Concurrent deformation processes in the Matese massif area (Central-Southern Apennines, Italy)

We investigated the interseismic GPS velocity field across the transition zone between Central and Southern Apennine comprising the Meta–Mainarde-Venafro and Alto Molise–Sannio-Matese mounts. The kinematic field obtained by combining GPS network solutions is based on data collected by the unpublished episodic campaigns carried out on Southern Apennine Geodetic network (SAGNet from 2000 to 2013), IGM95 network (Giuliani et al., 2009 from 1994 to 2007) and continuous GPS stations. The data collected after the 29 December 2013 earthquake (Mw 5.0) until early 2014 allowed estimating displacements at 15 SAGNet stations. The extension rate computed across the Matese massif along an anti-Apennine profile is 2.0±0.2 mm/yr. The interseismic velocities projected along the profile show that the maximum extension does not follow the topographic high of the Apennines but is shifted toward the eastern outer belt. No significant GPS deformation corresponding to inner faults systems of the Matese massif is detected. Taking into account our results and other geophysical data, we propose a conceptual model, which identifies the 2013–2014 seismic sequence as not due to an extensional deformation style usual along the Apennine chain. In fact, we have measured too large “coseismic” displacements, that could be explained as the result of tectonic regional stress, CO2-rich fluid migration and elastic loading of water in the karst Matese massif. We recognized a tensile source as model of dislocation of 2013–2014 earthquakes. It represents a simplification of a main fault system and fracture zone affecting the Matese massif. The dislocation along NE-dipping North Matese Fault System (NMFS) could be the driving mechanism of the recent seismic sequences. Moreover, to the first time the SAGnet GPS data collected from 1994 to 2014, are share and available to the scientific community in the open access data archive.INGV and DPCS1-C1 - 2012-2021.Published2282342T. Deformazione crostale attivaJCR Journa

Association of immune-related adverse events with the outcomes of immune checkpoint inhibitors in patients with dMMR/MSI-H metastatic colorectal cancer

Background: Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs. Methods: We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models. Results: Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two's effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, 'aggregated' burden scores were developed to distinguish 'protective' (endocrine and musculoskeletal) and 'harmful' (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS. Conclusions: Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response

Upfront Modified Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Panitumumab Versus Fluorouracil, Leucovorin, and Oxaliplatin Plus Panitumumab for Patients With RAS/BRAF Wild-Type Metastatic Colorectal Cancer: The Phase III TRIPLETE Study by GONO

PURPOSE To verify whether the intensification of the upfront chemotherapy backbone with a modified schedule of modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) increases the activity of fluorouracil, leucovorin, and oxaliplatin when both regimens are combined with panitumumab as initial treatment for RAS and BRAF wild-type (wt) metastatic colorectal cancer (mCRC).METHODS TRIPLETE was a prospective, open-label, phase III trial in which previously untreated patients with unresectable RAS and BRAF wt mCRC were randomly assigned 1:1 to modified FOLFOX/panitumumab (control group) or mFOLFOXIRI/panitumumab (experimental group) up to 12 cycles, followed by fluorouracil/-leucovorin/panitumumab until disease progression. The primary end point was objective response rate (ORR) according to RECIST 1.1. Hypothesizing an ORR of 60% in the control group, 432 cases provided 90% power to a two-sided chi-square test for heterogeneity with a two-sided alpha error of .05 to detect >= 15% differences between arms (ClinicalTrials.gov identifier: NCT03231722).RESULTS From September 2017 to September 2021, 435 patients were enrolled (control group/experimental group: 217/218) in 57 Italian sites. One hundred sixty (73%) patients treated with mFOLFOXIRI plus panitumumab and 165 (76%) patients treated with modified FOLFOX plus panitumumab achieved RECIST response (odds ratio 0.87, 95% CI, 0.56 to 1.34, P= .526). No differences in early tumor shrinkage rate (57%/58%, P = .878) and deepness of response (median: 48%/47%, P = .845) were reported, nor in RO resection rate (25%/29%, P = .317). No significant difference between arms was reported in terms of progression-free survival (median progression-free survival: 12.7 in the experimental group v 12.3 months in the control group, hazard ratio: 0.88, 95% CI, 0.70 to 1.11, P = .277).CONCLUSION The intensification of the upfront chemotherapy backbone in combination with panitumumab does not provide additional benefit in terms of treatment activity at the price of increased gastrointestinal toxicity in patients with RAS and BRAF wt mCRC. (C) 2022 by American Society of Clinical Oncolog

TRIBE-2: A phase III, randomized, open-label, strategy trial in unresectable metastatic colorectal cancer patients by the GONO group

