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Sabrina Bimonte,1,* Piergiacomo Di Gennaro,2,* Anna Crispo,2 Sergio Coluccia,2 Assunta Luongo,2 Alfonso Amore,3,4 Egidio Celentano,2 Francesco Del Prato,1 Daniela Schiavo,1 Davide Nocerino,1 Marco Cascella,5 Arturo Cuomo1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 2Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 3Melanoma and Sarcoma Surgery Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 4PhD School of Applied Medical-Surgical Sciences, University of Rome Tor Vergata, Rome, Italy; 5Department of Medicine, University of Salerno, Salerno, Italy*These authors contributed equally to this workCorrespondence: Anna Crispo, Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Via Mariano Semmola 53, Naples, Italy, Tel +39 081 17770298, Email a.crispo@istitutotumori.na.itPurpose: Breakthrough cancer pain (BTcP) is a temporary exacerbation of pain that “breaks through” a phase of adequate pain control by an opioid-based therapy. The non-predictable BTcP (NP-BTcP) subtype occurs in the absence of any specific activity. Evidence showed that gender differences exist in pain response sensitivity and clinical pain risk. This analysis aimed to signify the gender differences for the NP-BTcP phenomenon.Patients and Methods: This is a secondary analysis of the Italian Oncologic Pain multiSetting-Multicentric Survey (IOPS-MS), the largest study on BTcP. The subset of NP-BTcP cases for non-gender-specific cancer was considered. Univariable and multivariate analyses were conducted to identify gender differences for the NP-BTcP profile about its intensity, number of episodes per day, and type. A metastatic status-stratified analysis was performed to compare gender with the main clinical variables among the population with NP-BTcP.Results: Males exhibited a higher occurrence of BTcP in the thorax region compared to females (15% vs 11%, respectively, p = 0.03). Males also had a higher onset of BTcP, a higher BTcP therapy dosage (33% vs 28%, p = 0.04, mean: 201 vs 186, p = 0.02) and a lower Karnofsky score (mean: 46.9 vs 49.2, p = 0.03) compared to females. Similar gender differences were found for metastatic patients in the BTcP site (14% vs 8.5%, respectively; p = 0.01), peak onset (33% vs 27%, p = 0.02), BTcP therapy dosage (199 vs 185, p=0.04), and Karnofsky score (mean 47.5 vs 50.4, p = 0.009). Phenotype 2 was more characterized by non-metastatic males (41% vs 23%, p = 0.020) while non-metastatic females presence was predominant among others.Conclusion: In this study, gender differences according to site, onset and dosage of BTcP were found. The phenotype characterization of BTcP needs to be further investigated for a possible useful function in the management of cancer-related pain in non-metastatic patients.Keywords: non-predictable breakthrough cancer pain, gender cancer pain, cluster analysis

Marco Cascella,1 Federica Monaco,2 Ornella Piazza1 1Anesthesia and Pain Medicine, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081, Italy; 2Anesthesia and Pain Management, ASL NA/1, Naples, ItalyCorrespondence: Marco Cascella, Anesthesia and Pain Medicine, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via S. Allende, Baronissi, 84081, Italy, Email m.cascella@istitutotumori.na.it; mcascella@unisa.it

Tamara Zec,1 Raffaela Di Napoli,1 Lydwine Fievez,1 Mohamed Ben Aziz,1 Alessandro Ottaiano,2 Alessandro Vittori,3 Francesco Perri,4 Marco Cascella5 1Department of Anesthesiology, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, 1000, Belgium; 2SSD Innovative Therapies for Abdominal Metastases, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, 80100, Italy; 3Department of Anesthesia and Critical Care, ARCO ROMA, Ospedale Pediatrico Bambino Gesù IRCCS, Piazza S. Onofrio 4, Rome, 00165, Italy; 4Medical and Experimental Head and Neck Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, 80100, Italy; 5Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, 80100, ItalyCorrespondence: Francesco Perri, Email f.perri@istitutotumori.na.itAbstract: In cancer patients undergoing surgery, tumor biology and anticancer treatments can increase the risk of perioperative bleeding and blood transfusions. Notably, blood transfusions can be potentially associated with an increased risk of life-threatening immune responses, acute lung injury, postoperative infections, and thromboembolism. Moreover, the link between perioperative transfusion and increased risk of cancer recurrence cannot be excluded. On the other hand, cancer patients have an increased risk of thromboembolism due to cancer itself and antineoplastic systemic treatments including chemotherapy and anti-angiogenic drugs. In this complex scenario, effective and safe strategies aimed at the prevention of blood transfusions are warranted. This narrative review addresses the efficacy, and the safety of the synthetic antifibrinolytic agent tranexamic acid (TXA) when used perioperatively in cancer surgery. Although in not oncologic surgery the use of TXA has been extensively studied, in the setting of cancer patients requiring surgery, the evidence is scarce. An overview of the ongoing clinical research is also provided.Keywords: tranexamic acid, cancer surgery, oncology, anemia, blood transfusion, anti-fibrinolytic

