Urban-Rural Disparities in the Lung Cancer Surgical Treatment Pathway: The Paradox of a Rich, Small Region

Introduction: Rural populations in large countries often receive delayed or less effective diagnosis and treatment for lung cancer. Differences are related to population-based factors such as lower pro capita income or increased risk factors or to differences in access to facilities. Switzerland is a small, rich country with peculiar geographic and urban characteristics.We explored the relationship between lung cancer diagnostic-surgical pathway and urban-rural residency in our region. Methods: We retrospectively analyzed the medical records of 280 consecutive patients treated for primary non-small cell lung cancer at our institution (2017-2021). This is a regional tertiary center for diagnosis and treatment, and data were extracted from a prospectively collected clinical database. We included anatomical lung resection. Collected variables included patients and surgical characteristics, risk factors, comorbidities, histology and staging, symptoms (vs. incidental diagnosis), general practitioner (GP) involvement, health insurance, and suspected test-treatment interval. The exposure was rurality, defined by the 2009 rural-urban residency classification from the Department of Land. Results: A total of 150 patients (54%) lived in rural areas. Rural patients had a higher rate of smoking history (93% vs. 82%; p = 0.007). Symptomatic vs. incidental diagnosis did not differ as well as previous cancer rate, insurance, and pathological staging. In rural patients, there was a greater burden of comorbidities (mean Charlson Comorbidity Index Age-Adjusted 5.3 in rural population vs. 4.8 in urban population, p = 0.05), and GP was more involved in the diagnostic pathway (51% vs. 39%, p = 0.04). The interval between the first suspected test and treatment was significantly shorter (56 vs. 66.5 days, p = 0.03). Multiple linear regression with backward elimination was run. These variables statistically predicted the time from the first suspected test and surgical treatment [F(3, 270), p < .05, R 2 = 0.24]: rurality (p = 0.04), GP involvement (p = 0.04), and presence of lung cancer-related symptoms (p = 0.02). Conclusions: In our territory with inhomogeneous population distribution and geographic barriers, residency has an impact on the lung cancer pathway. It seems paradoxical that rural patients had a shorter route. The more constant involvement of GP might explain this finding, having suggested more tests for high-risk patients in the absence of symptoms or follow-ups. This did not change the staging of surgical patients, but it might be essential for the organization of an effective lung cancer screening program. Keywords: lung cancer; rurality; screening; surgical treatment; treatment disparitie

Modello numerico di flusso e trasporto del sistema acquifero della pianura del Cecina (Toscana, Italia), con l'uso di elaborazioni GIS Groundwater Flow and Transport Model in Cecina Plain (Tuscany, Italy) using GIS processing

This work provides a groundwater flow and transport model of trichlorethylene and tetrachlorethylene contamination in the Cecina's coastal aquifer. The contamination analysis, with source located in the Poggio Gagliardo area (Montescudaio, Pisa), was necessary to optimize the groundwater monitoring and remediation design. The work was carried out in two phases: • design of a conceptual model of the aquifer using GIS analysis of many stratigraphic, chemical and hydrogeological data, collected from 2004 to 2012 in six aqueduct wells; • implementation of a groundwater flow and transport numerical model using the MODFLOW 88/96 and MT3D code and the graphical user interface GroundWaterVistas 5. The conceptual model hypothesizes a multilayer aquifer in the coastal plain extended to the sandy-clay hills, recharged by rainfall and by the Cecina River. The aquifer shows important hydrodynamic features affecting both the contamination spreading, due to the presence of a perched and heavily polluted layer separate from the underlying productive aquifer, and the hydrological balance, due to a thick separation layer that limits exchanges between the river and the second groundwater aquifer. The numerical model, built using increasingly complex versions of the initial conceptual model, has been calibrated using monitoring surveys conducted by the Environmental Protection Agency of Regione Toscana (ARPAT), in order to obtain possible forecast scenarios based on the minimum and maximum flow periods, and it is currently used as a tool for decision support regarding the reclamation and/or protection of the aquifer. Future developments will regard the implementation of the multilayer transport model, based on a new survey, and the final coupling with the regional hydrological model named MOBIDIC

MRE11 inhibition highlights a replication stress-dependent vulnerability of MYCN-driven tumors

MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors

Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease

This is the final version. Available on open access from Lippincott, Williams & Wilkins via the DOI in this recordNational Institute for Health Research (NIHR)European Union Horizon 202

Caratterizzazione idrogeologica e sviluppo di un modello numerico del sistema acquifero costiero della Versilia

