Impact of the healthcare reorganization of the Local Health Authority services in Rieti (Italy) during the SARS-CoV-2 pandemic.

Background: The need to contain the spread of the SARS-CoV-2 pandemic has forced national and local organizations to define and implement targeted emergency response and management measures. As the knowledge about the infection grew, a wider range of organizational measures were deployed. Methods: This study involves the SARS-CoV-2 infected people managed by the Local Health Authority of Rieti (Italy). Diagnostic test waiting times and hospital admission rates in the Province of Rieti are investigated as the pandemic evolved. Trends were analyzed in relation to the tempora spreading of SARS-CoV-2, to the organizational actions taken by the Local Health Authority of Rieti, and to the deployment of actions across the territory. A municipalities classification of the province of Rieti was conducted after a cluster analysis based on the diagnostic test waiting times and the hospital admission rates. Results: Our findings show a declining trend, thus indicating a possible positive effect of the measures taken to contain the pandemic. The cluster analysis of the municipalities of the Province of Rieti makes evident an inhomogeneous geographical distribution of examined parameters (diagnostic test waiting times and the hospital admission rates), demonstrating the capability of Local Health Authority of Rieti to reach even the most disadvantaged areas and implying that the differences are due to the demographical variabilities. Conclusion: Despite some limitations, this study outlines the importance of management measures in response of the pandemic. These measures should adapt to social, cultural and geographical nature of the territory involved. The findings of the present study will contribute to the update of further pandemic preparedness plans of the Local Health Authorities.

The First Case of Haemophagocytic Lymphohistiocytosis Triggered by the Booster Dose of Anti-SARS-CoV-2 Vaccine in a Patient with β-Thalassemia

Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening systemic hyperinflammatory disease, which can have several aetiologies. Clinical case: a 48-year-old woman affected by a transfusion-dependent β-thalassemia was hospitalized in our haematology unit presenting with intermittent fever, haepatosplenomegaly and pancytopenia, which developed a few days after the booster dose of anti-SARS-CoV-2 mRNA vaccine. The investigations performed during hospitalization led to a diagnosis of HLH and steroid therapy where IV dexam-ethasone was initiated and provided benefits. Conclusions: the severity of HLH mandates early treatment, but the management of patients with post-vaccine HLH is still challenging and requires further study. No cases of HLH in patients with thalassemia were previously described.

Rubber band ligation (RBL) for haemorrhoids. The experience of three surgical units

Haemorrhoids are the most common proctological disorder with a high incidence per year and a prevalence up to 39% in the general population (1). This condition often leads to disruption in an individual's personal and working life. Management has considerable cost implications, and therefore, economic consequences( 2). Due to the fear of SARS-COVID infection the most of patients actually regret hospitalization for surgery and choose to delay the time of treatment. RBL can be proposed as successful procedure to patients with II-III grade with a short stay in the hospital. Treatment consists initially of conservative measures such as lifestyle advice, diet and toilet behaviour. When conservative hemorrhoid therapy is ineffective, many physicians may choose other non-surgical modalities rubber band ligation, injection sclerotherapy, cryotherapy, manual dilation of the anus infrared photocoagulation, bipolar diathermy( 3), direct current electrocoagulation( 4). Rubber band ligation (RBL) was established as one of the most important, cost-effective and commonly used treatments for first-to third-degree internal hemorrhoids. It is a very effective non-surgical treatment for internal hemorrhoids. causing fibrosis, retraction, and fixation of the hemorrhoidal cushions. Rubber band ligation is also more effective than sclerotherapy and infra-red coagulation, but more painful. Overall complications occur in less than 10%. A retrospective study of 186 patients outpatients who underwent RBL with a minimum follow-up of 12 months is reported. Results confirmed it is effective until 1 year with a low rate of complications and could be offered as conservative treatment for I to III grade hemorrhoids.