Rossella Di Franco,1 Marco Cascella,2 Mario Fusco,3 Valentina Borzillo,1 Esmeralda Scipilliti,1 Piera Ferraioli,1 Eva Iannacone,1 Giampaolo De Palma,1 Giustino Silvestro,1 Federica Gherardi,1 Sergio Buonopane,1 Domingo Alberti,1 Giuseppe Totaro,1 Roberto Manzo,1 Giovanna Guida,1 Arturo Cuomo,2 Sandro Pignata,4 Marilena Di Napoli,4 Sabrina Rossetti,4 Egidio Celentano,5 Anna Crispo,5 Maria Grimaldi,5 Vincenzo Ravo,1 Paolo Muto1 1Department of Radiation Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia; 2Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Napoli, Italia; 3Cancer Registry Unit, ASL Napoli 3 SUD, Napoli, Italia; 4Department of Uro-Gynecological, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia; 5Epidemiology and Biostatistics Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, ItaliaCorrespondence: Rossella Di Franco, Department of Radiation Oncology, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italia, Email r.difranco@istitutotumori.na.itBackground: In the Italian Campania Region, 30.517 new cases of solid cancer have been diagnosed, in 2019. Of those, patients with metastatic disease are up to 20%. This class of patients is extremely diversified and copious, and the offer of radiotherapy may vary in different geographical areas within the same region. The aim of this observational multicenter retrospective and prospective trial is to evaluate the occurrence of metastatic metastatic cancer patients candidates for palliative radiotherapy in several areas of a great Italian region, the management of the disease through RT approaches, and its impact on cancer-related pain and overall HRQoL.Methods: This is a multicenter, retrospective and prospective observational investigation. The retrospective part of the study concerns all patients enrolled with a diagnosis of metastatic disease and treated in RT centers within the Campania Region between January 2019 and July 2020. The prospective phase is going to involve all the metastatic patients with an indication of palliative RT. Considering regional epidemiological data, we expect an enrollment of 12.500– 21.000 patients in 5 years.Conclusion: The MAMETIC Trial in an observational study designed for investigating on the use of radiotherapy in patients with advanced disease within a regional area, and for evaluating the local response to the patient’s request. It can be a unique opportunity, not only to highlight possible geographic differences but also to regularly collect and share data to standardize the therapeutic offer within the regional area. ClinicalTrials.gov ID NCT04595032, retrospectively registered.Keywords: palliative care, metastatic disease, radiotherapy, cancer pain, breakthrough cancer pain, quality of life

Sabrina Bimonte,1,* Cira Antonietta Forte,1,* Massimiliano Cuomo,2 Gennaro Esposito,1 Marco Cascella,1 Arturo Cuomo1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy; 2S.C. Project Management e Formazione, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy*These authors contributed equally to this workCorrespondence: Sabrina BimonteDivision of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, ItalyEmail s.bimonte@istitutotumori.na.itAbstract: Coronavirus disease-19 (COVID-19) pandemic is currently ongoing worldwide and causes a lot of deaths in many countries. Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the US FDA to counteract the emergency. Thus, it can be useful to find alternative therapies based on the employment of natural compounds, with antiviral features, to circumvent SARS-CoV-2 infection. Pre-clinical studies highlighted the antiviral activities of epigallocatechin-3-gallate (EGCG), a catechin primarily found in green tea, against various viruses, including SARS-CoV-2. In this review, we summarize this experimental evidence and highlight the potential use of EGCG as an alternative therapeutic choice for the treatment of SARS-CoV-2 infection.Keywords: COVID-19, EGCG, SARS-CoV-2, tea polyphenols, antiviral properties

