Publications by authors named "Antonio Russo"

595 Publications

Effectiveness of a Psychosocial Care Quality Improvement Strategy to Address Quality of Life in Patients With Cancer: The HuCare2 Stepped-Wedge Cluster Randomized Trial.

JAMA Netw Open 2021 Oct 1;4(10):e2128667. Epub 2021 Oct 1.

Medical Oncology Division, Department of Oncology, ASST of Cremona, Cremona, Italy.

Importance: Many patients with cancer who would benefit from psychosocial care do not receive it. Implementation strategies may favor the integration of psychosocial care into practice and improve patient outcomes.

Objective: To evaluate the effectiveness of the Humanization in Cancer Care (HuCare) Quality Improvement Strategy vs standard care as improvement of at least 1 of 2 domains (emotional or social function) of patient health-related quality of life at baseline and 3 months. A key secondary aim included investigation of the long-term effect.

Design, Setting, And Participants: HuCare2 was a multicenter, incomplete, stepped-wedge cluster randomized clinical trial, conducted from May 30, 2016, to August 28, 2019, in three 5-center clusters of cancer centers representative of hospital size and geographic location in Italy. The study was divided into 5 equally spaced epochs. Implementation sequence was defined by a blinded statistician; the nature of the intervention precluded blinding for clinical staff. Participants included consecutive adult outpatients with newly diagnosed cancer of any type and stage starting medical cancer treatment.

Interventions: The HuCare Quality Improvement Strategy comprised (1) clinician communication training, (2) on-site visits for context analysis and problem-solving, and (3) implementation of 6 evidence-based recommendations.

Main Outcomes And Measures: The primary outcome was the difference between the means of changes of individual scores in emotional or social functions of health-related quality of life detected at baseline and 3-month follow-up (within each group) and during the postintervention epoch compared with control periods (between groups). Long-term effect of the intervention (at 12 months) was assessed as a secondary outcome. Intention-to-treat analysis was used.

Results: A total of 762 patients (475 [62.3%] women) were enrolled (400 HuCare Quality Improvement Strategy and 362 usual care); mean (SD) age was 61.4 (13.1) years. The HuCare Quality Improvement Strategy significantly improved emotional function during treatment (odds ratio [OR], 1.13; 95% CI, 1.04-1.22; P = .008) but not social function (OR, 0.99; 95% CI, 0.89-1.09; P = .80). Effect on emotional function persisted at 12 months (OR, 1.05; 95% CI, 1.00-1.10; P = .04).

Conclusions And Relevance: In this trial, the HuCare Quality Improvement Strategy significantly improved the emotional function aspect of health-related quality of life during cancer treatment and at 12 months, indicating a change in clinician behavior and in ward organization. These findings support the need for strategies to introduce psychosocial care; however, more research is needed on factors that may maximize the effects.

Trial Registration: ClinicalTrials.gov Identifier: NCT03008993.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.28667DOI Listing
October 2021

Is there any room for PD-1 inhibitors in combination with platinum-based chemotherapy as frontline treatment of extensive-stage small cell lung cancer? A systematic review and meta-analysis with indirect comparisons among subgroups and landmark survival analyses.

Ther Adv Med Oncol 2021 21;13:17588359211018018. Epub 2021 Jul 21.

Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, Palermo, Italy.

Background: The addition of PD-L1 inhibitors to platinum-based chemotherapy (CT) has newly received United States Food and Drug Administration (FDA) approval in extensive stage-small cell lung cancer (ES-SCLC). PD-1 agents similarly improved survival rates, even if not yet supported by international regulatory agencies. The current work aims to assess different efficacy and safety profiles among chemoimmunotherapy plus immuno-oncology (CT+IO) approaches according to different immune checkpoint inhibitor (ICI) subtypes.

Material & Methods: We included in our meta-analysis six first-line randomised controlled trials (RCTs) comparing the association of single-agent ICI with CT CT alone in ES-SCLC. Pooled hazard ratios (HRs) and risk ratios (RRs) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), 12-month duration of response rate (DORR), disease control rate (DCR), treatment-related adverse events (TRAEs) and discontinuation rates (DRs) were obtained. Moreover, we performed indirect comparisons according to ICI subtypes, also among subgroups and landmark survival analyses.

Results: Although no ORR benefit was observed, our results showed how CT+IO significantly improved DORR, resulting in improved PFS and OS with no differences in TRAEs; however, CT+IO led to a significant increase in DR. Interestingly, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, the use of cisplatin, and the absence of brain metastases seem to be associated with a survival gain using CT+IO in ES-SCLC. Indirect comparisons suggested a slight advantage in favour of programmed cell death-1 (PD-1) and programmed death ligand 1 (PD-L1) over anti-CTLA-4 agents in terms of efficacy with no additional safety concerns. No further differences were observed between PD-1 and PD-L1 inhibitors among subgroups and landmark survival analyses with benefit trends towards anti-PD-1 in terms of DORR and DR.

Conclusion: While confirming a survival advantage of CT+IO in selected patients, these results suggested the association of PD-1 inhibitors with CT as a viable option for novel therapeutic approaches in the frontline management of ES-SCLC. Further trials evaluating anti-CTLA-4 agents should be carefully studied in biomarker-selected patients.
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http://dx.doi.org/10.1177/17588359211018018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8504650PMC
July 2021

S-Adenosylmethionine Supplementation May Reduce Cancer-Related Fatigue: A Prospective Evaluation Using the FACIT-F Questionnaire in Colon Cancer Patients Undergoing Oxaliplatin-Based Chemotherapy Regimens.

Chemotherapy 2021 Oct 13:1-8. Epub 2021 Oct 13.

Medical Oncology Unit, Università Campus Bio-Medico di Roma, Rome, Italy.

Background: Fatigue is a common distressing symptom for patients living with chronic or acute diseases, including liver disorders and cancer (Cancer-Related Fatigue, CRF). Its etiology is multifactorial, and some hypotheses regarding the pathogenesis are summarized, with possible shared mechanisms both in cancer and in chronic liver diseases. A deal of work has investigated the role of a multifunctional molecule in improving symptoms and outcomes in different liver dysfunctions and associated symptoms, including chronic fatigue: S-adenosylmethionine (SAM; AdoMet). The aim of this work is actually to consider its role also in oncologic settings.

Patients And Methods: Between January 2006 and December 2009, at the University Campus Bio-Medico of Rome, 145 patients affected by colorectal cancer in adjuvant (n = 91) or metastatic (n = 54; n = 40 with liver metastases) setting and treated with oxaliplatin-based regimen (FOLFOX for adjuvant and bevacizumab + XELOX for metastatic ones), 76 of which with the supplementation of S-adenosylmethionine (AdoMet; 400 mg b.i.d.) (57% of adjuvant patients and 44% of metastatic ones) and 69 without AdoMet supplementation, were evaluated for fatigue prevalence using the Functional Assessment of Chronic Illnesses Therapy-Fatigue (FACIT-F) questionnaire, at 3 and 6 months after the beginning of oncologic treatment. Notably, the number of patients with liver metastases was well balanced between the group of patients treated with AdoMet and those who were not.

Results: Among patients receiving oxaliplatin-based chemotherapy, both in adjuvant and in metastatic settings, after just 3 months from the beginning of chemotherapy, mean scores from questionnaire domains like FACIT-F subscale (7.9 vs. 3.1, p = 0.006), FACIT physical (6.25 vs. 3.32, p = 0.020), FACIT emotional (4.65 vs. 2.19, p = 0.045), and FACIT-F total score (16.5 vs. 8.27, p = 0.021) were higher in those receiving supplementation of AdoMet, resulting in reduced fatigue; a significant difference was maintained even after 6 months of treatment.