Background: Chemotherapy plus bevacizumab is a standard first-line treatment for unresectable metastatic colorectal cancer patients. Different chemotherapy backbones may be chosen, including one to three drugs, based on patients' general conditions and comorbidities, treatments' objectives, and disease characteristics. TRIBE trial demonstrated a significant advantage in terms of progression-free survival and overall survival for FOLFOXIRI plus bevacizumab as compared with FOLFIRI plus bevacizumab. Based on recent evidence, the de-intensification of the upfront regimen after 4-6 months of treatment is nowadays regarded as a valuable option. Moreover, the prolonged inhibition of angiogenesis, and in particular the continuation of bevacizumab beyond the evidence of disease progression, is an efficacious strategy in the treatment of metastatic colorectal cancer patients. Methods/design: TRIBE-2 is a prospective, open-label, multicentric phase III randomized trial in which unresectable and previously untreated metastatic colorectal cancer patients are randomized to receive first-line FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression or FOLFOXIRI plus bevacizumab followed by the re-introduction of the same regimen after disease progression. The primary endpoint is to compare the efficacy of the two proposed treatment strategies in terms of Progression Free Survival 2. Discussion: The TRIBE-2 study aims at answering the question whether the upfront use of FOLFOXIRI improves the clinical outcome of metastatic colorectal cancer patients, when compared with the pre-planned, sequential use of oxaliplatin-based and irinotecan-based doublets. Both proposed treatment strategies are designed to exploit the effectiveness of the prolonged inhibition of angiogenesis, alternating short (up to 4 months) induction periods and less intensive maintenance phases. Trial registration: TRIBE2 is registered at Clinicaltrials.gov: NCT02339116. January 12, 2015. TRIBE-2 is registered at EUDRACT 2014-004436-19, October 10, 2014

Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the “CARACAS” study

Background: Molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking. Patients and methods: In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. On pre-treatment tumour tissue samples, we assessed Human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by FoundationOne CDx. Tumour-infiltrating lymphocytes were characterised on haematoxylin-eosine-stained samples. Primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. Secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers. Results: High PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01-0.68; p = 0.019) and PFS (HR = 0.44; 95%CI = 0.15-1.27; p = 0.129). High expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19-1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20-0.92; p = 0.03). Neither OS (HR = 1.30; 95%CI = 0.72-2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74-2.31; p = 0.357) was affected by high (>1.2) Tumour-infiltrating lymphocytes count. High TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13-0.81; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23-1.00; p = 0.015). Conclusions: To our knowledge, TranslaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors

Intra-and extra-hospitalization monitoring of vital signs. Two sides of the same coin. Perspectives from Lims and Greenline study operators

Background: In recent years, due to the epidemiological transition, the burden of very complex patients in hospital wards has increased. Telemedicine usage appears to be a potential high-impact factor in helping with patient management, allowing hospital personnel to assess conditions in out-of-hospital scenarios. Methods: To investigate the management of chronic patients during both hospitalization for disease and discharge, randomized studies (LIMS and Greenline-HT) are ongoing in the Internal Medicine Unit at ASL Roma 6 Castelli Hospital. The study endpoints are clinical outcomes (from a patient’s perspective). In this perspective paper, the main findings of these studies, from the operators’ point of view, are reported. Operator opinions were collected from structured and unstructured surveys conducted among the staff involved, and their main themes are reported in a narrative manner. Results: Telemonitoring appears to be linked to a reduction in side-events and side-effects, which represent some of most commons risk factors for re-hospitalization and for delayed discharge during hospitalization. The main perceived advantages are increased patient safety and the quick response in case of emergency. The main disadvantages are believed to be related to low patient compliance and an infrastructural lack of optimization. Conclusions: The evidence of wireless monitoring studies, combined with the analysis of activity data, suggests the need for a model of patient management that envisages an increase in the territory of structures capable of offering patients subacute care (the possibility of antibiotic treatments, blood transfusions, infusion support, and pain therapy) for the timely management of chronic patients in the terminal phase, for which treatment in acute wards must be guaranteed only for a limited time for the management of the acute phase of their diseases

