Road Tunnels Operation: Effectiveness of Emergency Teams as a Risk Mitigation Measure

Managing a major event in a road tunnel requires more resources than an open-air event. In the case of fire, the confined environment of road tunnels can represent a critical situation for both users and rescuers. The safety level of a tunnel can be estimated by using dedicated risk models that consider, on the one hand, the traffic (type, quantity and distribution) of a tunnel and, on the other hand, the structural and plant safety measures. According to the European Directive, road tunnel managers can adopt additional safety measures aimed at increasing the level of safety for users exposed to the consequences of an accidental event. One of these measures is the rapid intervention of emergency teams located in the proximity of the tunnel. These teams use pick-up and scooter vehicles properly equipped to cope with a fire event and have detailed knowledge of the specific tunnel system. A further advantage of the emergency teams is the possibility of supporting the evacuation of tunnel users by providing indications on emergency exits, bypasses and safe places considering the evolution of the specific event. In this perspective, the present research contributes to the evaluation of the emergency teams’ effectiveness. Thus, the emergency team was included as a safety measure within a risk analysis model for road tunnels developed by the authors in previous works. After an analysis of the technical and scientific literature, we focused on 15 interventions carried out on some highway tunnels in Italy between the year 2019 and the year 2021. The intervention times of the teams were analyzed using data provided by Strada dei Parchi S.p.A., a company that manages 14 highway tunnels in Italy. These 14 tunnels range in length from 589 m to 10,121 m and are subject to the European Directive. The observed intervention times of the emergency teams range between 2 min and 10 min with an average value of 5.9 min. Such a short intervention time is possible because emergency teams are in the proximity of the different tunnels. Because of the short intervention time and the training of the personnel, all the fires were properly managed by the teams. Furthermore, considering the results of the scientific literature and the data presented in this work, it was possible to estimate and validate an effectiveness value (higher than 90%) of the emergency teams to be used within the risk analysis model developed by the authors and which can also be used in other risk analysis models

TRAM: a New Quantitative Methodology for Tunnel Risk Analysis

The paper illustrates and describes the structure of a new quantitative model of risk analysis for road tunnels named TRAM (Tunnel Risk Analysis Model). The result of the model, in accordance with the European Directive and the Italian Legislative Decree, returns the F-N curves of societal risk, in other words functions that relate the frequency of occurrence of an accidental scenario (F) with the expected consequences in terms of potential victims (N). Starting from two types of initial events, a fire and a Dangerous Goods (DG) release, a total of 18 accidental scenarios was defined. The frequencies of occurrence of each accidental scenario is obtained using the Event Tree Analysis (ETA) technique. For each scenario, the number of fatalities, expressed in terms of deaths, is obtained by simulating the formation dynamics of the queue of vehicles, using a model able to calculate the queue length, depending on traffic, the vehicle type, as well as the closure time of the tunnel. Then, a distribution model of the potentially exposed users has been defined and coupled with an egress model. The users’ tenability is estimated on the basis of the egress model and the evolution of each accidental scenario, which is evaluated using a zone model. The proposed model can simulate each of the 18 accidental scenarios in several different positions along the tunnel, considering the impact that different tunnel infrastructure measures, equipment and management procedures can have on the users egress and on the propagation of the effects of the accidental scenarios. The model is able to consider the interdependence between these measures and their reliability in terms of their availability in an emergency situation. Finally, to validate the model, comparisons are made with the QRAM software developed by PIARC for some representative case studies. Through this model, it is possible to perform the risk analysis of a tunnel in an actual configuration and compare the expected value of damage with the corresponding one of the tunnel in a virtual configuration, as prescribed by the Italian decree compliant with the European Directive 2004/54/EC

Quality of life of therapies for hormone receptor positive advanced/metastatic breast cancer: Regulatory aspects and clinical impact in Europe