SEROLOGIC RESPONSE TO THE SECOND AND THIRD DOSE OF THE SARS-COV-2 VACCINE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: RESULTS OF A PROSPECTIVE, CENTRALIZED, MULTICENTER STUDY

Background: Patients with chronic lymphocytic leukemia (CLL) show high infection-related morbidity and mortality due to variable degree of humoral and cellular immune deficiency. High Covid-related mortality and reduced response to the SARS-Cov-2 vaccine have been reported in this patient population. Aims: We carried out a prospective multicenter study to define the rate of CLL patients with an appropriate immune response after the mRNA SARS-CoV2 vaccine (Pfizer-BioNTech;Moderna). Methods: Two-hundred patients with CLL received the first dose of the SARS-CoV-2 vaccine between February and August 2021. Centralized assessment of the anti-SARS-Cov-2 IgG levels (Sero Index, Kantaro Quantitative SARS-CoV-2 IgG Antibody, RUO-R&D System) was performed at the Istituto Superiore di Sanità of Rome, Italy. The median followup of this study is 10.7 months (range 1-12.9). Results: The median age of patients was 70 years, the median IgG level was 635 mg/dl, 61% of patients were IGHV unmutated, and 34% showed TP53 disruption. The majority of patients, 83.5%, were previously treated. Prior treatment included chemoimmunotherapy in 20 (10%) patients, ibrutinib-based therapy in 72 (36%;front-line, 21%;advanced line, 15%), venetoclax-based therapy in 75 (37.5%;front-line, 13.5%;advanced line, 24%). Overall, 135 (77.5%) patients had been previously treated with rituximab, 33 (16.5%) of them within 12 months before vaccination. We assessed the serologic response after the second dose of the SARS-CoV2 vaccine in 195 patients while five were excluded from the analysis (positive test before vaccination, 3 patients;lost to the follow-up, 1;Richter syndrome, 1). Adequate levels of anti-SARS-Cov-2 IgG were detected in 76/195 (39%) patients. Age (<70 vs.≥ 70 years;p <0.0001), CIRS value (<6 vs. ≥6;p=0.005), beta-2 microglobulin (<3.5 vs. ≥ 3.5mg/dl;p=0.04), IgG levels (<550 vs. ≤ 550 mg/dl;p <0.0001), prior treatment (p=0.0001), number of prior treatments (0+1 vs. ≥ 2;p=0.002) and the time between prior rituximab and vaccination (>12 vs. ≤12 month;p=0.001) showed a significant impact on the humoral response. In multivariate analysis only age (OR: 0.92 [95% CI: 0.92-0.97] p=0.0001), IgG levels (OR: 0.28 [95% CI: 0.13-0.58] p<0.001), and the time between prior rituximab and vaccination (OR: 0.10 [95% CI: 0.03-0.37] p=0.001), revealed a significant and independent impact on response. When the analysis was restricted to patients who received targeted therapy, in addition to the younger age (OR: 0.96 [95% CI: 0.92-0.99] p=0.04), higher IgG levels at baseline (OR: 0.31 [95% CI: 0.12-0.79] p=0.014), longer time between the start of ibrutinib or venetoclax-based therapy and vaccination (<18 vs.≥18 months;OR: 0.17 [95% CI: 0.06-0.44], p <0.0001) showed a favorable and independent impact on response. Ninety-three% (182/195) of patients received a third dose of the vaccine. A significant increase in the rate of serologic responses, 51.5% (85/165 evaluated patients, p=0.019), was observed after the booster dose. Moreover, a response was detected in 25% (26/103 evaluated patients) of previously seronegative patients. Summary/Conclusion: In this prospective, multicenter, centralized study, we recorded an effective immune response to the SARS-CoV-2 vaccine in about a third of patients with CLL. Younger age, higher IgG levels, no prior treatment, or stable disease after targeted therapy that suggest preserved immunocompetence were associated with a greater likelihood of achieving an effective immune response. A booster dose of the SARS-CoV-2 vaccine proved beneficial also in previously seronegative patients.