Discussion And Conclusions: Mechanisms and strategies for managing CRF are not fully understood. This work aimed at investigating the possible role of S-adenosylmethionine supplementation in improving fatigue scores in a specific setting of cancer patients, using a FACIT-F questionnaire, a well-validated quality of life instrument widely used for the assessment of CRF in clinical trials.
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http://dx.doi.org/10.1159/000517376DOI Listing
October 2021

Effectiveness and Safety of Non-Vitamin K Oral Anticoagulants in Non-Valvular Atrial Fibrillation Patients: Results of A Real-World Study in a Metropolitan Area of Northern Italy.

J Clin Med 2021 Sep 30;10(19). Epub 2021 Sep 30.

Epidemiology Unit, Agency for Health Protection (ATS) of Milan, C.so Italia, 19, 20122 Milan, Italy.

Background: New oral anticoagulant agents (NOACs) are valid alternatives for vitamin K antagonists (VKA) in patients with non-valvular atrial fibrillation (NVAF) for stroke prevention. In clinical practice, NOACs users may differ from patients enrolled in clinical trials in age or comorbidities, and thus it is a critical issue to evaluate the effectiveness and safety of NOACs in the real-world. Accordingly, we assessed two-year overall mortality and hospital admissions for myocardial infarction, stroke or bleeding in patients with NVAF users of NOACs compared to warfarin-treated patients.

Methods: This is a population-based retrospective new user active comparator study. All atrial fibrillation patients who were naïve and not switcher users of oral anticoagulants from January 2017 to December 2019 were included ( = 8543). Data were obtained from the electronic health records of the Milan Agency for Health Protection, Italy. Two-year risks for overall mortality, myocardial infarction, stroke and bleeding were computed using Cox models. Age, sex, number of comorbidities, use of platelet aggregation inhibitors and Proton pump inhibitors and area of residence were used as confounding factors. We also controlled by indication bias-weighting NOACs and warfarin users based on the weights computed by a Kernel propensity score.

Results: For all NOACs, we found a decrease in the risks compared with warfarin for mortality (from -25% to -49%), hospitalization for myocardial infarction (from -16% to -27%, statistically significant for apixaban, edoxaban and rivaroxaban) and ischemic stroke (from -23% to -41%, significant for dabigatran and apixaban). The risk of bleeding was decreased for rivaroxaban (-33%) and numerically but not significantly for the other NOACs.

Conclusions: After two years of follow-up, in comparison with warfarin, NOACs users showed a significant reduction of overall mortality (all NOACs), hospital admission for myocardial infarction (apixaban and edoxaban), ischemic stroke (dabigatran) and bleeding (rivaroxaban).
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http://dx.doi.org/10.3390/jcm10194536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509661PMC
September 2021

Clinical radiographic outcomes and survivorship of medial pivot design total knee arthroplasty: a systematic review of the literature.

Arch Orthop Trauma Surg 2021 Oct 11. Epub 2021 Oct 11.

Istituto Ortopedico Galeazzi IRCCS Chirurgia Articolare Sostitutiva e Chirurgia Ortopedica, Via Riccardo Galeazzi 4, 20161, Milan, Italy.

Background: Total knee arthroplasty is a reliable procedure able to reduce pain and disability in patients suffering from osteoarthritis. However, a considerable percentage of patients still experiences unsatisfactory results. Medial pivot total knee arthroplasty has been introduced in the clinical practice to overcome problems related with classic design implants and better mimic native knee kinematics. The aim of this study was to analyze survivorship and clinical and radiographic outcomes of medial pivot implants.

Methods: A systematic research was conducted in eight different databases. Thirty-four studies met the inclusion criteria and were included in the analysis. Data on objective and patients-reported outcomes, radiographic alignment, and survivorship were collected and analyzed. Revision rate was expressed as revision per 100 components years.

Result: A total of 3377 procedures were included. Mean follow-up was 85.7 months (range, 12-182). The revision per 100 components years was 0.19, which corresponds to a revision rate of 1.9% after 10 years. Mean post-operative range of motion was 117.3 ± 0.4°. Mean clinical and functional Knee Society Score were, respectively, 85.9 ± 1.1 and 84.7 ± 3.5 at final follow-up. Post-operative femorotibial alignment was 177.1 ± 0.5°. Alfa and beta angles were 95.7 ± 0.1° and 89.2 ± 0.1°, respectively. Gamma and delta angles were 2.3 ± 0.6° and 86.7 ± 0.4°.

Conclusion: Medial pivoting implants provided excellent survivorship and low revision rate, as well as good-to-excellent results in term of objective and patient-reported clinical outcomes, and reliable correction of radiographic parameters. More high-quality studies with long-term follow-up are needed to clarify the role of medial pivoting implants.
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http://dx.doi.org/10.1007/s00402-021-04210-6DOI Listing
October 2021

Enlarging the spectrum of cluster headache: Extracranial autonomic involvement revealed by voice analysis.

Headache 2021 Oct 7;61(9):1452-1459. Epub 2021 Oct 7.

Headache Center, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: People with cluster headache (CH) are frequently burdened by misdiagnosis or diagnostic delay. The peculiar somatic and behavioral changes characterizing patients with CH are not useful to improve diagnostic accuracy. In our clinical experience, we noticed a typical voice quality with low and croaking tone in patients with CH. In this cross-sectional study, we evaluated, by digital voice analysis, whether it is possible to identify typical voice quality characterizing patients with CH compared with healthy controls (HCs). Furthermore, to investigate whether putative differences in voice characteristics could be underpinned by constitutional aspects or pathological processes of vocal cords, subjects underwent a videolaryngostroboscopy. Smoking habits and alcohol consumption were specifically investigated.

Methods: After conducting digital recording of the voices from both patients with CH and HCs in a soundproof insulated cabin in the laboratory of the Audiology Department, a set of voice parameters was analyzed. We included the measures of fundamental frequency, calculations of jitter and shimmer, and noise-to-harmonics ratios as well as quantities related to the spectral tilt (i.e., H1-H2, H1-A1, H1-A2, and H1-A3) in 20 patients with CH and in 13 HCs. A videolaryngostroboscopy was performed in all subjects.

Results: Patients with CH, explored during the cluster bout period, showed significantly lower second harmonic (H1-H2) values compared with HCs (-6.9 ± 7.6 vs. 2.1 ± 6.7, p = 0.002), usually characterizing the so-called creaky voice. By using a laryngoscopy investigation, a significantly higher prevalence of mild to moderate vocal cord edema and laryngopharyngeal reflux signs were found in patients with CH (100% of patients with CH vs. 15% of HC, p < 0.001).

Conclusion: Creaky phonation is a "physiological mode of laryngeal operation" usually underpinned by shortened and thickened vocal folds. Creaky voice phonation can be due to a vocal fold's reduced capability to become slack or flaccid secondary to vocal cord edema underpinned by laryngopharyngeal reflux affecting the phonatory mechanisms in patients with CH. The laryngopharyngeal reflux may represent a dysautonomic sign related to the increased parasympathetic tone during in-bout period, reinforcing the hypothesis of an extracranial autonomic dysfunction as part of CH clinical picture.
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http://dx.doi.org/10.1111/head.14222DOI Listing
October 2021

Not all 557/558 codons mutations have the same prognostic influence on recurrence-free survival: breaking the exon 11 mutations in gastrointestinal stromal tumors (GISTs).