L’insieme degli studi compiuti nella presente ricerca ha consentito di incrementare le conoscenze idrogeologiche, idrodinamiche ed idrogeochimiche sul sistema acquifero costiero della Versilia in una fascia di territorio che si estende tra il Fiume omonimo e il Fiume Camaiore – Fosso dell’Abate. La ricerca ha una sua specificità nell’l’impiego innovativo di codici di calcolo per lo sviluppo e la taratura di un modello di flusso e di simulazione del fenomeno di intrusione salina. La metodologia di studio è stata articolata in due fasi principali: la prima finalizzata alla definizione del modello concettuale del sistema acquifero, cioè alla realizzazione dello schema idrogeologico - idrodinamico, con particolare attenzione ai meccanismi di ricarica - discarica delle falde, all’individuazione di eventuali rapporti fiume - falda e alla caratterizzazione chimica delle acque; la seconda fase di modellazione matematica ha riguardato lo sviluppo e la taratura del modello di flusso e di simulazione del fenomeno di intrusione marina, mediante l’impiego dei softwares AQUA3D 6.0 [Vatnaskil Consulting Engineers, 2000] e FEFLOW 5.1 [WASY – Institute for Water Resources Planning and Systems Research Ltd., 2004], entrambi con discretizzazione e risoluzione numerica agli elementi finiti – FEM

Groundwater Flow and Transport Model in Cecina Plain (Tuscany, Italy) using GIS processing

This work provides a groundwater flow and transport model of trichlorethylene and tetrachlorethylene contamination in the Cecina’s coastal aquifer. The contamination analysis, with source located in the Poggio Gagliardo area (Montescudaio, Pisa), was necessary to optimize the groundwater monitoring and remediation design. The work was carried out in two phases: • design of a conceptual model of the aquifer using GIS analysis of many stratigraphic, chemical and hydrogeological data, collected from 2004 to 2012 in six aqueduct wells; • implementation of a groundwater flow and transport numerical model using the MODFLOW 88/96 and MT3D code and the graphical user interface GroundWaterVistas 5. The conceptual model hypothesizes a multilayer aquifer in the coastal plain extended to the sandy-clay hills, recharged by rainfall and by the Cecina River. The aquifer shows important hydrodynamic features affecting both the contamination spreading, due to the presence of a perched and heavily polluted layer separate from the underlying productive aquifer, and the hydrological balance, due to a thick separation layer that limits exchanges between the river and the second groundwater aquifer. The numerical model, built using increasingly complex versions of the initial conceptual model, has been calibrated using monitoring surveys conducted by the Environmental Protection Agency of Regione Toscana (ARPAT), in order to obtain possible forecast scenarios based on the minimum and maximum flow periods, and it is currently used as a tool for decision support regarding the reclamation and/or protection of the aquifer. Future developments will regard the implementation of the multilayer transport model, based on a new survey, and the final coupling with the regional hydrological model named MOBIDIC

Tracking the outcomes of surgical treatment of Stage 2 and 3 empyema: introduction and consolidation of minimally invasive approach

BACKGROUND We described the results of surgical treatment of empyema, tracing outcomes throughout the passage from the open thoracotomy (OT) approach to video-assisted thoracoscopic surgery (VATS) in a single institute. METHODS We retrospectively analyzed the records of 88 consecutive patients treated for Stage 2 and 3 empyema (2010-2019). We divided the study period into three groups: OT period (2010-2013), early VATS (2014-2017, from the introduction of VATS program, until acme of learning curve), and late VATS (2018-2019). Groups were compared to investigate the outcomes evolution. RESULTS Most relevant findings of the study were significant variation in postoperative length of stay (median [interquartile range]: 9 days [7.5-10], 10 [7.5-17.5], and 7 [5-10] for OT period, early VATS, and late VATS, respectively, p = 0.005), hospital admission referral to thoracic surgery interval (7.5 days [4.5-11], 6.5 [3-9], and 2.5 [1.5-5.5], p = 0.003), chest tube duration (5.5 days [5-7.5], 6 [4-6], 4 [3-5], p = 0.003), and proportion of operation performed by residents (3 [15%], 6 [16.7%], 14 [43.6%], p = 0.01). CONCLUSIONS Our findings pictured the trajectory evolution of outcomes during introduction and consolidation of VATS treatment of empyema. During the early phase, we observed a decline in some indicators that improved significantly in the late VATS period. After a learning curve, all outcomes showed better results and we entered into a teaching phase

Adult idiopatic occlusion of Monro foramina: intraoperative endoscopic reinterpretation of radiological data and review of the literature

Adult idiopathic occlusion of the foramen of Monro (AIOFM) is a rare condition, with only few cases described in the modern literature. We propose that AIOFM may result from unilateral or bilateral occlusion of Monro foramina, as well as from progression of a monolateral hydrocephalus. Different surgical strategies may be required for effective treatment according to the type of occlusion. To date, only 12 cases of AIOFM have been reported in the literature. We report the cases of two patients, aged 20 and 47 years respectively, who presented with intracranial hypertension secondary to bilateral ventricular dilatation due to obstruction at the level of the foramen of Monro. Both patients were successfully treated with endoscopic fenestration of the primarily obstructed foramen of Monro and, in one patient, fenestration of the septum. We propose that septum pellucidum displacement could play a role in the occlusion of the second foramen of Monro. AIOFM can, therefore, result also from unilateral stenosis of Monro. The difference in AIOFM (i.e. unilateral vs bilateral) will be useful in guiding the most suitable surgical approach in this rare condition