DIFFERENTIAL IFN GENES EXPRESSION in the UPPER AIRWAYS of CHILDREN and ADULTS

Background: Children generally develop a mild disease after SARS-CoV-2 infection;it has been shown (Loske J al., 2021) that higher basal expression of relevant pattern recognition receptors may result in a stronger early innate antiviral than in adults. However, how the early interferon (IFN) response differs from that in adults is not fully characterized. Hence, we aimed to investigate the expression of several IFN-related genes in nasopharyngeal (NP) cells from children and adults with asymptomatic or mild COVID-19, not requiring hospitalization. Methods: Children and adults attending emergency departments (ED) of Sapienza University Hospital, to perform SARS-CoV-2 molecular tests, were enrolled from November 2020 to February 2021, after informed consent was obtained. RNA from residual NP swabs was purified and 200 ng were reverse transcribed. Gene expression of genes coding for type I and III IFNs and for the well-known markers of IFNs' activation, ISG15 and ISG56, was measured by exonuclease-based Real time PCR assays with relative quantification to the invariant gene GUS (the 2-ΔCt method). Results: Residual NP cells from a total of 132 children and adults were included in the study;56 had SARS-CoV-2 positive results and 76 resulted negative. The expression of all tested genes showed a moderate significant inverse correlation with age, with the exception of ISG15. Participants were further stratified in age groups (< 16;16-35;36-65 years) resulting in: 25 SARS-CoV-2 negative and 26-positive children;14 SARS-CoV-2 negative and 16-positive young adults and 37 SARS-CoV-2 negative and 14-positive adults. In SARS-CoV-2 negative samples, higher levels of all study genes were found in children, while significantly decreasing in young and elderly adults. Among SARS-CoV-2 positive samples, those from children showed significantly higher levels of type I IFNs and of IFN lambda2 whereas ISG15 was far more elevated in adults. Moreover, levels of all type I IFNs, and of IFN lambda2, were significantly higher in individuals with no symptoms (65% of children and 44% of the young adults), whereas ISG15 was elevated in those with a mild COVID-19. Conclusion: The higher baseline expression of IFN-related genes in children may prompt a quicker activation of the IFN response after SARS-CoV-2 infection and contribute to effective control of viral replication;the higher ISG activation in adults may be caused by the inflammatory response and associated to COVID-19 symptoms.

CONTINUOUS THERAPY WITH CARFILZOMIB-LENALIDOMIDE-DEXAMETHASONE (KRD): A MULTICENTRIC EXPERIENCE IN REAL-LIFE

The irreversible proteasome inhibitor Carfilzomib has a proven efficacy in doublet and triplet combinations for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) as shown in the ENDEAVOR and ASPIRE trials. Here we retrospectively analyzed a series of RRMM patients treated with KRd regimen over 18 cycles to evaluate efficacy and tolerability of continuous treatment (Table 1). Data were elaborated using SPSS Statistics Version 26. Overall survival (OS) was calculated from the time of the beginning of treatment until the date of death for any cause or last follow-up visit. Progression free survival (PFS) was defined as the time from the beginning of treatment to documented progression. OS and PFS were analysed by the Kaplan-Meier test. The statistical significance level was set at the 95th percentile. 36 patients were enrolled at one Calabrian and three Sicilian centres on behalf of the Sicilian Myeloma Network from June 2016 to November 2021. 24 of them were on first relapse (66,6%). Median number of cycles was 31.5 (range 18-61). Overall response rate (ORR) at first response to KRd was 92%: 3 patients (8%) achieved a complete response (CR), 14 patients (39%) achieved a very good partial response (VGPR), 16 (45%) achieved PR, 2 (5%) a minimal response (MR) and 1 (3%) had a stable disease (SD). ORR at best response was 97% (56% CR, 30% VGPR, 4% PR), 1 patient (3%) had SD. At last follow up ORR was 53%: (36% CR, 8% VGPR, 8% PR), one (3%) had a SD. Progression disease (PD) occurred in 16 patients (44%), 15 of them were exposed to another treatment, among them 9 patients were exposed to at least two more treatments including novel agents (Daratumumab, Pomalidomide, Belantamab- Mafodotin). Median PFS was not reached and so was median OS calculated from the beginning of KRd. 9 patients (25%) reported grade 3-4 hematological AEs, 13 patients experienced (36%) grade 3-4 nonhematological AEs, only 3 (8%) cardiovascular AEs. Lenalidomide was reduced in 21 (58%), interrupted in 9 (25%) patients due to serious adverse events (SAEs). During Sars-Cov-2 pandemic waves, to reduce hospital admission, 8 patients who achieved at least VGPR continue halved Carfilzomib administration schedule (total dose 27 mg/m2 once every 2 weeks instead of twice) maintaining previous response except for 1 patient who experienced PD (at cycle 32, after one more year of KRD treatment). Real-world experiences often significantly diverge from randomized clinical trials for patients selection resulting into differences in terms of efficacy and tolerability. In our study KRd combination deepened response over time without relevant toxicity as showed also in a subgroup analysis of ASPIRE and ENDEAVOR. In addition, schedule modification during Sars-Cov-2 pandemic reduced the number of hospital admissions without losing quality of response, thus opening the question of which is the best administration regimen of Carfilzomib as maintenance. (Table Presented).