Ther Adv Med Oncol 2021 30;13:17588359211049779. Epub 2021 Sep 30.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, Palermo, Italy.

Background: Although the gastrointestinal stromal tumor (GIST) genotype is not currently included in risk-stratification systems, a growing body of evidence shows that the pathogenic variant (PV) type and codon location hold a strong prognostic influence on recurrence-free survival (RFS). This information has particular relevance in the adjuvant setting, where an accurate prognostication could help to better identify high-risk tumors and guide clinical decision-making.

Materials And Methods: Between January 2005 and December 2020, 96 patients with completely resected GISTs harboring a KIT proto-oncogene receptor tyrosine kinase () exon 11 PV were included in the study. We analyzed the type and codon location of the PV according to clinicopathological characteristics and clinical outcome; the metastatic sites in relapsed patients were also investigated.

Results: Tumors harboring a exon 11 deletion or deletion/insertion involving the 557 and/or 558 codons, showed a more aggressive clinical behavior compared with tumors carrying deletion/deletion/insertion in other codons, or tumors with duplication/insertion/single-nucleotide variant (SNV) (7-year RFS: 50% 73.1% 88.2%, respectively;  < 0.001). Notably, among 18 relapsed patients with 557 and/or 558 deletion or deletion/insertion, 14 patients (77.8%) harbored deletions simultaneously involving 557 and 558 codons, while only 4 patients (22.2%) harbored deletions involving only 1 of the 557/558 codons. Thus, when 557 or 558 deletions occurred separately, the tumor showed a prognostic behavior similar to the GIST carrying deletions outside the 557/558 position. Remarkably, patients with GISTs stratified as intermediate risk, but carrying the 557/558 deletion, showed a similar outcome to the high-risk patients with tumors harboring deletions in codons other than 557/558, or duplication/insertion/SNV.

Conclusion: Our data support the inclusion of the PV type and codon location in routine risk prediction models, and suggest that intermediate-risk patients whose GISTs harbor 557/558 deletions may also need to be treated with adjuvant imatinib like the high-risk patients.
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http://dx.doi.org/10.1177/17588359211049779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488518PMC
September 2021

The psychological correlates of fatigue in Parkinson's disease: Contribution of maladaptive metacognitive beliefs.

Parkinsonism Relat Disord 2021 Sep 29;91:135-138. Epub 2021 Sep 29.

Department of Advanced Medical and Surgical Sciences - MRI Research Center Vanvitelli-FISM, University of Campania "Luigi Vanvitelli", Piazza Miraglia 2, 80138, Naples, Italy. Electronic address:

Introduction: Psychological factors can underlie fatigue in neurological disorders, but its relationship to fatigue in Parkinson's disease (PD) has not been explored. We assessed the association between maladaptive metacognitive beliefs and presence of fatigue in PD.

Methods: Ninety-eight consecutive outpatients with PD (61% male; median age: 66.50 years) were assessed in terms of demographic, clinical, medication treatment, cognitive, or behavioural characteristics including metacognitive beliefs (Metacognitions Questionnaire-30 or MCQ). Fatigue was ascertained by PD-related diagnostic criteria. Univariate statistical approach (Mann-Whitney and Pearson chi-square tests) was used to compare PD patients with (f-PD) or without (nf-PD) fatigue in terms of demographic, clinical, medication treatment, cognitive, behavioural, and metacognitive measures.

Results: Twenty-one PD patients (21%) displayed fatigue. The f-PD group scored higher on the MCQ-total score, MCQ-Cognitive Confidence subscale, and all behavioral measures (p < 0.01) relative to nf-PD. They also had a more advanced Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale-III score.

Conclusion: Maladaptive metacognitive beliefs such as the lack of cognitive confidence may play a key role to trigger and maintain fatigue in PD. Future studies, using a multivariate statistical approach, are needed to confirm these preliminary findings in a larger sample of patients with fatigue and to assess if modification of such metacognitive beliefs has the potential to ameliorate fatigue in PD.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.020DOI Listing
September 2021

Is There a Gender Difference in the Response to onabotulinumtoxinA in Chronic Migraine? Insights from a Real-Life European Multicenter Study on 2879 Patients.

Pain Ther 2021 Sep 26. Epub 2021 Sep 26.

Neuroscience Section, Department of Applied Clinical Sciences and Biotechnology, University of L'Aquila, Via Vetoio 1 Coppito, 67100, L'Aquila, Italy.

Introduction: Migraine is mostly a female disorder because of its lower prevalence in men. Less than 20% of patients included in the available studies on migraine treatments are men; hence, the evidence on migraine treatments might not apply to men. The aims of the present study were to provide reliable information on the effectiveness of onabotulinumtoxinA (BT-A) for chronic migraine in men and to compare clinical benefits between men and women.

Methods: We performed a pooled patient-level gender-specific analysis of real-life data on BT-A for chronic migraine of patients followed-up to 9 months. We reported the 50% responder rates during each BT-A cycle, defined as percentage of reduction in monthly headache days (MHDs) compared to baseline, along with 75% and 30% responder rates. We also reported the mean decrease in MHDs and in days of acute medication use (DAMs) during each BT-A cycle as compared to baseline. We also evaluated the reasons for stopping the treatment within the third cycle.

Results: We included an overall cohort of 2879 patients, 522 of whom (18.1%) were men. In men, 50% responder rates were 27.7% during the first BT-A cycle, 29.2% during the second, and 35.6% during the third cycle; in women, the corresponding rates were 26.6%, 33.5%, and 41.0%. In the overall cohort, responder rates did not differ between men and women during the first two cycles; during the third cycle, the distribution was different (P < 0.001) mostly because of higher rates of treatment stopping and non-responders in men. In the propensity score matched cohort, the trend was maintained but lost its statistical significance. Both men and women had a significant decrease in MHDs and in DAMs with BT-A treatment (P < 0.001). There were no gender differences in those changes with the only exception of MHD decrease which, during the third cycle, was lower in men than in women (7.4 vs 8.2 days, P = 0.016 in the overall cohort and 9.1 vs 12.5 days, P = 0.009 in the propensity score matched cohort). At the end of follow-up, 152 men and 485 women stopped BT-A treatment (29.1% vs 20.6%; P < 0.001). The relative proportion of patients stopping treatment because of inadequate response (less than 30% decrease in MHDs from baseline) was higher in men than in women (42.8% vs 39.6%), while the proportion of patients stopping because of adverse events was higher in women than in men (5.6% vs 0%; P = 0.031).

Conclusions: Our pooled analysis suggests that the response to BT-A is significant in both men and women with a small gender difference in favor of women. Men tended to stop the treatment more frequently than women. We emphasize the need for more gender-specific data on migraine treatments from randomized controlled trials and observational studies.
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http://dx.doi.org/10.1007/s40122-021-00328-yDOI Listing
September 2021

Algorithm for Individual Prediction of COVID-19 Hospitalization from Symptoms: Development and Implementation Study.

JMIR Public Health Surveill 2021 Sep 14. Epub 2021 Sep 14.

Epidemiology Unit, Agency for the Protection of Health of the Metropolitan Area of Milan, Via Conca del Naviglio 45, Milan, IT.

