroesophageal cancer.•There was low correlation between WES-tTMB and PD-L1 CPS.•WES-tTMB was associated significantly with pembrolizumab PFS and OS after excluding known MSI-H tumors.•Findings with FoundationOne®CDx-tTMB were similar to those with WES-tTMB.
Abstract
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.
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).
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.
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 < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64–32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25–7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not.
Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.
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