Alessandro Vittori,1 Emiliano Petrucci,2 Marco Cascella,3 Massimo Innamorato,4 Arturo Cuomo,3 Antonino Giarratano,5 Flavia Petrini,6 Franco Marinangeli7 1Department of Anesthesia and Critical Care, ARCO ROMA, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy; 2Department of Anesthesia and Intensive Care Unit, San Salvatore Academic Hospital of L’Aquila, L’Aquila, Italy; 3Department of Anesthesia and Critical Care, Istituto Nazionale Tumori - IRCCS, Fondazione Pascale, Naples, Italy; 4Department of Neuroscience, Pain Unit, Santa Maria delle Croci Hospital, AUSL Romagna, Ravenna, Italy; 5Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), Section of Anaesthesia, Analgesia, Intensive Care and Emergency, Policlinico Paolo Giaccone, University of Palermo, Palermo, Italy; 6SIAARTI (Italian Society of Anaesthesia, Analgesia, Reanimation and Intensive Care Medicine), Rome, Italy; 7Department of Anesthesiology, Intensive Care and Pain Treatment, University of L’Aquila, L’Aquila, ItalyCorrespondence: Alessandro VittoriDepartment of Anesthesia and Critical Care, ARCO ROMA, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, Rome, 00165, ItalyEmail alexvittori82@gmail.comBackground: Increased attention to the functional impact of chronic pain (CP), as highlighted by the 11th revision of the International Classification of Diseases (ICD-11) and advocated by the International Classification of Functioning, Disability and Health (ICF), is an important step forward for optimizing its management. Evidence about perspectives of Italian physicians on the relevance of musculoskeletal (MSK) pain care to improve patients’ functioning and Quality of Life is scant. The study aimed to investigate the physicians’ perception of the value of functional recovery in severe MSK pain patients, their attitude towards its assessment and achievement in Italy.Methods: A survey was conducted in Italy between October 2020 and January 2021. Specialist centers members of the SIAARTI (n = 395) were sent an online questionnaire encompassing the Italian pain therapy network. Participants rated their agreement to questionnaire items according to a 5-point Likert-type scale.Results: A total of 305 centers (77%) completed the survey. Most physicians rated the recovery of functioning as very relevant in MSK pain treatment and, when they assessed it, devoted great attention to the ability to perform daily activities, pain, ability to ambulate and sleep quality. Multidimensional questionnaires were less employed in favor of physical examination and pain intensity scales. Pharmacological therapy, rehabilitation and lifestyle changes and/or physical exercise were all rated optimal strategies to pursue the recovery of patients’ functioning. When considering pharmacological therapy, weak and strong opioids, either alone or combined with paracetamol, were the most frequently employed analgesics.Conclusion: Clinicians seem to recognize the recovery of functioning as equally important as pain intensity reduction, but there is a need of streamlining available tools to effectively assess both across different MSK pain patients.Keywords: chronic musculoskeletal pain, recovery of functioning, pain care models

Marco Cascella,1 Alfredo Del Gaudio,2 Alessandro Vittori,3 Sabrina Bimonte,1 Paola Del Prete,4 Cira Antonietta Forte,1 Arturo Cuomo,1 Elvio De Blasio2,5 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, Italy; 2DSC Anestesia e Rianimazione 2, IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013, FG, Italy; 3Department of Anesthesiology and Critical Care, ARCO, Bambino Gesù Children’s Hospital, Rome, Italy; 4Direzione Scientifica, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, Italy; 5Multidisciplinary Emergency Unit for COVID-19 Campania, Naples, 80100, ItalyCorrespondence: Sabrina BimonteDivision of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, ItalyTel +39 0815903221Email s.bimonte@istitutotumori.na.itAbstract: Although the respiratory manifestations of COVID-19 are predominant, signs and symptoms of an extra-pulmonary involvement are usually encompassed among the clinical picture of the disease. Several painful manifestations can occur during the acute phase but also as short- or long-term complications. Myalgia, joint pain, sore throat, abdominal pain, chest pain, and headache usually accompany respiratory symptoms, but they can also occur as isolated clinical findings or can be expressed regardless of the severity of COVID-19. On these premises, given the vast spectrum of clinical manifestations and the complexity of their pathogenesis, it would be more appropriate to refer to “COVID-pain”, an umbrella term useful for encompassing all these clinical manifestations in a separate chapter of the disease. In this scenario, we addressed the topic from a molecular perspective, trying to provide explanations for the underlying pathophysiological processes. Consequently, this narrative review is aimed at dissecting the mechanisms of acute and chronic painful manifestations, summarizing fundamental concepts on the matter, controversies, current research gaps, and potential developments in this field.Keywords: COVID-19, SARS-CoV-2, COVID-pain, COVID-19 complications

Marco Cascella,1 Sabrina Bimonte,1 Raffaela Di Napoli2 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – “Fondazione G. Pascale, Naples, Italy; 2Department of Anesthesiology, Institut Jules Bordet, Université Libre De Bruxelles, Bruxelles 1000, BelgiumCorrespondence: Marco CascellaDivision of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – “Fondazione G. Pascale, Via Semmola 1. 80100, Naples, ItalyTel +39 0815903221Fax +39 0815903778Email m.cascella@istitutotumori.na.itAbstract: The emergence from anesthesia is the stage of general anesthesia featuring the patient’s progression from the unconsciousness status to wakefulness and restoration of consciousness. This complex process has precise neurobiology which differs from that of induction. Despite the medications commonly used in anesthesia allow recovery in a few minutes, a delay in waking up from anesthesia, called delayed emergence, may occur. This phenomenon is associated with delays in the operating room, and an overall increase in costs. Together with the emergence delirium, the phenomenon represents a manifestation of inadequate emergence. Nevertheless, in delayed emergence, the transition from unconsciousness to complete wakefulness usually occurs along a normal trajectory, although slowed down. On the other hand, this awakening trajectory could proceed abnormally, possibly culminating in the manifestation of emergence delirium. Clinically, delayed emergence often represents a challenge for clinicians who must make an accurate diagnosis of the underlying cause to quickly establish appropriate therapy. This paper aimed at presenting an update on the phenomenon, analyzing its causes. Diagnostic and therapeutic strategies are addressed. Finally, therapeutic perspectives on the “active awakening” are reported.Keywords: general anesthesia, anesthesia emergence, delayed emergence, emergence delirium