Background: The coronavirus disease 2019 (COVID-19) pandemic has generated a huge strain on the health care system worldwide. The metropolitan area of Milan, Italy was one of the most hit area in the world.

Objective: Risk prediction models developed combining administrative data bases and basic clinical data are needed to stratify individual patient risk for public health purposes.

Methods: A predictive algorithms was developed in 36,834 COVID-19 patients between the 8th of March and the 9th of October 2020, in order to foresee the risk of being hospitalized. Exposures considered were age, sex, comorbidities and symptoms associated with COVID-19 (vomiting, cough, fever, diarrhoea, myalgia, asthenia, headache, anosmia, ageusia, and dyspnoea). The outcome was hospitalizations and emergency department admissions for COVID-19. Discrimination and calibration of the model were assessed.

Results: The predictive model showed a good fit for predicting COVID-19 hospitalization (C-index 0.79), a good overall prediction accuracy (Brier score 0.14) and was well calibrated (intercept -0.0028, slope 0.9970). Using these results, 118,804 patients with COVID-19 from October 25 to December 11, 2020 were stratified into low, medium and high risk for COVID-19 severity. Among the overall population, 67,030 (56%) were classified as low-risk, 43,886 (37%) medium-risk, and 7,888 (7%) high-risk, with 89% of the overall population being assisted at home, 9% hospitalized, and 2% dead. Among those assisted at home, most people (60%) were classified as low risk, whereas only 4% were classified at high risk. According to ordinal logistic regression, the OR of being hospitalised or dead was 5.0 (95% CI 4.6-5.4) in high-risk patients and 2.7 (95% CI 2.6-2.9) in medium-risk patients, as compared to low-risk patients.

Conclusions: A simple monitoring system, based on primary care datasets with linkage to COVID-19 testing results, hospital admissions data and death records may assist in proper planning and allocation of patients and resources during the ongoing COVID-19 pandemic.

Clinicaltrial:
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http://dx.doi.org/10.2196/29504DOI Listing
September 2021

Risk of thyroid as a first or second primary cancer. A population-based study in Italy, 1998-2012.

Cancer Med 2021 Oct 17;10(19):6855-6867. Epub 2021 Sep 17.

Mantova Cancer Registry, Epidemilogy Unit, Agenzia di Tutela della Salute (ATS) della Val Padana, Mantova, Italy.

Background: The number of patients living after a cancer diagnosis is increasing, especially after thyroid cancer (TC). This study aims at evaluating both the risk of a second primary cancer (SPC) in TC patients and the risk of TC as a SPC.

Methods: We analyzed two population-based cohorts of individuals with TC or other neoplasms diagnosed between 1998 and 2012, in 28 Italian areas covered by population-based cancer registries. Standardized incidence ratios (SIRs) of SPC were stratified by sex, age, and time since first cancer.

Results: A total of 38,535 TC patients and 1,329,624 patients with other primary cancers were included. The overall SIR was 1.16 (95% CI: 1.12-1.21) for SPC in TC patients, though no increase was shown for people with follicular (1.06) and medullary (0.95) TC. SPC with significantly increased SIRs was bone/soft tissue (2.0), breast (1.2), prostate (1.4), kidney (2.2), and hemolymphopoietic (1.4) cancers. The overall SIR for TC as a SPC was 1.49 (95% CI: 1.42-1.55), similar for all TC subtypes, and it was significantly increased for people diagnosed with head and neck (2.1), colon-rectum (1.4), lung (1.8), melanoma (2.0), bone/soft tissue (2.8), breast (1.3), corpus uteri (1.4), prostate (1.5), kidney (3.2), central nervous system (2.3), and hemolymphopoietic (1.8) cancers.

Conclusions: The increased risk of TC after many other neoplasms and of few SPC after TC questions the best way to follow-up cancer patients, avoiding overdiagnosis and overtreatment for TC and, possibly, for other malignancies.
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http://dx.doi.org/10.1002/cam4.4193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495271PMC
October 2021

Between-sex variability of resting state functional brain networks in amyotrophic lateral sclerosis (ALS).

J Neural Transm (Vienna) 2021 Sep 1. Epub 2021 Sep 1.

Department of Advanced Medical and Surgical Sciences, MRI Research Center SUN-FISM, Università degli Studi della Campania "Luigi Vanvitelli", 80138, Naples, Italy.

The organization of brain functional connectivity (FC) has been shown to differ between sexes. Amyotrophic lateral sclerosis (ALS) is characterized by sexual dimorphism, showing sex-specific trends in site of onset, phenotypes, and prognosis. Here, we explored resting state (RS) FC differences within major large-scale functional networks between women and men in a sample of ALS patients, in comparison to healthy controls (HCs). A group-level independent component analysis (ICA) was performed on RS-fMRI time-series enabling spatial and spectral analyses of large-scale RS FC networks in 45 patients with ALS (20 F; 25 M) and 31 HCs (15 F; 16 M) with a focus on sex-related differences. A whole-brain voxel-based morphometry (VBM) was also performed to highlight atrophy differences. Between-sex comparisons showed: decreased FC in the right middle frontal gyrus and in the precuneus within the default mode network (DMN), in affected men compared to affected women; decreased FC in the right post-central gyrus (sensorimotor network), in the right inferior parietal gyrus (right fronto-parietal network) and increased FC in the anterior cingulate cortex and right insula (salience network), in both affected and non-affected men compared to women. When comparing affected men to affected women, VBM analysis revealed atrophy in men in the right lateral occipital cortex. Our results suggest that in ALS sex-related trends of brain functional and structural changes are more heavily represented in DMN and in the occipital cortex, suggesting that sex is an additional dimension of functional and structural heterogeneity in ALS.
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http://dx.doi.org/10.1007/s00702-021-02413-0DOI Listing
September 2021

Disconnectome of the migraine brain: a "connectopathy" model.

J Headache Pain 2021 Aug 28;22(1):102. Epub 2021 Aug 28.

Headache Center, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", Naples, Italy.

Background: In the past decades a plethora of studies has been conducted to explore resting-state functional connectivity (RS-FC) of the brain networks in migraine with conflicting results probably due to the variability and susceptibility of signal fluctuations across the course of RS-FC scan. On the other hand, the structural substrates enabling the functional communications among the brain connectome, characterized by higher stability and reproducibility, have not been widely investigated in migraine by means of graph analysis approach. We hypothesize a rearrangement of the brain connectome with an increase of both strength and density of connections between cortical areas specifically involved in pain perception, processing and modulation in migraine patients. Moreover, such connectome rearrangement, inducing an imbalance between the competing parameters of network efficiency and segregation, may underpin a mismatch between energy resources and demand representing the neuronal correlate of the energetically dysfunctional migraine brain.

Methods: We investigated, using diffusion-weighted MRI imaging tractography-based graph analysis, the graph-topological indices of the brain "connectome", a set of grey matter regions (nodes) structurally connected by white matter paths (edges) in 94 patients with migraine without aura compared to 91 healthy controls.

Results: We observed in migraine patients compared to healthy controls: i) higher local and global network efficiency (p < 0.001) and ii) higher local and global clustering coefficient (p < 0.001). Moreover, we found changes in the hubs topology in migraine patients with: i) posterior cingulate cortex and inferior parietal lobule (encompassing the so-called neurolimbic-pain network) assuming the hub role and ii) fronto-orbital cortex, involved in emotional aspects, and visual areas, involved in migraine pathophysiology, losing the hub role. Finally, we found higher connection (edges) probability between cortical nodes involved in pain perception and modulation as well as in cognitive and affective attribution of pain experiences, in migraine patients when compared to healthy controls (p < 0.001). No correlations were found between imaging and clinical parameters of disease severity.

Conclusion: The imbalance between the need of investing resources to promote network efficiency and the need of minimizing the metabolic cost of wiring probably represents the mechanism underlying migraine patients' susceptibility to triggers. Such changes in connectome topography suggest an intriguing pathophysiological model of migraine as brain "connectopathy".
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http://dx.doi.org/10.1186/s10194-021-01315-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400754PMC
August 2021

Antitumor Effect of Cabozantinib in Bone Metastatic Models of Renal Cell Carcinoma.

Biology (Basel) 2021 Aug 16;10(8). Epub 2021 Aug 16.

Department of Medical Oncology, Campus Bio-Medico University of Rome, 00128 Rome, Italy.

Background: The presence of bone metastases in renal cell carcinoma (RCC) negatively affects patients' survival. Data from clinical trials has highlighted a significant benefit of cabozantinib in bone metastatic RCC patients. Here, we evaluated the antitumor effect of cabozantinib in coculture models of renal cell carcinoma (RCC) and osteoblasts (OBs) to investigate whether and how its antiproliferative activity is influenced by OBs.

Methods: Bone/RCC models were generated, coculturing green fluorescent protein (GFP)-tagged Caki-1 and 786-O cells with human primary OBs in a "cell-cell contact" system. RCC proliferation and the OB molecular profile were evaluated after the cabozantinib treatment.

Results: The Caki-1 cell proliferation increased in the presence of OBs ( < 0.0001), while the 786-O cell growth did not change in the coculture with the OBs. The cabozantinib treatment reduced the proliferation of both the Caki-1 ( < 0.0001) and 786-O ( = 0.03) cells cocultured with OBs. Intriguingly, the inhibitory potency of cabozantinib was higher when Caki-1 cells grew in presence of OBs compared to a monoculture ( < 0.001), and this was similar in 786-O cells alone or cocultured with OBs. Moreover, the OB pretreatment with cabozantinib "indirectly" inhibited Caki-1 cell proliferation ( = 0.040) without affecting 786-O cell growth. Finally, we found that cabozantinib was able to modulate the OB gene and molecular profile inhibiting specific proliferative signals that, in turn, could affect RCC cell growth.

Conclusions: Overall, the "direct" effect of cabozantinib on OBs "indirectly" increased its antitumor activity in metastatic RCC Caki-1 cells but not in the primary 786-O model.
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http://dx.doi.org/10.3390/biology10080781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389553PMC
August 2021

Is there any place for PD-1/CTLA-4 inhibitors combination in the first-line treatment of advanced NSCLC?-a trial-level meta-analysis in PD-L1 selected subgroups.

Transl Lung Cancer Res 2021 Jul;10(7):3106-3119

Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy.

Background: The advent of immuno-oncology (IO) represented a breakthrough in non-small cell lung cancer (NSCLC) therapy over the last few years. However, establishing the optimal therapeutic options among programmed death-ligand 1 (PD-L1) selected subgroups still addresses an unmet need in the clinical setting.

Methods: We performed a systematic review and finally included eleven first-line randomized controlled trials to compare efficacy and safety outcomes among first-line IO treatment strategies versus standard platinum-based chemotherapy (CT) according to PD-L1 expression level (<1%, 1-49%, ≥50%). Pooled hazard ratios (HRs) and risk ratios (RRs) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), treatment-related adverse events (TRAEs), and discontinuation rates were obtained.

Results: Our results demonstrated that among the different IO-based strategies (single-agent IO, Combo-IO, IO + CT) the IO + CT approach resulted in a significant increase of the ORR, albeit with no relevant improvement of survival in patients with PD-L1 ≥50%. As regards patients with negative PD-L1 expression, no significant differences in terms of activity and efficacy profile have been detected between the IO + CT and the dual checkpoint blockade. Of note, in the PD-L1 1-49% subgroup, the use of anti-PD-1 agents in association with CT led to a statistically significant gain in OS. As concerns safety, the dual checkpoint blockade seemed to be better tolerated than IO + CT.

Conclusions: This meta-analysis suggested the current limited role of PD-1/CTLA-4 inhibitors combination in PD-L1-high and/or -low advanced NSCLC patients while emerging as a potentially effective and tolerable option in particular PD-L1 negative subgroups.
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http://dx.doi.org/10.21037/tlcr-21-52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350096PMC
July 2021

Functional connectivity changes in complex migraine aura: beyond the visual network.

Eur J Neurol 2021 Aug 12. Epub 2021 Aug 12.

Headache Center, Department of Advanced Medical and Surgical Sciences, University of Campania 'Luigi Vanvitelli', Naples, Italy.

Background And Purpose: Although the majority of migraine with aura (MwA) patients experience simple visual aura, a discrete percentage also report somatosensory, dysphasic or motor symptoms (the so-called complex auras). The wide aura clinical spectrum led to an investigation of whether the heterogeneity of the aura phenomenon could be produced by different neural correlates, suggesting an increased visual cortical excitability in complex MwA. The aim was to explore whether complex MwA patients are characterized by more pronounced connectivity changes of the visual network and whether functional abnormalities may extend beyond the visual network encompassing also the sensorimotor network in complex MwA patients compared to simple visual MwA patients.

Methods: By using a resting-state functional magnetic resonance imaging approach, the resting-state functional connectivity (RS-Fc) of both visual and sensorimotor networks in 20 complex MwA patients was compared with 20 simple visual MwA patients and 20 migraine without aura patients.

Results: Complex MwA patients showed a significantly higher RS-Fc of the left lingual gyrus, within the visual network, and of the right anterior insula, within the sensorimotor network, compared to both simple visual MwA and migraine without aura patients (p < 0.001). The abnormal right anterior insula RS-Fc was able to discriminate complex MwA patients from simple aura MwA patients as demonstrated by logistic regression analysis (area under the curve 0.83).

Conclusion: Our findings suggest that higher extrastriate RS-Fc might promote cortical spreading depression onset representing the neural correlate of simple visual aura that can propagate to sensorimotor regions if an increased insula RS-Fc coexists, leading to complex aura phenotypes.
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http://dx.doi.org/10.1111/ene.15061DOI Listing
August 2021

The tumor-agnostic treatment for patients with solid tumors: a position paper on behalf of the AIOM- SIAPEC/IAP-SIBioC-SIF Italian Scientific Societies.

Crit Rev Oncol Hematol 2021 Sep 8;165:103436. Epub 2021 Aug 8.

Department of Oncology, Humanitas Gavazzeni, Bergamo, Italy.

The personalized medicine is in a rapidly evolving scenario. The identification of actionable mutations is revolutionizing the therapeutic landscape of tumors. The morphological and histological tumor features are enriched by the extensive genomic profiling, and the first tumor-agnostic drugs have been approved regardless of tumor histology, guided by predictive and druggable genetic alterations. This new paradigm of "mutational oncology", presents a great potential to change the oncologic therapeutic scenario, but also some critical aspects need to be underlined. A process governance is mandatory to ensure the genomic testing accuracy and homogeneity, the economic sustainability, and the regulatory issues, ultimately granting the possibility of translating this model in the "real world". In this position paper, based on experts' opinion, the AIOM-SIAPEC-IAP-SIBIOC-SIF Italian Scientific Societies revised the new agnostic biomarkers, the diagnostic technologies available, the current availability of agnostic drugs and their present indication.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103436DOI Listing
September 2021

POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes.

