Biomarker-Guided Anti-Egfr Rechallenge Therapy in Metastatic Colorectal Cancer

Anticossos monoclonals anti-EGFR; Càncer colorectal metastàticAnticuerpos monoclonales anti-EGFR; Cáncer colorrectal metastásicoAnti-EGFR monoclonal antibodies; Metastatic colorectal cancerThe prognosis of patients with metastatic colorectal cancer (mCRC) who progressed to the first and the second lines of treatment is poor. Thus, new therapeutic strategies are needed. During the last years, emerging evidence suggests that retreatment with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MAbs) in the third line of mCRC patients, that have previously obtained clinical benefit by first-line therapy with anti-EGFR MAbs plus chemotherapy, could lead to prolonged survival. The rationale beyond this “rechallenge” strategy is that, after disease progression to first line EGFR-based therapy, a treatment break from anti-EGFR drugs results in RAS mutant cancer cell decay, restoring the sensitivity of cancer cells to cetuximab and panitumumab. In fact, rechallenge treatment with anti-EGFR drugs has shown promising clinical activity, particularly in patients with plasma RAS and BRAF wild type circulating tumor DNA, as defined by liquid biopsy analysis at baseline treatment. The aim of this review is to analyze the current knowledge on rechallenge and to investigate the role of novel biomarkers that can guide the appropriate selection of patients that could benefit from this therapeutic strategy. Finally, we discuss on-going trials and future perspectives.Regione Campania (I-Cure Research Project, Grant number: Cup 21C17000030007), Gruppo Oncologico dell’Italia Meridionale (GOIM)

CLINICAL RESULTS OF COLLAGENASE TREATMENT FOR DUPUYTREN’S DISEASE: A CASE SERIES STUDY WITH 2-YEARS FOLLOW-UP

ABSTRACT Objectives: This study aims to report our experience with Clostridium Histolyticum collagenase (CCH) to support the importance of its clinical use and assess its clinical efficacy, complications, and recurrences. Methods: This prospective observational study of 66 patients with a 2-year follow-up. Patients with an extension lag major of 20° at the metacarpophalangeal joint (MPJ) and/or proximal interphalangeal joint (PIPJ) were included. We collected data on demographic and anamnestic details, MPJ and PIPJ contracture degrees, DASH score, complications, and recurrences. Results: The mean pre-injection contracture was 34° for MPJ and 31° for PIPJ. At the 2-year follow-up, the mean contracture for the MPJ and PIPJ were respectively 3° and 14.5°. The mean DASH score decreased from 21.8 before injection to 10,4 after 2 years. The disease recurrence occurred in 34.8% of the patients, all with PIPJ contracture. The main complication was skin breakage (25.7%). Conclusion: The CCH injections remain a consistent option in treating DD; withdrawal from the European market deprives surgeons and patients of low invasiveness and safe tool for treating DD. Level of evidence IV, Therapeutic study investigating treatment results, Case series

Retrospective Study of Regorafenib Versus TAS-102 Efficacy and Safety in Chemorefractory Metastatic Colorectal Cancer (mCRC) Patients: A Multi-institution Real Life Clinical Data