Sabrina Bimonte, Marco Cascella Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – “Fondazione G. Pascale, Naples, ItalyCorrespondence: Sabrina Bimonte Email s.bimonte@istitutotumori.na.itAbstract: Ovarian cancer represents the principal leading cause of women dying in the world. The first standard of care involved surgical resection followed by chemotherapy with taxane and platinum, mainly connected with cytotoxic chemotherapies causing diverse severe side effects. Unfortunately, recurrence represents a significant problem, and finally, patients develop resistance to cytotoxic chemotherapy. Other alternative treatments had been developed so far to reduce side effects; however, the outcomes are yet not empowering. Current shreds of evidence showed that epigallocatechin-3-gallate (EGCG) possesses an anticancer effect on ovarian carcinoma, mainly through the inhibition of different genetic signaling pathways which are closely linked with tumorigenesis. This review recapitulates these findings and highlights the roles of EGCG for the chemoprevention and treatment of ovarian cancer.Keywords: epigallocatechin-3-gallate, EGCG, ovarian cancer, antitumor properties, chemoprevention

Arturo Cuomo,1 Anna Crispo,2 Andrea Truini,3 Silvia Natoli,4 Orazio Zanetti,5 Paolo Barone,6 Marco Cascella11Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 2S.C. Epidemiologia e Biostatistica, Istituto Nazionale Tumori, IRCCS Fondazione G. Pascale, Naples, Italy; 3Department of Human Neuroscience, University Sapienza, Rome, Italy; 4Department of Clinical Science and Translational Medicine, Tor Vergata University of Rome, Rome, Italy; 5U.O. Alzheimer, IRCCS Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy; 6Center for Neurodegenerative Disease-CEMAND, University of Salerno, Fisciano, ItalyAbstract: In Parkinson’s disease (PD), pain represents a significant issue in terms of prevalence, clinical features, and treatment. Painful manifestations not strictly related to the disease are often amplified by the motor dysfunction. On the other hand, typical pain problems may specifically concern this vulnerable population. In turn, pain may have a deep impact on patients’ health-related quality of life. However, pain treatment in PD remains an unmet need as only about half of patients with pain use analgesics and pain is often managed by simply increasing doses of PD medications. In this complex scenario, pain treatments should follow multimodal approaches through a careful combination of pharmacological agents with non-pharmacological strategies, depending on the type of pain and the clinical context. A multidisciplinary approach involving medical specialists from different disciplines could be a winning strategy to address the issue. This work is aimed to provide practical suggestions useful for different types of clinicians and care professionals for pain management in this vulnerable population.Keywords: Parkinson disease, pain management, pain assessment, opioids, acetaminophen, non-steroidal anti-inflammatory agents

Aldo Giudice,1 Antonio Barbieri,2 Sabrina Bimonte,3 Marco Cascella,3 Arturo Cuomo,3 Anna Crispo,1 Giovanni D’Arena,4 Massimiliano Galdiero,5 Maria Elena Della Pepa,5 Gerardo Botti,6 Michele Caraglia,7 Mario Capunzo,8 Claudio Arra,2 Maurizio Montella11Epidemiology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 2S.S.D Sperimentazione Animale, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 3Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy; 4Hematology and Stem Cell Transplantation Unit, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; 5Department of Experimental Medicine, Università della Campania “Luigi Vanvitelli”, 80134 Naples, Italy; 6Scientific Direction, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, Naples, Italy; 7Department of Biochemistry, Biophysics and General Pathology, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; 8Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081 Salerno, ItalyAbstract: Breast cancer is the most common malignancy among women worldwide. Various studies indicate that prolonged exposure to elevated levels of estrogens is associated with development of breast cancer. Both estrogen receptor-dependent and independent mechanisms can contribute to the carcinogenic effects of estrogens. Among them, the oxidative metabolism of estrogens plays a key role in the initiation of estradiol-induced breast cancer by generation of reactive estrogen quinones as well as the associated formation of oxygen free radicals. These genotoxic metabolites can react with DNA to form unstable DNA adducts which generate mutations leading to the initiation of breast cancer. A variety of endogenous and exogenous factors can alter estrogen homeostasis and generate genotoxic metabolites. The use of specific phytochemicals and dietary supplements can inhibit the risk of breast cancer not only by the modulation of several estrogen-activating enzymes (CYP19, CYP1B1) but also through the induction of various cytoprotective enzymes (eg, SOD3, NQO1, glutathione S-transferases, OGG-1, catechol-O-methyltransferases, CYP1B1A, etc.) that reestablish the homeostatic balance of estrogen metabolism via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent and independent mechanisms.Keywords: reactive estrogen quinones, breast carcinogenesis, depurinating estrogen–DNA adducts, dietary phytochemicals, nuclear factor erythroid 2-related factor 2