Oncogene 2021 Oct 6;40(40):5893-5901. Epub 2021 Aug 6.

Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, 90127, Palermo, Italy.

POLE, POLD1, and NTHL1 are involved in DNA replication and have recently been recognized as hereditary cancer-predisposing genes, because their alterations are associated with colorectal cancer and other tumors. POLE/POLD1-associated syndrome shows an autosomal dominant inheritance, whereas NTHL1-associated syndrome follows an autosomal recessive pattern. Although the prevalence of germline monoallelic POLE/POLD1 and biallelic NTHL1 pathogenic variants is low, they determine different phenotypes with a broad tumor spectrum overlapping that of other hereditary conditions like Lynch Syndrome or Familial Adenomatous Polyposis. Endometrial and breast cancers, and probably ovarian and brain tumors are also associated with POLE/POLD1 alterations, while breast cancer and other unusual tumors are correlated with NTHL1 pathogenic variants. POLE-mutated colorectal and endometrial cancers are associated with better prognosis and may show favorable responses to immunotherapy. Since POLE/POLD1-mutated tumors show a high tumor mutational burden producing an increase in neoantigens, the identification of POLE/POLD1 alterations could help select patients suitable for immunotherapy treatment. In this review, we will investigate the role of POLE, POLD1, and NTHL1 genetic variants in cancer predisposition, discussing the potential future therapeutic applications and assessing the utility of performing a routine genetic testing for these genes, in order to implement prevention and surveillance strategies in mutation carriers.
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http://dx.doi.org/10.1038/s41388-021-01984-2DOI Listing
October 2021

Immune checkpoint inhibitors at any treatment line in advanced NSCLC: Real-world overall survival in a large Italian cohort.

Lung Cancer 2021 09 17;159:145-152. Epub 2021 Jul 17.

Epidemiology Unit, Agency for Health Protection (ATS) of Milan, C.so Italia 52, 20122 Milano, Italy. Electronic address:

Objectives: To estimate the average treatment effect of immune checkpoint inhibitors in any line of treatment in a 2016-2018 population-based cohort of patients with advanced non-small-cell lung cancer (NSCLC).

Materials And Methods: The cohort, and information on the tumor, were derived from the cancer registry of the Agency for Health Protection of Milan, Italy. Inclusion criteria were adult age, microscopically confirmed NSCLC, stage IIIB or IV at diagnosis, and having received at least one line of treatment. Treatment with all licensed anti PD-1/PD-L1 inhibitors was derived from inpatients and outpatients' pharmaceutical databases of the ATS and vital status at 31 December 2019 from the health registry office of the Lombardy region. We investigated, with a causal approach, the relationship between survival and anti PD-1/PD-L1 treatment at any line constructing a directed acyclic graph and fitting a Marginal Structural Cox Model (MSCM).

Results: Of 1673 subjects, 324 received anti PD-1/PD-L1 at any treatment line. Overall, one-year survival was 61.1% (95 %CI, 55.6-66.2%) in the group treated with anti PD-1/PD-L1 at any line and 31.1% (95 %CI, 28.6-33.5%) among not treated. One-year hazard ratio (HR) of death for not treated vs. treated was 2.15 (95 %CI, 1.91-2.41), decreasing to 1.23 (95 %CI, 1.03-1.46) at two years and reaching one in the third year.

Conclusion: In un unselected population-based cohort with advanced lung cancer, treatment with anti PD-1/PD-L1 at any line lowered the hazard of death up to two-years from date of diagnosis, confirming the efficacy of immunotherapy outside clinical trials.
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http://dx.doi.org/10.1016/j.lungcan.2021.06.019DOI Listing
September 2021

Residential exposure to traffic-borne pollution as a risk factor for acute cardiocerebrovascular events: a population-based retrospective cohort study in a highly urbanized area.

Int J Epidemiol 2021 08;50(4):1160-1171

Epidemiology Unit, Agency for Health Protection of Milan, Milan, Italy.

Background: Long-term exposure to traffic-borne noise and air pollution has been variably associated with incidence of acute vascular events, namely acute myocardial infarction, ischaemic stroke and haemorrhagic stroke. This study aims at exploring this association within a highly urbanized city.

Methods: This is a population-based retrospective dynamic cohort study including all residents aged ≥ 35 years in the municipality of Milan over the years 2011-18 (1 087 110 inhabitants). Residential exposure to road traffic noise (day-evening-night levels) and nitrogen dioxide was estimated using a noise predictive model and a land use regression model, respectively. Cox proportional hazards regression analyses were performed to assess the incidence of acute vascular events and specific outcomes in single-exposure and two-exposure models including adjustment for sociodemographic confounders, fine particulate matter and surrounding greenness.

Results: A total of 27 282 subjects (2.5%) had an acute vascular event. Models using nitrogen dioxide produced inconsistent results. The strongest effect was observed for noise, with an optimal cut-off for dichotomization set at 70 dBA (hazard ratio 1.025, 95% confidence interval 1.000-1.050). This association was observed specifically for ischaemic and haemorrhagic stroke. When stratifying by age group and sex, a remarkable effect was found for haemorrhagic stroke in men aged <60 years (hazard ratio 1.439, 95% confidence interval 1.156-1.792).

Conclusions: Living by roads with a day-evening-night noise level above 70 dBA exerts a small but tangible independent effect on the risks of both ischaemic and haemorrhagic stroke. It is urgent to propose mitigation measures against pollution and noise originating from vehicular traffic in order to reduce their impact, especially in the population younger than 60 years.
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http://dx.doi.org/10.1093/ije/dyab068DOI Listing
August 2021

Dementia as Risk Factor for Severe Coronavirus Disease 2019: A Case-Control Study.

Front Aging Neurosci 2021 29;13:698184. Epub 2021 Jun 29.

Infectious Diseases Unit, Department of Mental Health and Public Medicine, University of Campania Luigi Vanvitelli, Naples, Italy.

Background: The aim of the present study was to investigate the outcome of patients with SARS-CoV-2 infection and dementia.

Patients And Methods: In a multicenter, observational, 1:2 matched case-control study all 23 patients with a history of dementia, hospitalized with a diagnosis of SARS-CoV-2 infection from February 28th 2020 to January 31st 2021 were enrolled. For each Case, 2 patients without dementia observed in the same period study, pair matched for gender, age (±5 years), PaO/FiO (P/F) ratio at admission (<200, or >200), number of comorbidities (±1; excluding dementia) were chosen (Control group).

Results: The majority of patients were males (60.9% of Cases and Controls) and very elderly [median age 82 years (IQR: 75.5-85) in the Cases and 80 (IQR: 75.5-83.75) in the Controls]. The prevalence of co-pathologies was very high: all the Cases and 43 (93.5%) Controls showed a Charlson comorbidity index of at least 2. During hospitalization the patients in the Case group less frequently had a moderate disease of COVID-19 (35 vs. 67.4%, = 0.02), more frequently a severe disease (48 vs. 22%, = 0.03) and more frequently died (48 vs. 22%, = 0.03). Moreover, during coronavirus disease 2019 (COVID-19), 14 (60.8%) patients in the Case group and 1 (2.1%; < 0.000) in the Control group showed signs and symptoms of delirium.