In recent years, the number of trials incorporating health-related quality of life (HRQoL) data has increased. The impact of HRQoL on regulatory decision making in the European context and on clinical practice is not well established. We conducted an analysis of the role of QoL data extracted from the clinical trials of the drugs approved for hormone receptor positive/HER2-negative advanced/metastatic breast cancer (mBC). The results from the HRQoL were collected and a meta-analysis was performed to evaluate the impact of experimental drugs compared to standard treatments. The results showed a non-detrimental effect in HRQoL from the new treatments. As regards the approval process, from an examination of the European Medicine Agency (EMA) documents, HRQoL was reported nonextensively and contained and discussed in the European assessment reports (EPARs) for eleven trials in the approval process and cited in three cases in the EPARs and summary of medicinal product characteristics (SmPC). An effort should be made by all the stakeholders to increase the visibility of the HRQoL results in order to allow increased consideration in the approval process to make QoL data more easily and visibly available for the clinician and the patients. The evaluation should be reflected in the SmPC in order to increase the amount of information provided to the physician

Immune infiltrate composition across intrinsic subtypes in hormone receptor (HR)+/HER2- early breast cancer (BC) enrolled in the prospective LETLOB trial.

Background In HR+/HER2- early BC, high tumour infiltrating lymphocytes (TIL) levels predict higher pathological complete response to neoadjuvant chemotherapy, but are associated with shorter overall survival (Denkert, Lancet Oncol 2018). HR+/HER2- BC is a biologically heterogeneous disease, encompassing all BC molecular intrinsic subtypes, with different clinical behaviour (Cejalvo, CTR 2018). Little is known concerning the distribution of TIL levels and immune infiltrate composition across intrinsic subtypes in HR+/HER2- BC. Methods Gene-expression data (Affymetrix platform) from pre-treatment frozen core-biopsies was available from 66 postmenopausal patients with HR+/HER2- early BC from the LETLOB trial (neoadjuvant letrozole+/-lapatinib) (Guarneri, JCO 2014). Intrinsic subtype was assigned using a research-based PAM50 subtype predictor. Relative leukocyte fractions were calculated using CIBERSORT (Newman, Nature Methods 2015), a deconvolution method based on RNA gene-expression signatures. Pre-treatment stromal TILs were assessed on centralized HES slides according to recommendations (Salgado, Ann Oncol 2015). Results Intrinsic subtype distribution was as follows: basal 18% (N = 12), HER2-enriched 8% (N = 5), Luminal A 39% (N = 25), Luminal B 36% (N = 24). Non-luminal subtypes (HER2-enriched and Basal) had significantly higher baseline TIL levels than luminal subtypes (median (range): 7 (0-100) and 2 (0-35), respectively; p = 0.038). Non-luminal subtypes also presented higher fractions of CD4 memory activated T-cells (p = 0.018), γδ T-cells (p = 0.010) and M1 macrophages (p = 0.001) and lower fractions of T-regulatory cells (p = 0.002) than luminal subtypes. Conclusions In HR+/HER2- early BC, non-luminal subtypes show higher TIL levels and a more pro-inflammatory anti-tumour immune infiltrate composition. This immune heterogeneity across intrinsic subtypes should be considered when analysing the complex prognostic role of TILs in HR+/HER2- early BC

Phase 2 study of NAB-paclitaxel in SensiTivE and refractory relapsed small cell lung cancer (SCLC) (NABSTER TRIAL)