A single-centre survey on the adherence to colorectal cancer screening (CRCS) in Apulia: Impact of the Organized Region Screening Strategy (ORSS)

Background: A great disparity in CRCS adherence exists between the various Regions of Italy, ranging from 98% (North) to 44% (South). The AIRTUM report in 2019 counted almost 2900 new CRC diagnosis for the Apulian Region, while CRCS adherence was inferior to 5%. To counterbalance this trend, an ORSS has been started since September 2019, consisting in an invitation to faecal occult blood tests for people aged 50-70 years. The effects of this strategy have not yet been quantified, while SARS-COV2 pandemic interference is unknown. The aim of our study was to evaluate the percentage of patients with recent CRC diagnosis by screening in a period across the start of the ORSS and unravel the reasons for patient refusal. Material and methods: Patients aged >50 years and residing in Apulia with CRC diagnosis made at the Division of Medical Oncology in “A.O.U. Consorziale Policlinico di Bari” between May 2018 and April 2021 were interviewed by phone. Hereditary or IBD related CRC were both considered exclusion criteria. We collected data about the cause of diagnosis, knowledge of CRCS, how the subjects were informed about screening and reasons for non-adhesion. Close relatives were also asked if had joined or intended to take part in CRCS since they were considered a very sensitized population. Results: We enrolled 130 patients, including 60 diagnosed before and 70 after September 2019. Overall, 10% of patients had received a diagnosis of CRC by screening. Of these, 1% was diagnosed before the start of the ORSS and 9% after. Only 23% of participants were sufficiently learned of CRCS across the study period, while invitation was received from ORSS in 14% and from general practitioners (GP) in 6%. The major reasons for CRCS denial were “diffidence” (65%) and “futility” (35%). Among close relatives of people with recent CRC history, a 24% of CRCS adherence was observed, while another 50% of them said that intended to take the test. Conclusions: We found an inadequate adherence to CRCS mainly due to poor consciousness of CRC disease and prevention, while it significantly increased in sensitized people. Moreover, the higher percentage of CRC diagnoses made by CRCS since 2019 may represent a direct effect of the ORSS, although the number of persons invited is still not enough. These data confirm the gap of the Apulia from other Italian Regions regarding the reluctance to carry out CRCS and suggest greater investments in awareness campaigns for the population and GP.