Arturo Cuomo,1,* Sabrina Bimonte,1,* Cira Antonietta Forte,1 Gerardo Botti,2 Marco Cascella1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy; 2Scientific Direction, Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy *These authors contributed equally to this work Abstract: Chronic pain is described as a manifestation of real or potential tissue damage. It is identified as a perception influenced by the complex interactions of biological, psychological, and social factors. Different types of pain and their comorbidities dramatically affect patients’ quality of life and their families. Due to diverse etiology and pathogenesis, pain management represents a controversial issue in clinical practice. In 1986, the WHO developed a three-step ladder model based on the use of analgesics for pain management according to pain intensity in a linear up or down movement. Despite its huge value for pain relief, this model has some limitations, and some controversies in the pharmacotherapy of pain management have arisen so far. To bypass these difficulties, the concept of WHO analgesic ladder has been contested and changed into a four bidirectional step model which postulates the use of the invasive procedures (neuromodulatory and neurosurgical procedures). Moreover, with the introduction of the neuromatrix theory for dealing the acute and the chronic pain, the WHO model was newly reinterpreted and changed into a platform analgesic model that includes multimodal pharmacological and alternative treatments applicable to all pain conditions, although excludes the precision therapies. Here, we summarize and revise these concepts in order to propose a new model termed “trolley analgesic model” that will allow adopting tailored therapies with dynamic multimodal approaches for pain management according to 1) the pain intensity, 2) the physiopathology of pain, 3) the complexity of symptoms, 4) the presence of comorbidity, and 5) the physiopathological factors and the social context. Keywords: cancer and no-cancer pain management, personalized treatment, analgesic trolley, multimodal approaches

Sabrina Bimonte,1 Vittorio Albino,2 Mauro Piccirillo,2 Aurelio Nasto,3 Carlo Molino,4 Raffaele Palaia,2 Marco Cascella1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy; 2Division of Hepatobiliary Surgical Oncology, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy; 3UOC Chirurgia Generale ad Indirizzo Oncologico, POA Tortora, Pagani, Salerno, Italy; 4A Cardarelli Chirurgia Generale – AORN, Naples, Italy Abstract: Hepatocellular carcinoma (HCC), a primary liver malignancy, is one of the deadliest cancers worldwide. Despite orthotopic liver transplantation and hepatic resection representing the principal lines of treatment for this pathology, only a minority of patients can be resected owing to cirrhosis or late diagnosis. Keeping in mind the end goal of conquering these challenges, new alternative approaches have been proposed. Accumulating evidence has demonstrated that epigallocatechin-3-gallate (EGCG), the principal catechin of green tea with multiple biological properties, is able to modulate different molecular mechanisms underlying HCC, mainly through its antioxidant activity. In this article, we revise these findings reported in the literature, in order to highlight the potential roles of EGCG in the treatment of HCC. The CAMARADES criteria were applied for quality assessment of animal studies, and a narrative synthesis performed. New bits of information available for translational perspectives into clinical practice are addressed. Keywords: hepatocellular carcinoma, epigallocatechin-3-gallate, tumor progression, preclinical studies

M Cascella,1 CA Forte,1 S Bimonte,1 G Esposito,1 C Romano,2 R Costanzo,2 A Morabito,2 A Cuomo1 1Department of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy; 2Thoracic Medical Oncology, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy Background: Previous studies have shown the efficacy of tapentadol (TP) for chronic cancer pain. We evaluated multiple effectiveness aspects of TP prolonged release on moderate–severe cancer-related pain, neuropathic pain (NeP), patient satisfaction, and quality of life. Methods: An observational prospective study was conducted on 80 cancer patients. Opioid-naïve patients received a starting dose of prolonged-release TP 50 mg twice daily, and opioid-experienced patients were switched to TP, not to exceed 500 mg/day. Treatment response was evaluated at 3, 6, 30–40, and 60–70 days through response rate, numeric rating-scale scoring, survival analysis (time to event for response), pain-intensity difference, TP escalation-index percentage, and effects on NeP. The drug-sparing effect on concomitant therapies was evaluated. Results: Seventy of 80 patients (88%) were responders to treatment (95% CI 78%–94%). Compared to T0, pain-intensity reductions were statistically significant for all intervals (P

Sabrina Bimonte,1,* Antonio Barbieri,2,* Marco Cascella,1,* Domenica Rea,2,* Giuseppe Palma,2 Vitale Del Vecchio,2 Cira Antonietta Forte,1 Francesco Del Prato,1 Claudio Arra,1 Arturo Cuomo2 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – “Fondazione G. Pascale”, 2Animal Facility Unit, Department of Research, National Cancer Institute “G. Pascale”, Naples, Italy *These authors contributed equally to this work Background: Naloxone is viewed as a specific competitive opioid antagonist acting at the level of opioid receptors (µ, δ, and κ) with blended agonist-adversary or agonist action. The role of naloxone in tumor cell growth has been poorly studied in human cancer cell lines.Materials and methods: In the present study, we report findings from in vitro and in vivo experiments performed to evaluate the effects of naloxone on human breast cancer cell growth and progression. In vitro assays were conducted on estrogen receptor-negative human breast carcinoma cells, MDA.MB231, treated with naloxone at different concentrations (10–100 µM). In vivo experiments were performed on a mouse model of human triple-negative breast cancer generated by using MDA.MB231 injected subcutaneously in mice. Naloxone was daily intraperitoneally injected in mice at 0.357 mg/kg for 2 weeks and at 0.714 mg/kg for the next 2 weeks. Microvessels formation was detected by fluorescein isothiocyanate-dextran (100 µL) injected into the tail vein of mice and confirmed by immunohistochemistry with CD31 on mice tumor sections.Results: In vitro tests showed that the cell proliferation of MDA.MB231 was inhibited by naloxone in a dose-dependent manner, whereas the cell death was increased. In vivo studies demonstrated that tumors of mice treated with naloxone were significantly smaller than those observed in the control groups, as long as naloxone was administered. Finally, naloxone was not able to impair the microvessel formation in tumors of treated mice.Conclusion: Our data showed, for the first time, that naloxone reduced breast cancer progression without affecting angiogenesis. Keywords: naloxone, breast cancer, proliferation, microvessel formation, angiogenesis

Marco Fiore,1,* Marco Cascella,2,* Sabrina Bimonte,2 Alberto Enrico Maraolo,3 Ivan Gentile,3 Vincenzo Schiavone,4 Maria Caterina Pace1 1Department of Anaesthesiological, Surgical and Emergency Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy; 2Department of Support for Clinical Activities and Critical Area, Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS “Fondazione G. Pascale”, Via Mariano Semmola, Naples, Italy; 3Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy; 4Division of Anesthesia and Intensive Care, Hospital “Pineta Grande”, Castel Volturno, Italy *These authors contributed equally to this work Abstract: Fungal infections of the liver, most commonly caused by Candida spp., often occur in patients with hematologic malignancies treated with chemotherapy. Colonization of the gastrointestinal tract is thought to be the main origin of dissemination of Candida; mucositis and neutropenia facilitate the spread of Candida from the gastrointestinal tract to the liver. Hepatic involvement due to other fungi is a less common infectious complication in this setting. Fungal infections represent a less common cause of hepatic abscesses in non-oncohematologic population and the trend appears to be decreasing in recent years. Understanding of the etiology and epidemiology of fungal infections of the liver is indicated for an appropriate antimicrobial therapy and an overall optimal management of fungal liver infections. Keywords: fungal liver infections, antifungal agents, hepatosplenic candidiasis, acute disseminated candidiasis, life-threatening infections

Marco Fiore,1 Alberto Enrico Maraolo,2 Sebastiano Leone,3 Ivan Gentile,2 Arturo Cuomo,4 Vincenzo Schiavone,5 Sabrina Bimonte,4 Maria Caterina Pace,1 Marco Cascella4 1Department of Anaesthesiological, Surgical and Emergency Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy; 2Department of Clinical Medicine and Surgery, Section of Infectious Diseases, University of Naples Federico II, Naples, Italy; 3Division of Infectious Diseases, “San Giuseppe Moscati” Hospital, Avellino, Italy; 4Division of Anesthesia, Department of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – Fondazione G. Pascale, Naples, Italy; 5Division of Anesthesia and Intensive Care, Hospital “Pineta Grande”, Castel Volturno, Italy Abstract: Spontaneous peritonitis (SP) is the most common infection among decompensated end-stage liver disease patients. SP is the infection of ascitic fluid (neutrophil ascitic count ≥250/mL) without an alternative focus of abdominal infection. According to the causative agent, clinicians can make the diagnosis of spontaneous bacterial peritonitis or spontaneous fungal peritonitis. The mortality rate is very high, ranging from one-fifth of the patients with spontaneous bacterial peritonitis to four-fifths of the patients with spontaneous fungal peritonitis. An immediate and accurate diagnosis can improve the outcome in end-stage liver disease patients. The aim of this work is to provide physicians with a practical diagnostic guidance for SP diagnosis according to current evidence, in order to improve the management of cirrhotic patients with infected ascitic fluid. Keywords: cirrhosis, spontaneous bacterial peritonitis, spontaneous fungal peritonitis, bacteriascites, fungal ascites

Sabrina Bimonte,1,* Marco Cascella,1,* Vincenzo Schiavone,2 Farrokh Mehrabi-Kermani,3 Arturo Cuomo1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori – IRCCS – “Fondazione G. Pascale”, Naples, Italy; 2Division of Anesthesia and Intensive Care, Hospital “Pineta Grande”, Castel Volturno, Caserta, Italy; 3Division of Neurosurgery, Hospital “Pineta Grande”, Castel Volturno, Caserta, Italy *These authors contributed equally to this work Abstract: Neuropathic pain (NP) is a complex and chronic disease caused by lesions or defects of the somatosensory nervous system. The treatments normally used for managing NP usually lack efficacy. Several animal models of NP have been engineered in order to understand the molecular mechanisms underlying NP and to find alternative molecules to use as new therapeutic agents. Preclinical in vivo studies identified the epigallocatechin-3-gallate (EGCG), a main active component of green tea (Camellia sinensis), as a possible therapeutic molecule for NP treatment due to its anti-inflammatory and antioxidant properties. Interestingly, it has been shown that EGCG reduced bone cancer pain. The purpose of this article is to discuss the potential use of EGCG for control and treatment of NP, by reviewing the preclinical studies reported in the literature and by shedding light on the potential schemes based on EGCG’s application in clinical practices. Keywords: epigallocatechin-3-gallate, EGCG, natural compound, neuropathic pain, animal models of neuropathic pain, cancer bone pain

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9  GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36  GeV/c^{2}, rejecting cross sections above 9.2×10^{-48}  cm at the 90% confidence level.

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector.

We estimate the amount of Ar37 produced in natural xenon via cosmic-ray-induced spallation, an inevitable consequence of the transportation and storage of xenon on the Earth's surface. We then calculate the resulting Ar37 concentration in a 10-tonne payload (similar to that of the LUX-ZEPLIN experiment) assuming a representative schedule of xenon purification, storage, and delivery to the underground facility. Using the spallation model by Silberberg and Tsao, the sea-level production rate of Ar37 in natural xenon is estimated to be 0.024 atoms/kg/day. Assuming the xenon is successively purified to remove radioactive contaminants in 1-tonne batches at a rate of 1 tonne/month, the average Ar37 activity after 10 tons are purified and transported underground is 0.058-0.090 μBq/kg, depending on the degree of argon removal during above-ground purification. Such cosmogenic Ar37 will appear as a noticeable background in the early science data, while decaying with a 35-day half-life. This newly noticed production mechanism of Ar37 should be considered when planning for future liquid-xenon-based experiments.

The nature of dark matter and properties of neutrinos are among the mostpressing issues in contemporary particle physics. The dual-phase xenontime-projection chamber is the leading technology to cover the availableparameter space for Weakly Interacting Massive Particles (WIMPs), whilefeaturing extensive sensitivity to many alternative dark matter candidates.These detectors can also study neutrinos through neutrinoless double-beta decayand through a variety of astrophysical sources. A next-generation xenon-baseddetector will therefore be a true multi-purpose observatory to significantlyadvance particle physics, nuclear physics, astrophysics, solar physics, andcosmology. This review article presents the science cases for such a detector.

The reference to the article is Manuscript ID EPJC-20-06-042 from the internal review perspective. The reference to the article as published, is: (Table presented.).

The projected sensitivity of the LUX-ZEPLIN (LZ) experiment to two-neutrino and neutrinoless double β decay of Xe134 is presented. LZ is a 10-tonne xenon time-projection chamber optimized for the detection of dark matter particles and is expected to start operating in 2021 at Sanford Underground Research Facility, USA. Its large mass of natural xenon provides an exceptional opportunity to search for the double β decay of Xe134, for which xenon detectors enriched in Xe136 are less effective. For the two-neutrino decay mode, LZ is predicted to exclude values of the half-life up to 1.7×1024 years at 90% confidence level (CL) and has a three-sigma observation potential of 8.7×1023 years, approaching the predictions of nuclear models. For the neutrinoless decay mode LZ, is projected to exclude values of the half-life up to 7.3×1024 years at 90% CL.

LUX-ZEPLIN is a dark matter detector expected to obtain world-leading sensitivity to weakly-interacting massive particles interacting via nuclear recoils with a ∼7-tonne xenon target mass. This paper presents sensitivity projections to several low-energy signals of the complementary electron recoil signal type: 1) an effective neutrino magnetic moment, and 2) an effective neutrino millicharge, both for pp-chain solar neutrinos, 3) an axion flux generated by the Sun, 4) axionlike particles forming the Galactic dark matter, 5) hidden photons, 6) mirror dark matter, and 7) leptophilic dark matter. World-leading sensitivities are expected in each case, a result of the large 5.6 t 1000 d exposure and low expected rate of electron-recoil backgrounds in the

LUX-ZEPLIN (LZ) is a dark matter detector expected to obtain world-leadingsensitivity to weakly interacting massive particles (WIMPs) interacting vianuclear recoils with a ~7-tonne xenon target mass. This manuscript presentssensitivity projections to several low-energy signals of the complementaryelectron recoil signal type: 1) an effective neutrino magnetic moment and 2) aneffective neutrino millicharge, both for pp-chain solar neutrinos, 3) an axionflux generated by the Sun, 4) axion-like particles forming the galactic darkmatter, 5) hidden photons, 6) mirror dark matter, and 7) leptophilic darkmatter. World-leading sensitivities are expected in each case, a result of thelarge 5.6t 1000d exposure and low expected rate of electron recoil backgroundsin the $

The LUX-ZEPLIN dark matter search aims to achieve a sensitivity to the WIMP-nucleon spin-independent cross-section down to (1–2)×10−12 pb at a WIMP mass of 40 GeV/c2. This paper describes the simulations framework that, along with radioactivity measurements, was used to support this projection, and also to provide mock data for validating reconstruction and analysis software. Of particular note are the event generators, which allow us to model the background radiation, and the detector response physics used in the production of raw signals, which can be converted into digitized waveforms similar to data from the operational detector. Inclusion of the detector response allows us to process simulated data using the same analysis routines as developed to process the experimental data.

Two-phase xenon detectors, such as that at the core of the forthcoming LZdark matter experiment, use photomultiplier tubes to sense the primary (S1) andsecondary (S2) scintillation signals resulting from particle interactions intheir liquid xenon target. This paper describes a simulation study exploringtwo techniques to lower the energy threshold of LZ to gain sensitivity tolow-mass dark matter and astrophysical neutrinos, which will be applicable toother liquid xenon detectors. The energy threshold is determined by the numberof detected S1 photons; typically, these must be recorded in three or morephotomultiplier channels to avoid dark count coincidences that mimic realsignals. To lower this threshold: a) we take advantage of the doublephotoelectron emission effect, whereby a single vacuum ultraviolet photon has a$\sim20\%$ probability of ejecting two photoelectrons from a photomultipliertube photocathode; and b) we drop the requirement of an S1 signal altogether,and use only the ionization signal, which can be detected more efficiently. Forboth techniques we develop signal and background models for the nominalexposure, and explore accompanying systematic effects, including the dependenceon the free electron lifetime in the liquid xenon. When incorporating doublephotoelectron signals, we predict a factor of $\sim 4$ sensitivity improvementto the dark matter-nucleon scattering cross-section at $2.5$ GeV/c$^2$, and afactor of $\sim1.6$ increase in the solar $^8$B neutrino detection rate.Dropping the S1 requirement may allow sensitivity gains of two orders ofmagnitude in both cases. Finally, we apply these techniques to even lowermasses by taking into account the atomic Migdal effect; this could lower thedark matter particle mass threshold to $80$ MeV/c$^2$.

LUX-ZEPLIN (LZ) is a second-generation direct dark matter experiment with spin-independent WIMP-nucleon scattering sensitivity above 1.4×10-48cm2 for a WIMP mass of 40GeV/c2 and a 1000days exposure. LZ achieves this sensitivity through a combination of a large 5.6t fiducial volume, active inner and outer veto systems, and radio-pure construction using materials with inherently low radioactivity content. The LZ collaboration performed an extensive radioassay campaign over a period of six years to inform material selection for construction and provide an input to the experimental background model against which any possible signal excess may be evaluated. The campaign and its results are described in this paper. We present assays of dust and radon daughters depositing on the surface of components as well as cleanliness controls necessary to maintain background expectations through detector construction and assembly. Finally, examples from the campaign to highlight fixed contaminant radioassays for the LZ photomultiplier tubes, quality control and quality assurance procedures through fabrication, radon emanation measurements of major sub-systems, and bespoke detector systems to assay scintillator are presented.

The LUX-ZEPLIN (LZ) experiment will enable a neutrinoless double β decay search in parallel to the main science goal of discovering dark matter particle interactions. We report the expected LZ sensitivity to Xe136 neutrinoless double β decay, taking advantage of the significant (>600 kg) Xe136 mass contained within the active volume of LZ without isotopic enrichment. After 1000 live-days, the median exclusion sensitivity to the half-life of Xe136 is projected to be 1.06×1026 years (90% confidence level), similar to existing constraints. We also report the expected sensitivity of a possible subsequent dedicated exposure using 90% enrichment with Xe136 at 1.06×1027 years.

Deep underground environments are ideal for low background searches due to the attenuation of cosmic rays by passage through the earth. However, they are affected by backgrounds from γ-rays emitted by 40K and the 238U and 232Th decay chains in the surrounding rock. The LUX-ZEPLIN (LZ) experiment will search for dark matter particle interactions with a liquid xenon TPC located within the Davis campus at the Sanford Underground Research Facility, Lead, South Dakota, at the 4850-foot level. In order to characterise the cavern background, in-situ γ-ray measurements were taken with a sodium iodide detector in various locations and with lead shielding. The integral count rates (0–3300 keV) varied from 596 Hz to 1355 Hz for unshielded measurements, corresponding to a total flux from the cavern walls of 1.9 ± 0.4 γ cm−2s−1. The resulting activity in the walls of the cavern can be characterised as 220 ± 60 Bq/kg of 40K, 29 ± 15 Bq/kg of 238U, and 13 ± 3 Bq/kg of 232Th.

We describe the design and assembly of the LUX-ZEPLIN experiment, a direct detection search for cosmic WIMP dark matter particles. The centerpiece of the experiment is a large liquid xenon time projection chamber sensitive to low energy nuclear recoils. Rejection of backgrounds is enhanced by a Xe skin veto detector and by a liquid scintillator Outer Detector loaded with gadolinium for efficient neutron capture and tagging. LZ is located in the Davis Cavern at the 4850’ level of the Sanford Underground Research Facility in Lead, South Dakota, USA. We describe the major subsystems of the experiment and its key design features and requirements.