Conclusion: Patients with dementia are vulnerable and have an increased risk of a severe disease and death when infected with COVID-19.
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http://dx.doi.org/10.3389/fnagi.2021.698184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276052PMC
June 2021

Stepwise endo-/epicardial catheter ablation for atrial fibrillation: The Mediterranea approach.

J Cardiovasc Electrophysiol 2021 08 12;32(8):2107-2115. Epub 2021 Jul 12.

Department of Clinical, Special, and Dental Sciences, Cardiology and Arrhythmology Clinic, University Hospital "Ospedali Riuniti", Marche Polytechnic University, Ancona, Italy.

Background: Outcomes of catheter ablation (CA) among patients with nonparoxysmal atrial fibrillation (AF) are largely disappointing.

Objective: We sought to evaluate the feasibility, effectiveness, and safety of a single-stage stepwise endo-/epicardial approach in patients with persistent/longstanding-persistent AF.

Methods: We enrolled 25 consecutive patients with symptomatic persistent (n = 4) or longstanding-persistent (n = 21) AF and at least one prior endocardial procedure, who underwent CA using an endo-/epicardial approach. Our anatomical stepwise protocol included multiple endocardial as well as epicardial (Bachmann's bundle [BB] and ligament of Marshall ablations) components, and entailed ablation of atrial tachycardias emerging during the procedure. The primary outcome was freedom from any AF/atrial tachycardia episode after a 3-month blanking period. The secondary outcome was patients' symptom status during follow-up.

Results: The stepwise endo-/epicardial approach allowed sinus rhythm restoration in 72% of patients, either directly (n = 6, 24%) or after AF organization into atrial tachycardia (n = 12, 48%). BB's ablation was commonly implicated in arrhythmia termination. After a median follow-up of 266 days (interquartile range, 96 days), survival free from AF/atrial tachycardia was 88%. Antiarrhythmic drugs could be discontinued in 22 patients (88%). As compared to baseline, more patients were asymptomatic at 9-month follow-up (0% vs. 56%, p = .02). Five patients (20%) developed mild medical complications, whereas one subject (4%) had severe kidney injury requiring dialysis.

Conclusion: A single-stage endo-/epicardial CA resulted in favorable rhythm and symptom outcomes in a cohort of patients with symptomatic persistent/longstanding-persistent AF and one or more prior endocardial procedures. Epicardial ablation of BB was commonly implicated in procedural success.
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http://dx.doi.org/10.1111/jce.15151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457187PMC
August 2021

The prognostic relevance of HER2-positivity gain in metastatic breast cancer in the ChangeHER trial.

Sci Rep 2021 07 2;11(1):13770. Epub 2021 Jul 2.

Department of Ematology and Oncology, Pugliese-Ciaccio Hospital, Catanzaro, Italy.

In metastatic breast cancer (mBC), the change of human epidermal growth factor receptor 2 (HER2) status between primary and metastatic lesions is widely recognized, however clinical implications are unknown. Our study address the question if relevant differences exist between subjects who preserve the HER2 status and those who gain the HER2 positivity when relapsed. Data of patients affected by HER2-positive mBC, treated with pertuzumab and/or trastuzumab-emtansine (T-DM1) in a real-world setting at 45 Italian cancer centers were retrospectively collected and analyzed. From 2003 to 2017, 491 HER2-positive mBC patients were included. Of these, 102 (20.7%) had been initially diagnosed as HER2-negative early BC. Estrogen and/or progesterone receptor were more expressed in patients with HER2-discordance compared to patients with HER2-concordant status (p < 0.0001 and p = 0.006, respectively). HER2-discordant tumors were characterized also by a lower rate of brain metastases (p = 0.01) and a longer disease free interval (p < 0.0001). Median overall survival was longer, although not statistically significant, in the subgroup of patients with HER2-discordant cancer with respect to patients with HER2-concordant status (140 vs 78 months, p = 0.07). Our findings suggest that patients with HER2-positive mBC with discordant HER2 status in early BC may have different clinical, biological and prognostic behavior compared to HER2-concordant patients.
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http://dx.doi.org/10.1038/s41598-021-92774-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253801PMC
July 2021

Validazione di un nuovo algoritmo per identificare le anomalie cromosomiche utilizzando i flussi sanitari correnti: il Registro delle malformazioni congenite di Milano.

Epidemiol Prev 2021 May-Jun;45(3):196-204

UOC Epidemiology Unit, Agency for Health Protection of the Metropolitan Area of Milan (Italy);

Objectives: to assess the potential of a new algorithm based on current healthcare databases to identify potential cases of malformation, particularly chromosomal anomalies associated with terminations of pregnancy.

Design: retrospective observational study.

Setting And Participants: Registry of Congenital Anomalies of Milan, live births, still births, and termination of pregnancies for fetal anomalies from 2012 to 2016, detected by using current healthcare data.

Main Outcome Measures: prevalence between 2012 and 2016 of congenital malformations recorded by Milan's Registry of Congenital Anomalies, with particular regard to chromosomal anomaly trends. Variation in the percentage of malformations detected from terminations of pregnancy.

Results: prevalence of malformations increased from 270 in 2012 to 283 per 10,000 in 2016; specifically, chromosomal abnormalities increased from 35 to 51 per 10,000 births. The algorithm detected a greater proportion of anomalies associated with therapeutic abortion, especially with respect to chromosomal anomalies, with an increase from 57.7% in 2012 to 75.8% in 2016 (test for trend p=0.002).

Conclusions: the proposed algorithm identified a greater number of chromosomal anomalies that caused termination of pregnancy and may be applied to existing Italian registries to evaluate the quality of healthcare services, in particular with regard to the effectiveness of prenatal trisomy screening policies. The algorithm may also be used where no active surveillance systems are present, as well as in epidemiological studies, to assess environmental impact on congenital anomalies.
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http://dx.doi.org/10.19191/EP21.3.P196.065DOI Listing
July 2021

Prevalence and Spectrum of Germline and Variants of Uncertain Significance in Breast/Ovarian Cancer: Mysterious Signals From the Genome.

Front Oncol 2021 11;11:682445. Epub 2021 Jun 11.

Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, Palermo, Italy.

About 10-20% of breast/ovarian (BC/OC) cancer patients undergoing germline genetic testing have been shown to harbor Variants of Uncertain Significance (VUSs). Since little is known about the prevalence of germline VUS in Southern Italy, our study aimed at describing the spectrum of these variants detected in BC/OC patients in order to improve the identification of potentially high-risk variants helpful in patient clinical management. Eight hundred and seventy-four BC or OC patients, enrolled from October 2016 to December 2020 at the "Sicilian Regional Center for the Prevention, Diagnosis and Treatment of Rare and Heredo-Familial Tumors" of University Hospital Policlinico "P. Giaccone" of Palermo, were genetically tested for germline variants through Next-Generation Sequencing analysis. The mutational screening showed that 639 (73.1%) out of 874 patients were -, whereas 67 (7.7%) were carriers of germline VUSs, and 168 (19.2%) harbored germline pathogenic/likely pathogenic variants. Our analysis revealed the presence of 59 different VUSs detected in 67 patients, 46 of which were affected by BC and 21 by OC. Twenty-one (35.6%) out of 59 variants were located on gene, whereas 38 (64.4%) on . We detected six alterations in and two in with unclear interpretation of clinical significance. Familial anamnesis of a patient harboring the -c.3367G>T suggests for this variant a potential of pathogenicity, therefore it should be carefully investigated. Understanding clinical significance of germline VUS could improve, in future, the identification of potentially high-risk variants useful for clinical management of BC or OC patients and family members.
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http://dx.doi.org/10.3389/fonc.2021.682445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226162PMC
June 2021

Immune Checkpoint Inhibitors and Cardiotoxicity: An Analysis of Spontaneous Reports in Eudravigilance.