Stroke network performance during COVID-19 pandemic: A meta-analysis

Background and Aims: The effect of the COVID pandemic on stroke networks performance are unclear, particularly with consideration of drip & ship versus mothership models. We systematically reviewed and metaanalyzed variations in stroke admissions, rate and timing of reperfusion treatments during the COVID pandemic versus the prepandemic timeframe. Methods: The systematic review followed registered protocol (PROSPERO-CRD42020211535), PRISMA and MOOSE guidelines. We searched MEDLINE, EMBASE and Cochrane CENTRAL until 9/10/ 2020, for studies reporting variations in ischemic stroke admissions, treatment rates and timing in COVID vs control-period. Primary outcome was the weekly admission incidence rate ratio (IRR=admissions during COVID-period/admissions during control-period). Secondary outcomes were (i) changes in rate of patients undergoing reperfusion treatment and (ii) time metrics for pre-and in-hospital phase. Results: Twenty-nine studies were included in qualitative synthesis, with 212960 patients observed for 532 cumulative weeks (325 control-period, 207 COVID-period). COVID-period was associated with a significant reduction in stroke admission rates (IRR=0.69, 95%CI, 0.61-0.79) and a higher relative presentation with large vessel occlusion stroke (RR=1.62, 95%CI, 1.24-2.12). Proportions of patients treated with intravenous thrombolysis remained unchanged, while endovascular treatment increased (RR=1.14, 95%CI, 1.02-1.28). Onset-to-door time was longer for drip&ship compared to mothership model (+32 minutes vs-12 minutes, pmeta-regression =.03). Conclusions: Despite a 35% drop in stroke admissions during the pandemic, proportions of patients receiving reperfusion and time-metrics were not inferior to control-period, justifying allocation of resources to keep stroke networks up and running.

Treatment of cll relapsed/refractory patients in covid-19 pandemic: A real-life experience with venetoclax-rituximab combination in southern Italy

Background: Given the multifactorial immune defect characterizing chronic lymphocytic leukemia (CLL), it appears conceivable that these patients have risk factors that increase their likelihood of complications and death from COVID-19. Aims: To evaluate incidence and severity of COVID-19 cases in a well-defined cohort of patients with CLL receiving venetoclax-based combinations. Methods: We administered a survey to a cohort of CLL treating hematologists from hematological centers in southern Italy. Participants were asked: a) to indicate whether they had offered a test for detection of COVID-19 infection (mainly nasopharyngeal swabs) only to CLL patients who reported symptoms or universally;b) to provide information on the incidence of COVID-19 infection and its severity;c) to specify reasons of possible treatment modifications. The survey was restricted to relapsed-refractory (R/R) CLL patients treated from Feb 1st to Dec 31th 2020 with time-limited venetoclax/rituximab (VR) combination as recommended by MURANO protocol (venetoclax for up to 2 years plus rituximab for the first 6 months), within their clinical practice. Results: A specific questionnaire was sent to 30 CLL hematologists, but only 26 responded to all questions. We considered suitable for the present analysis the 24 questionnaires compiled by hematologists who declared to have treated at least one patient with VR combination in the observation period. Of those, 20.8% worked in academic hospitals. Overall, the survey allowed to collect data on 124 patients who were treated with VR combination. The median number of patients treated in each center was 5 (range,1-15).COVID-19 surveillance tests consisted of viral RNA reverse transcriptase PCR (RT-PCR) on nasopharyngeal swabs. Generally, a policy of universal SARS-CoV-2 testing to be performed on patients at different time-points of therapy was used. Most patients (83/124, 66.9%) were tested before beginning the ramp-up with venetoclax;moreover 66/124 (53.2%) were regularly tested before each rituximab infusion (Fig 1).Reasons for potential change of the schedule of treatment were also investigated. The survey revealed that adherence to treatment was relatively high (70.8%). Only 29.1% physicians modified the therapeutic program mainly because of grade 3 neutropenia. Changes consisted of transient interruption of venetoclax, reduction of doses, and delay of rituximab infusion.Only 2/124 patients (1.6%) had a symptomatic RT-PCR proven diagnosis of COVID-19 infection and required hospitalization. Both patients needed oxygen therapy and admission into an intensive care unit. Of those, 1 patient who was receiving VR combination at the time of COVID infection, eventually died. The second patient developed COVID-19 infection while receiving venetoclax monotherapy (after the VR combination period). He recovered from COVID-19 infection and after 21 days of treatment interruption, he was able to restart venetoclax. Summary/Conclusion: Results of the present survey provide information, thus far lacking, on the use in real-world clinical practice of VR combination during the COVID19 pandemic in 2020. Current literature on the prevalence of COVID-19 infection in CLL, has some limitations (i.e., small size sample, heterogeneity of treatment, restriction to only the first pandemic wave);this survey, performed on a large number of CLL patients treated with VR combination only seems to provide additional information on safe management of CLL treatment during the COVID19 pandemic.