Background: Despite sensitivity to first-line chemotherapy, most small-cell lung cancer (SCLC) patients relapse. In this setting, topotecan demonstrated modest activity with significant toxicity. Paclitaxel was also active. This study was designed to evaluate activity and safety of nab-paclitaxel in relapsed SCLC. Methods: In this multicentre prospective Phase 2 trial, patients with refractory or sensitive SCLC progressed to first-line platinum-based chemotherapy received nab-paclitaxel 100 mg/smq on days 1, 8, 15 every 4 weeks up to six cycles, progressive disease or intolerable toxicity. Primary endpoint was investigator-assessed objective tumour response. Secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). Results: Of the 68 patients treated, partial response was 8% in the refractory cohort and 14% in the sensitive cohort. Most common toxicities of any grade were fatigue (54%), anaemia (38%), neutropenia (29%), leukopenia (26%) and diarrhoea (21%). Median PFS was similar in both refractory (1.8 months) and sensitive cohorts (1.9 months), while median OS was longer in sensitive one (6.6 versus 3.6 months). Conclusions: Although nab-paclitaxel has shown some modest anti-tumour activity in relapsed SCLC, associated with a favourable toxicity profile, the primary end-point of the study was not met. Clinical Trial registration: Clinical Trial registration number is ClinicalTrials.gov Identifier: NCT03219762

Europe is Not a Tree - L'Europa non è un albero

Redazionale del #7 della rivista ARDET

Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer

Background: Even with contemporary treatment strategies, more than 10% of HER2-positive early stage breast cancer patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive breast cancer. Methods: A total of 677 HER2-positive stage I-III breast cancer patients from ShortHER trial, Cher-LOB trial, and 2 institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site specific) was evaluated using competing risk analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. Results: Stage III and high HER2DX risk score identified patients at the highest risk of distant relapse as first event (10-year incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared with other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-year incidence 3.8% vs 0.6%, P =. 005), basal-like tumors were associated with an increased risk of lung metastases (10-year incidence 11.1% vs 2.6%, P =. 001), and luminal tumors developed more frequently bone-only metastases (10-year incidence 5.1% vs 2.0%, P =. 042). When added to stage or HER2DX risk score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. Conclusions: The integration of intrinsic molecular subtypes with stage or HER2DX risk score predicts site-specific metastatic risk in HER2-positive breast cancer, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence

Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE Trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Materials and Methods:This is an open-label, national multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC.The primary endpoint was the objective response rate (ORR) for evaluable patients (pts). The study was designed according to the Simon's two stage optimal design. We chose the lower activity (p0) of 0.20 and target activity level (p1) of 0.35. A prospective, molecular correlative study has been being carried out on germinal DNA of study population to assess the role of BRCA mutations and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016, 83 evaluable pts (37 in the first stage, 46 in the second one) were enrolled. They received a median number of 6 cycles of treatment (range 1-24). The ORR (CR+PR) was 37.35% (90% CI: 28.47-46.93) and the clinical benefit rate (CR+PR+SD 65 24wks) was 48.78% (90% CI: 39.24%-58.39%). The most common grade 3-4 adverse events (> 10% of patients) were neutropenia and liver toxicity. With a median follow-up of 28.8 months, the median progression-free survival (PFS) and overall survival (OS) were 5.1 months (95% CI: 4.2-7.0) and 14.7 months (95% CI: 10.2-20.0), respectively. BRCA1/2 deleterious mutations were observed in 15 (22%) out of 68 genotyped pts. Women with BRCA1/2 mutations were associated with worse ORR, PFS and OS than those with BRCA1/2 wild-type. A panel of SNPs in genes of study drug metabolism pathways was evaluated. Among these, CYP3A4 392A >G and FGD4 2044236G>A SNPs were associated with greater liver toxicity by logistic regression analysis. Furthermore, CDA*2 79A>C, RRM1 2455 A>G, and CYP2C8 416G>A SNPs were associated with poorer overall survival by Cox proportional hazards model. Conclusions:The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify pts with high probability of response with negligible toxicity

Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs\u2009 6520% and TILs\u2009<20%. Median follow-up was 6.1\u2009years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P\u2009=\u20090.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs\u2009<20% and 95.7% for patients with TILs\u2009 6520% (P\u2009=\u20090.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9\u2009weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1\u2009year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P\u2009=\u20090.088). For patients with TILs\u2009<20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs\u2009 6520% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P\u2009=\u20090.064), resulting in a significant interaction (P\u2009=\u20090.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy