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Objectives: The prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated. Materials and Methods: We retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs. Results: Seventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504–1.033, p = 0.075) although not statistically significant at multivariate analysis. Conclusion: Bone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors.

Introduction: Patients with thoracic malignancies are at increased risk for mortality from coronavirus disease 2019 (COVID-19), and a large number of intertwined prognostic variables have been identified so far. Methods: Capitalizing data from the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure, and a tree-based model to screen and optimize a broad panel of demographics and clinical COVID-19 and cancer characteristics. Results: As of April 15, 2021, a total of 1491 consecutive eligible patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection procedure then identified the following seven major determinants of death: Eastern Cooperative Oncology Group—performance status (ECOG-PS) (OR = 2.47, 1.87–3.26), neutrophil count (OR = 2.46, 1.76–3.44), serum procalcitonin (OR = 2.37, 1.64–3.43), development of pneumonia (OR = 1.95, 1.48–2.58), C-reactive protein (OR = 1.90, 1.43–2.51), tumor stage at COVID-19 diagnosis (OR = 1.97, 1.46–2.66), and age (OR = 1.71, 1.29–2.26). The receiver operating characteristic analysis for death of the selected model confirmed its diagnostic ability (area under the receiver operating curve = 0.78, 95% confidence interval: 0.75–0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90%, and the tree-based model recognized ECOG-PS, neutrophil count, and c-reactive protein as the major determinants of

Objective: Surgical indications for cerebral cavernous malformations (CCMs) remain significantly center- and surgeon-dependent; available grading systems are potentially limited, as they do not include epileptologic and radiologic data. Several experienced authors proposed a new grading system for CCM and the first group of patients capable of providing its statistical validation was analyzed. Methods: A retrospective series of 289 CCMs diagnosed between 2008 and 2021 was collected in a shared anonymous database among 9 centers. The new grading system ranges from –1 to 10. For each patient with cortical and cerebellar cavernous malformations the grading system was applied, and a retrospective outcome analysis was performed. We proposed a score of 4 as a cutoff for surgical indication. Results: Operated patients with a score ≥4 were grouped with non-operated patients with a score <4, as they constituted the group that received correct treatment according to the new grading system. Patients with a score ≥4, who underwent surgery and had an improved outcome, were compared to patients with a score ≥4 who were not operated (P = 0.04), and to patients with a score <4 who underwent surgery (P < 0.001). Conclusions: This preliminary statistical analysis demonstrated that this new grading would be applicable in surgical reality. The cutoff score of 4 correctly separated the patients who could benefit from surgical intervention from those who would not. The outcome analysis showed that the treated patients in whom the grading system has been correctly applied have a better outcome than those in whom the grading system has not been applied.

Robotics is routinely used in several surgical fields. Different robots have been applied in neurosurgery, but only a few of them are relevant to neuroendoscopy. This chapter provides an overview of robotics applied to the different fields of cranial neuroendoscopy. It describes the advantages and disadvantages of reported preclinical prototypes and reviews the few clinical studies that have described robotics as applied to neuroendoscopic cranial surgery. Robotics in neurosurgical practice is a growing field of interest. As it stands, more research is needed to develop systems that are conceived specifically for cranial neuroendoscopy. Further preclinical and clinical studies are required to evaluate the benefits and limits of current commercially available systems.

Background: Lombardy was the most affected Italian region by the first phase of the COVID-19 pandemic and underwent urgent reorganization for the management of emergencies, including subarachnoid hemorrhage from a ruptured cerebral aneurysm (aSAH). The aim of the study was to define demographics, clinical, and therapeutic features of aSAH during the COVID-19 outbreak and compare these with a historical cohort. Methods: In this observational multicenter cohort study, patients aged 18 years or older, who were diagnosed with aSAH at the participating centers in Lombardy from March 9 to May 10, 2020, were included (COVID-19 group). In order to minimize bias related to possible SAH seasonality, the control group was composed of patients diagnosed with aSAH from March 9 to May 10 of the three previous years, 2017–2018-2019 (pre-pandemic group). Twenty-three demographic, clinical, and therapeutic features were collected. Statistical analysis was performed. Results: Seventy-two patients during the COVID-19 period and 179 in the control group were enrolled at 14 centers. Only 4 patients were positive for SARS-CoV-2. The “diagnostic delay” was significantly increased (+ 68%) in the COVID-19 group vs. pre-pandemic (1.06 vs. 0.63 days, respectively, p-value = 0.030), while “therapeutic delay” did not differ significantly between the two periods (0.89 vs. 0.74 days, p-value = 0.183). Patients with poor outcome (GOS at discharge from 1 to 3) were higher during the COVID-19 period (54.2%) compared to pre-pandemic (40.2%, p = 0.044). In logistic regression analysis, in which outcome was the dichotomized Glasgow Outcome Scale (GOS), five variables showed p-values < 0.05: age at admission, WFNS grade, treatment (none), days in ICU, and ischemia. Conclusions: We documented a significantly increased “diagnostic delay” for subarachnoid hemorrhages during the first COVID-19 outbreak in Lombardy. However, despite the dramatic situation that the healthcare system was expe

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations. Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events. Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3–4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively. Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.