INTRODUCTION: There have been significant developments in colorectal cancer (CRC) research over the last few years, with the introduction of new agents that have been prolonged median overall survival of metastatic colorectal cancer (mCRC). These therapies have improved patient outcomes; however, despite significant progress in strategies for cancer treatment, their use is limited by development of resistant mechanism. Almost 30% of patients with refractory mCRC will remain good candidates for further treatment. Regorafenib and TAS-102 are novel antitumor agents for patients with refractory mCRC. However, it is unclear which patients may derive a survival benefit from these drugs in real-life clinical practice.; METHODS: We performed a retrospective analysis evaluating safety and efficacy of TAS-102 and regorafenib in a cohort of refractory mCRC patients, in 3 different centers between January 1 2018 and May 31 2020, with the aim of assessing the optimal sequence treatment for these 2 drugs.; RESULTS: One hundred and forty mCRC patients were included in the analysis. Of these patients, 64 received regorafenib and 76 received TAS-102 as first treatment. After progression, in the regorafenib 24 (37%) patients switched to secondary treatment with TAS-102, instead, in the TAS-102 group, among 76 patients, 29 (45%) patients switched to secondary treatment with regorafenib. Disease control was achieved in 8 (12.5%) of 64 patients in the regorafenib group and 17 (22.4%) of 76 patients in the TAS-102 group. In terms of efficacy, the PFS and OS were similar in both treatment groups for primary and secondary treatments. AEs reported in this analysis were mostly consistent with the known safety profiles of regorafenib and TAS-102 in previous clinical trials.; CONCLUSION: The present study is the first one to compare the activity of the two agents in a large cohort of chemo-refractory mCRC patients providing more details about the best sequence, to be incorporated in clinical practice. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved

Antitumor Efficacy of Dual Blockade with Encorafenib + Cetuximab in Combination with Chemotherapy in Human BRAFV600E-Mutant Colorectal Cancer

PURPOSE: Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC. EXPERIMENTAL DESIGN: We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed. RESULTS: Antitumor activity of either FOLFIRI or E+C was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after E+C and a 45% loss of efficacy of E+C after FOLFIRI (P \u3c 0.001 for both). FOLFIRI-treated models had upregulation of epithelial-mesenchymal transition (EMT) and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared with E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control. CONCLUSIONS: These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC

The Gene Ontology knowledgebase in 2023

The Gene Ontology (GO) knowledgebase (http://geneontology.org) is a comprehensive resource concerning the functions of genes and gene products (proteins and noncoding RNAs). GO annotations cover genes from organisms across the tree of life as well as viruses, though most gene function knowledge currently derives from experiments carried out in a relatively small number of model organisms. Here, we provide an updated overview of the GO knowledgebase, as well as the efforts of the broad, international consortium of scientists that develops, maintains, and updates the GO knowledgebase. The GO knowledgebase consists of three components: (1) the GO-a computational knowledge structure describing the functional characteristics of genes; (2) GO annotations-evidence-supported statements asserting that a specific gene product has a particular functional characteristic; and (3) GO Causal Activity Models (GO-CAMs)-mechanistic models of molecular "pathways" (GO biological processes) created by linking multiple GO annotations using defined relations. Each of these components is continually expanded, revised, and updated in response to newly published discoveries and receives extensive QA checks, reviews, and user feedback. For each of these components, we provide a description of the current contents, recent developments to keep the knowledgebase up to date with new discoveries, and guidance on how users can best make use of the data that we provide. We conclude with future directions for the project

I diritti fondamentali in epoca di pandemia: esperienze a confronto Seminario interno del Corso di Alta Formazione in Giustizia costituzionale e tutela giurisdizionale dei diritti, anno 2021

Il Volume raccoglie i contributi di alcuni dei partecipanti al Seminario interno alla X edizione del Corso di Alta Formazione in Giustizia costituzionale e tutela giurisdizionale dei diritti fondamentali, organizzato dal Dipartimento di Giurisprudenza dell’Università di Pisa nel gennaio 2021. Il Corso, di cui tra il gennaio e il febbraio 2022 si è tenuta l’XI edizione, ha rappresentato negli anni tanto per i partecipanti come per i docenti un’occasione unica di proficuo confronto sulle tecniche e sugli strumenti di tutela dei diritti fondamentali, nell’ambito del quale si collocano a pieno titolo le testimonianze portate dai Corsisti su quello che oggi costituisce senza dubbio “il tema” dell’Agenda globale

I diritti fondamentali in epoca di pandemia: esperienze a confronto. Seminario interno al Corso di Alta Formazione in Giustizia costituzionale e tutela giurisdizionale dei diritti

