This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer.
The PANDORA trial is a prospective, phase II, ...open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α = 0.05, power = 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365).
Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study’s objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation).
This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.
•Neoadjuvant CRT followed by surgery ± adjuvant chemotherapy is the standard treatment of LARC.•However, a high percentage of patients will eventually develop a distant recurrence.•To improve patient outcomes, the use of consolidation durvalumab treatment after standard neoadjuvant CRT was investigated.•A neoadjuvant treatment with durvalumab following CRT showed promising activity and tolerability in the management of LARC.
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•Experimental assessment of engine exhaust line and turbocharging.•Double stage energy recovery proposal on the exhaust pressure and temperature.•Parallel auxiliary turbine recovery ...about 5% of engine power.•Bottomed ORC-unit recovery for further 5 % of engine power.•Net 7% with combined side effects evaluation (backpressure, weight increase)
Energy recovery has become an important solution that drives the transition to more sustainable propulsion, since the amount of thermal energy available from exhaust gases is huge. This energy can be transformed into electrical energy (without significantly affecting the powertrain) and directly used, for instance, in hybrid propulsion or driving auxiliaries.
A turbocharged diesel engine equipped with a variable geometry turbine (VGT) was tested to assess the maximum energy recoverable from exhaust gases through two different recovery stages. The first was achieved using the pressure difference between the value at the exhaust valves and the atmospheric datum (turbo-compounding). The second recovery stage was achieved thanks to the temperature of the exhaust gases after the first recovery, and performed using an organic Rankine cycle (ORC)-based power unit.
Therefore, these two combined stages of energy recovery were experimentally investigated in the medium–low load region of the ESC-13 homologation test, which is representative for real driving of heavy-duty engines. The first stage was performed on the turbocharging system by recovering the energy lost inside the VGT, through an additional turbine that operates in parallel with the main turbine that drives the compressor. It facilitates the recovery of a mechanical power of up to 3 kW, which was approximately equal to 5 % of the engine brake power at a specific medium–low load. The second stage was performed with an ORC-based unit bottomed to the first recovery section, exploiting the fact that after the first recovery, exhaust gases still have a high temperature, which can be used to feed the additional ORC based recovery unit. This second stage adds up to 3.5 kW of recovered mechanical energy, which represents 5 % of the engine brake power at the same medium–low engine load operating points. Therefore, a total of 10 % of the engine power was recovered in the two stages, which are characterized by proven technologies. Considering the engine working point at maximum power, the value was also higher, the combined recovery achieved a mechanical power of approximately 14 % of the engine brake power.
In this study, the detrimental effects related to the engine backpressure produced by the two recovery units and the additional weight of the vehicle were assessed, demonstrating a net overall specific fuel consumption reduction of approximately 5–7% in the medium–low operating region of the engine considered, and higher than 8% at the maximum engine power. The increase in complexity related to the two recovery stages invites to consider this technology for heavy-duty engines for long-hauling vehicles, in which the detrimental effects does not significantly affects fuel consumption.
The aim of this study was to determine the efficacy of the EAP regimen (etoposide, adriamycin and cisplatin) followed by the Machover schedule (fluorouracil and folinic acid) given as adjuvant ...treatment to patients with poor prognostic factors (N+ or T3/4).
Before randomisation, the subjects were stratified on the basis of node involvement (N+ or N-) and the time from surgery to randomisation (< or = 21 days or > 22 days). The surgical procedures for sub-total or total gastrectomy with D2 dissection were standardised among the participating centres.
Between December 1992 and December 1997, 274 patients were enrolled: 137 in the treatment arm and 137 in the control arm. The majority of the patients (90%) were N+. After a median follow up of 66 months (range 2-83), the 5-year overall survival (OS) was 52% in the treatment arm and 48% in the control arm hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.65-1.34; the 5-year disease-free survival (DFS) was 49% and 44%, respectively (HR: 0.83; 95% CI 0.59-1.17). Among the patients with N-/N+ (1-6), the 5-year OS was 61% in the treatment group and 60% in the control group; in those with N+ (1-6), it was 42% and 22%. The treatment was completed by 87% of patients. Drug-related grade 3/4 WHO toxicities included leukopenia (21%), nausea and vomiting (14%), mucositis (9%), neutropenia (3%) and thrombocytopenia (2%). There were two deaths due to sepsis.
Although our results are not statistically significant, there was a limited relative risk reduction in the patients receiving adjuvant therapy (17% in DFS and 7% in OS). The data suggest that D2 surgery may have a favourable impact on OS.
A numerical investigation dealing with dynamic rupture at a frictional interface between dissimilar materials is proposed. The numerical Finite Element model is comprised of two homogeneous and ...isotropic elastic solids which are brought into contact with friction by remote normal compression and shear traction. The applied shear traction is less than the required one to produce overall sliding of the two solids. The rupture is nucleated by decreasing instantaneously the friction coefficient to zero at the nucleation area. A “rupture” is considered when an initially sticking zone of the interface becomes in sliding state; after nucleation two propagating ruptures appeared.
The properties (velocity, generated waves, interface state …) of the obtained ruptures are here analyzed for a flat interface between dissimilar materials in function of the nucleation energy; then, the analysis of the effect of the interface roughness (sinusoidal asperities) is developed. The differentiated rupture inside the asperity and the conditions for coupling or uncoupling between the waves radiating in the two bodies, in function of the asperity dimensions, have been investigated. The aim of this work is to present the results from the non-linear finite element analysis in large transformations of the dynamic rupture at the interface with contact friction between two deformable bodies with and without roughness.
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