Los mantos de cabalgamiento de Bóixols, Montsec y Sierras Marginales constituyen la principal curvatura orogénica del frente surpirenaico central. La parte frontal de este saliente se caracteriza por unos antiformes con núcleo salino de orientación oblicua y despegados en los niveles evaporíticos sinorogénicos de la cuenca de antepaís del Ebro. Estas estructuras deforman los depósitos paleógenos de la cuenca de antepaís. Con la finalidad de explicar la evolución cinemática de estas estructuras y el papel de los niveles evaporíticos en la geometría del saliente, se llevó a cabo el estudio de las rotaciones de eje vertical (VAR) en el sector de Artesa de Segre-Cardona. Se muestrearon 80 estaciones de paleomagnetismo en los materiales detríticos del Eoceno superior-Oligoceno del sector. Su análisis muestra principalmente unas rotaciones antihorarias, relacionadas con el emplazamiento hacia el sur de los mantos de corrimiento surpirenaicos. Adicionalmente, el estudio magnetoestratigráfico de las series del Eoceno superior-Oligoceno permite acotar la edad de las rotaciones observadas., The Bóixols, Montsec and Sierras Marginales thrust sheets make up the principal orogenic curvature of the central South Pyrenean front. The frontal part of this thrust salient is characterized by a series of oblique salt-cored antiforms, which are detached above the synorogenic evaporitic layers of the Ebro forealnd basin. These structures deform the Paleogene deposits of the foreland basin. A study of vertical-axis rotations (VAR) was carried in the Artesa de Segre-Cardona area, aiming to explain the evolution of the kinematics of these structures and the role of the evaporitic detachment levels in the geometry of the salient. 80 paleomagnetic sites were sampled on the Eocene-Oligocene detritic levels in the area. Their analysis shows predominant anti-clockwise rotations, related to the southwards emplacement of the South-Pyrenean thrust sheets. Additionally, a magnetostratigraphic study of the upper Eocene-Oligocene succession add constraints to the age of the observed VAR.

Los niveles salinos depositados antes de la deformación, tanto en márgenes pasivos como en contextos orogénicos, producen una deformación diferencial en los niveles por encima y por debajo del despegue salino. La distribución de los despegues salinos controla el acortamiento diferencial y la formación de arcos orogénicos y el diapirismo puede generar minicuencas asociadas a rotaciones de ejes vertical durante su desarrollo. Nuestro estudio, con 65 estaciones paleomagnéticas, pretende deducir la cinemática de estructuras salinas mediante el estudio de una porción del Arco Vasco, en el margen norte de la Cuenca extensiva Vasco-Cantábrica, donde la cobertera de la sal está compartimentada por varias paredes salinas (diapiros de Bakio, Bermeo, Guernica y Mungia). Los resultados muestran rotaciones antihorarias predominantes y rotaciones horarias y antihorarias en flancos opuestos de los diapiros. Los test del pliegue revelan que algunas estaciones están remagnetizadas mientras otras muestran magnetizaciones ¿prefolding¿. Los experimentos de magnetismo de rocas en parte de las muestras estudiadas confirman estas observaciones. A pesar de que son necesarios más análisis para entender el origen y la distribución de las remagnetizaciones, es posible establecer un modelo cinemático preliminar de la deformación suprasal junto a los materiales despegados infrayacentes.

El análisis de la geometría y cinemática de estructuras oblicuas es necesario para entender su origen y evolución. En este trabajo el estudio de la fábrica magnética se utiliza como una herramienta para determinar la historia deformacional de los pliegues oblicuos situados en el autóctono deformado del sector nororiental de la cuenca de antepaís del Ebro. Un total de 149 estaciones han sido analizadas a partir del análisis de la fábrica magnética (anisotropía de la susceptibilidad magnética) con este objetivo. El muestreo se realizó en materiales detríticos sinorogénicos del Eoceno Superior-Oligoceno del sector de Artesa de Segre-Cardona. A pesar de la dirección de acortamiento regional aproximada N-S, oblicua con respecto a la orientación N045E a N135E de los pliegues estudiados, las direcciones obtenidas de la lineación magnética en la mayoría de los casos se encuentran contenidas en el plano de estratificación y paralelas a los ejes de los pliegues oblicuos. El análisis paleomagnético realizado de forma paralela a este estudio muestra la existencia de rotaciones anti-horarias de estos pliegues relacionadas con el emplazamiento del saliente de cabalgamientos del Pirineo Central (Peigney et al., 2021), lo que sugiere que los elipsoides magnéticos obtenidos han actuado como marcadores pasivos de la deformación registrando información relacionada con el acortamiento paralelo a las capas inicial (layer parallel shortening) y/o su plegamiento posterior.