An Unusual Case of Fulminant Heart Failure

A 51-year-old patient presented with a 10-day history of breathlessness and back pain. Significant background his- tory included human immunodeficiency virus-2 and hepatitis C virus infections. Physical examination showed end-inspiratory crackles and muffled cardiac sounds and his blood test showed an increased aspartate aminotransferase level (500 IU/L), ala- nine aminotransferase level (654 IU/L), and lactate dehydroge- nase level (2354 IU/L). His chest radiograph confirmed pulmo- nary edema, and the echocardiogram showed severe pericardial effusion (2.5 cm). A computed tomography scan of the chest showed an incidental finding of a 5-cm liver mass at the liver dome. The patient was admitted to the intensive care unit to undergo percutaneous drainage of his pericardial effusion, and he died a few hours later of acute heart failure unresponsive to cardiovascular support. The patient underwent a post-mortem examination. The liver and the heart are shown in Figures A and B, respectively. Figure A shows a multifocal liver tumor ranging in size from 1 to 7 cm maximum. The heart, the pericardium, and the aortic arch were widely involved by metastatic deposits (Figure B). A section of the vertebral bones and the lungs also showed further small metastatic deposits. Initial histology of the liver lesions and the heart showed small-cell carcinoma (SmCC) (Figure C, tumor cells between myocardial cells, H&E, original magnification, 100). We performed immunohisto- chemistry on the pulmonary deposits to rule out a primary pulmonary SmCC. No positivity was seen for thyroid transcrip- tion factor-1, caudal type homeobox transcription factor 2, CK7, CK20, chromogranin, synaptophysin, or CD56. Immuno- histochemical stains for hepatocyte paraffin 1 (Figure D), car- cinoembryonic antigen, and -fetoprotein showed a strong pos- itivity and TTF-1 negativity. On the basis of the macroscopic framework and immunohistochemical features, a diagnosis of metastatic SmCC of the liver was made. Cardiac metastases from hepatocellular carcinoma are very uncommon.1 Hepatic SmCCs are even more uncommon: to our knowledge, only 13 cases have been reported.2 They usually present with locally advanced or metastatic disease, and no disease-free survivors have been reported to date. Interestingly, they do not show any association with chronic liver disease or with hepatitis C/hepatitis B viruses, and high fetoprotein levels also seem to be uncommon

Tissutal and Fluidic Aspects in Osteopathic Manual Therapy: A Narrative Review

Over the years, several authors have discussed the possibility of considering somatic dysfunction (SD) as a “nosological element” detectable on palpation. There are many aspects to consider regarding the etiology and diagnosis of SD, and the literature on osteopathic issues provides details on physiological signs that characterize it, including tissue texture changes. Recent knowledge suggests that how tissue and, in particular, connective tissue, responds to osteopathic treatment may depend on the modulation of the inflammation degree. Low-grade inflammation (LGI) may act on the extracellular matrix (ECM) and on cellular elements; and these mechanisms may be mediated by biological water. With its molecules organized in structures called exclusion zones (EZ), water could explain the functioning of both healthy and injured tissues, and how they can respond to osteopathic treatment with possible EZ normalization as a result. The relationship between inflammation and DS and the mechanisms involved are described by several authors; however, this review suggests a new model relating to the characteristics of DS and to its clinical implications by linking to LGI. Tissue alterations detectable by osteopathic palpation would be mediated by body fluids and in particular by biological water which has well-defined biophysical characteristics. Research in this area is certainly still to be explored, but our suggestion seems plausible to explain many dynamics related to osteopathic treatment. We believe that this could open up a fascinating scenario of therapeutic possibilities and knowledge in the future

Pedestrian Inattention Blindness While Playing Pokémon Go as an Emerging Health-Risk Behavior: A Case Report

Cases of trauma resulting from the use of mobile phones while driving motor vehicles have become quite common in recent years. Road injuries incurred by people playing video games on mobile phones (or other media devices) while walking have also become a cause for concern. Pokémon Go has been the world's most popular game since it was launched in July 2016, with more than 15 million players trying to catch all Pokémon available in the game; however, the case detailed here is the first reported accident in the medical literature caused by a pedestrian distracted by the game while crossing a street

Tomato Yield, Quality, Mineral Composition and Antioxidants as Affected by Beneficial Microorganisms Under Soil Salinity Induced by Balanced Nutrient Solutions

With the aim of assessing the effects of beneficial microorganisms on greenhouse tomato “plum” grown under salinity conditions, research was carried out in southern Italy from summer to winter, by comparing two arbuscular mycorrhizal fungi (AMF) based formulates (Rizotech Plus, Myco Apply DR) and a non-inoculated control, in factorial combination with four soil electrical conductivities (1.5, 3.0, 4.5, 6.0 mS·cm−1 EC). The highest root colonization was 83% at 3.0 mS·cm−1 under AMF-based treatments and 34% at 1.5 mS·cm−1 in non-treated control; the latter attained lower values than AMF treatments at any soil EC. Harvest occurred 3.5 days earlier in control plants, six days earlier under 6.0 mS·cm−1 EC compared to 1.5 mS·cm−1. The inoculated plants always showed higher yield than the control ones and the highest production at 4.5 mS·cm−1 EC; control plants attained the highest yield under 3.0−4.5 mS·cm−1 EC. The highest values of most fruit quality indicators, mineral elements and antioxidant compounds and activity were recorded under AMF-based formulates inoculation and 6.0 mS·cm−1 soil EC. Beneficial microorganisms proved to be an effective environmentally friendly tool for improving tomato yield and quality performances in both normal and soil salinity conditions