Drug Saf 2021 Sep 18;44(9):957-971. Epub 2021 Jun 18.

Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, Naples, Italy.

Introduction: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (ADRs). Among immune-related ADRs, cardiac immune-related ADRs are rare, but also associated with high mortality rates.

Objective: The objective of this study was to evaluate the occurrence of cardiac ADRs reported with ICIs in the European spontaneous reporting system.

Methods: We retrieved individual case safety reports on ICI-induced cardiac ADRs from the website of suspected ADR ( www.adrreports.eu ) of the European pharmacovigilance database (Eudravigilance). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to 14 March, 2020. The reporting odds ratio and its 95% confidence interval were computed to assess the reporting frequency of cardiac ADRs for each ICI compared to all other ICIs.

Results: A total of 2478 individual case safety reports with at least one ICI as the suspected drug were retrieved from Eudravigilance, of which 249 (10%) reported more than one ICI. The three most reported ICIs were nivolumab (43.2%), pembrolizumab (32.5%), and the association of nivolumab/ipilimumab (9.4%). A total of 3388 cardiac ADRs were identified. Cardiac ADRs were serious (99.4%) and had a fatal outcome (30.1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was reported with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs (reporting odds ratio 1.09, 95% confidence interval 1.01-1.18).

Conclusions: Immune checkpoint inhibitor-induced cardiac ADRs were serious and had unfavorable outcomes. In our study, nivolumab was the only ICI with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs. In this regard, further head-to-head studies are needed.
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http://dx.doi.org/10.1007/s40264-021-01086-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370948PMC
September 2021

Clinical features, disease progression, and use of healthcare resources in a large sample of 866 patients from 24 headache centers: A real-life perspective from the Italian chROnic migraiNe (IRON) project.

Headache 2021 06 14;61(6):936-950. Epub 2021 Jun 14.

Unit of Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Roma, Italy.

Objective: To develop a dedicated Italian chronic migraine (CM) database (IRON project) to overcome disease misconceptions, improve clinical administration, reduce patients' burden, and rationalize economic resource allotment.

Background: Proper CM management requires a comprehensive appraisal of its full clinical, social, and economic complexity.

Methods: In this cross-sectional study, CM patients were screened in 24 certified headache centers with face-to-face interviews. Information on sociodemographic factors, medical history, characteristics of CM, and of prior episodic migraine (EM), and healthcare resource use was gathered using a semistructured web-based questionnaire.

Results: A total of 866 CM patients were enrolled. CM started ~20 years after EM onset (age at EM onset 17.4 ± 9.1 vs. age at CM onset 35.3 ± 12.5 [mean ± SD]). CM prophylaxis, used by 430/866 (49.6%) of the patients, was often ineffective, not tolerated, and prematurely discontinued. Medications and diagnostic workup, frequently inappropriate, were mostly subsidized by the Italian national health service. CM patients with ≥25 headache days/month revealed substantial clinical differences and heavier disability and economic burden compared with those with <25 headache days/month.

Conclusions: CM is a heterogeneous headache disorder deserving more in-depth clinical characterization, sharper diagnostic criteria, and tailored treatments. CM registries are expected to improve clinical management, resulting in increased disease awareness, better healthcare resource allocation, and reduced economic burden.
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http://dx.doi.org/10.1111/head.14123DOI Listing
June 2021

Clinical relevance of clonal hematopoiesis in the oldest-old population.

Blood 2021 Jun 14. Epub 2021 Jun 14.

IRCCS Humanitas Clinical Institute, Rozzano, Italy.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
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http://dx.doi.org/10.1182/blood.2021011320DOI Listing
June 2021

Effectiveness and Safety of CGRP-mAbs in Menstrual-Related Migraine: A Real-World Experience.

Pain Ther 2021 Jun 9. Epub 2021 Jun 9.

Department of Advanced Medical and Surgical Sciences (DAMS), Headache Center, University of Campania "Luigi Vanvitelli", Piazza Miraglia 2, 80138, Naples, Italy.

Introduction: Migraine shows a significantly higher prevalence in women, especially during reproductive age when menstrual-related hormonal fluctuations represent the most common migraine trigger. Indeed, over 50% of patients report a higher occurrence of migraine attacks during the perimenstrual window. Menstrual migraine attacks are consistently referred to as more disabling, less responsive to symptomatic treatments, longer in duration, and more prone to relapse than non-menstrual migraine attacks. Evidence strongly suggests that estrogen fluctuations are involved in migraine attacks worsening during the perimenstrual window through several mechanisms directly or indirectly involving the CGRP pathway. We aimed to evaluate whether mAbs blocking CGRP-ligand or receptor (CGRP-mAbs) could represent an effective and safe preventive treatment for menstrual migraine attacks in patients with menstrual-related migraine (MRM) with previous treatment failures.

Methods: Forty patients with MRM with at least three previous treatment failures received monthly CGRP-mAbs. At the baseline and after six CGRP-mAbs administrations, patients underwent to extensive interviews to assess frequency, duration, intensity, and responsiveness to painkiller intake of migraine attacks occurring during the perimenstrual window.

Results: After six administrations of CGRP-mAbs we observed a reduction of median menstrual migraine frequency (from 5 to 2 days per month), pain intensity (from 8/10 to 6/10), and attacks duration (from 24 to 8 h) (p < 0.001). Nevertheless, a significant increase in the percentage of responding to migraine painkillers was observed from 42.5% at baseline to 95% at T1 (p < 0.001).

Conclusions: CGRP-mAbs could represent a safe and effective preventive therapeutic strategy able to reduce the disabling burden of menstrual migraine attack frequency, duration, intensity, and significantly improve the response to painkillers. These findings could be related to and further indirectly prove the greater influence of CGRP-mediated mechanisms in the pathophysiology of menstrual migraine attacks.
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http://dx.doi.org/10.1007/s40122-021-00273-wDOI Listing
June 2021

Challenges and advances for the treatment of renal cancer patients with brain metastases: From immunological background to upcoming clinical evidence on immune-checkpoint inhibitors.

Crit Rev Oncol Hematol 2021 Jul 4;163:103390. Epub 2021 Jun 4.

Department of Oncology, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar di Valpolicella, Italy.

The introduction of checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC) treatment landscape, resulted in improvements in overall survival (OS) in metastatic patients. Brain metastases (BMs) are a specific metastatic site of interest representing a predictive factor of poor prognosis. Patients with BMs were usually excluded from prospective clinical trials in the past. Despite recent evidence suggest the efficacy and safety of ICIs, the BMs treatment remains a challenge; the immunotherapy responsiveness seems to be multifactorial and dependent on several factors, such as the genetic intratumor heterogeneity and the immunosuppressive role of the brain tumor microenvironment. This review, starting from the immunological background in RCC BMs, provide an overview of the upcoming evidence from clinical trials, address the issues related to the neuroradiological immunotherapy response evaluation and, with a look to the future, describes how the epigenetic modulation of immune evasion could represent a background for new therapeutic strategies.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103390DOI Listing
July 2021
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