Il Volume raccoglie i contributi di alcuni dei partecipanti al Seminario interno alla X edizione del Corso di Alta Formazione in Giustizia costituzionale e tutela giurisdizionale dei diritti fondamentali, organizzato dal Dipartimento di Giurisprudenza dell’Università di Pisa nel gennaio 2021. Il Corso, di cui tra il gennaio e il febbraio 2022 si è tenuta l’XI edizione, ha rappresentato negli anni tanto per i partecipanti come per i docenti un’occasione unica di proficuo confronto sulle tecniche e sugli strumenti di tutela dei diritti fondamentali, nell’ambito del quale si collocano a pieno titolo le testimonianze portate dai Corsisti su quello che oggi costituisce senza dubbio “il tema” dell’Agenda globale

Synergies between buildings retrofit and district heating. The role of DH in a decarbonized scenario for the city of Milano

The goal of this work is to present challenges and opportunities for the development of 4th generation district heating in future decarbonized scenarios for the Italian city of Milano. The work has been developed in the framework of a Climate-KIC project to support Milano municipality in developing decarbonization measures. The first part of the work consists in the evaluation of a geographical distribution of the civil sector heat demand according to a bottom-up approach based on open data. Thanks to this statistical tool, also buildings retrofit can be analysed. Three retrofit scenarios are simulated according to policy goals for 2030 and 2050, foreseeing a retrofit priority of worst energy performances buildings, resulting in 8.8TWh, for the first two scenarios, and 9.4TWh for the last one. The areas characterized by the majority of retrofit can be identified as the most suitable for low temperature district heating development. Renewables and low temperature waste heat sources are also assessed, resulting in 9.8TWh of available heat. The application of district heating in combination with the identified renewables is assessed in these scenarios with a clustering approach. The evaluation of potential diffusion of 4GDH is based on the comparison between the overall cost of district heating and the competing individual systems costs: district heating is considered feasible only in retrofitted buildings where district heating cost is lower than individual systems cost (about 0.7TWh in each scenarios). The retrofitting scenarios combined with the diffusion of renewable based 4GDH are assessed also in terms of environmental impact. The current greenhouse gas emissions related to the actual heating systems, evaluated through the Thermal Systems Regional Cadastre database, is compared to the district heating development scenarios and to individual heat pump system scenarios. The results show the highest reduction of emission in the district heating scenarios (65%)

Energy mapping and district heating as effective tools to decarbonize a city: Analysis of a case study in Northern Italy

The process of achieving decarbonization and greenhouse emissions’ reduction goals is facilitated and accelerated by the implementation of renewable-based DH rather than multiple individual renewables systems. This work presents an application case that demonstrates how an energy system based on conventional and carbon-emitting heat supply sources can be converted in a fully renewable network. In its current configuration, the city under study, located in Northern Italy, gets 40% of the total 160GWh of heat demand of the DH from a waste-to-energy plant, 9% from a biomass-fuelled ORC, 33% from natural gas cogeneration and 18% from natural gas boilers. In order to support the city’s municipality in developing decarbonization measures through the modernization of the current district heating network, the aim of this work is to investigate in detail the possibility to integrate local renewable and excess heat sources, whose availability and synergy with the heat demand has been highlighted by a recent mapping-based project developed with the Italian DH Association, AIRU, on the whole Italian territory. The present work can be therefore seen as a validation case study of the methodology developed at large-scale level in the latter project. The results of that analysis show that there are the conditions to meet 90% of the heating needs of the DH with renewables and waste heat recovery from two already existing plants, namely a wastewater treatment plant (WWTP) and a steelwork. The approach used in this work, in which different scenarios of integration are simulated in energyPRO, brought to the definition of the energy mix which evidenced a favourable cost–benefits ratio: 59% of thermal energy from the steelwork, 31% from the WWTP, 5% from the natural gas CHP and 5% from the boilers