COVID-19 prevalence and mortality in a large italian hemoglobinopathies cohort

Background: Data on SARS-CoV-2 infection in Hemoglobinopathies are still scarce and controversial. Since March 2020, we, as Italian Society for Thalassemia and Hemoglobinopathies (SITE), recommended close monitoring and set up an Italian survey to verify the impact of SARSCoV- 2 infection on patients with Hemoglobinopathies (EMO AER COVID-19 NCT04746066) among Italian Centers. Aims: To explore the hypothesis of an increased vulnerability of Hemoglobinopathies to SARS-COV2 infection. Methods: After SITE proposal and Ethics Committee approval, each participating Center entered data on a specific electronic Case Report Form (eCRF) (https://covid19.site-italia.org). Inclusion criteria included positive swab or serology and at least 15 days of follow-up from either the onset of symptoms or SARS-CoV2 positivity. This cut-off is updated to February 15, 2021. Results: Twenty-seven Centers that provide care to 6121 patients with Hemoglobinopathy (65% of the Italian population) recorded a total of 275 SARS-CoV2 infections (overall, prevalence 4.5%), in 191 transfusion- dependent thalassemia cases (TDT, prevalence 5.8%), 36 non-transfusion- dependent thalassemia (NTDT, prevalence 2.3%) and 48 sickle cell disease patients (SCD, prevalence 3.7%). Median age was 41 years (IQR: 30-48, range: 9 months-85 year). Twenty-eight patients (10 %) were pediatrics (median age: 6.5 years, IQR: 4-11). Most patients (72%) had comorbidities;134 (49%) had splenectomy or functional asplenia. We observed a broad spectrum of disease severity, ranging from no symptoms in 65 patients (24%) to multisystem organ failure and death in 5 patients: 2 TDT (age: 49 and 56 years), 1 NTDT (age: 45 years), 2 SCD (age: 57 years both). Overall, 56 (20%) patients required hospitalization, 12 in high-intensity care unit;10 required support by oxygen, 11 needed more intensive ventilation support with continuous positive airway pressure (CPAP), and 7 required intubation. Nine patients required ad hoc transfusion or more than scheduled. Two SCD patients of 9 and 20 months of age, respectively, recovered after a long and life-treating disease. One TDT patient experienced reinfection after 3 months from the first;one 30w-pregnant SCD woman developed COVID-19 without consequences for herself and the fetus. Overall clinical severity has been higher in SCD than in thalassemia patients. Summary/Conclusion: The prevalence of COVID-19 in Hemoglobinopathies apparently overlaps the general population (4.5% vs 4.6%), however, these patients are more strictly observed and we could postulate that the precautions suggested or self-applied by the patients were effective. The overall mortality is 1.8% vs 3.4% and the difference may be due to the younger age of patients with Hemoglobinopathies. Our data confirm the higher risk of severe disease and death in SCD.

Designing an Online Dungeons & Dragons Experience for Primary School Children

In this work, we present the results of a role-playing game experience carried out with a group of 9- to 12-year-old children during the COVID-19 emergence. The ‘harmony in education’ approach has been used to adapt the game design to the constraints imposed by the online context and the young age of the students involved. The results show the effectiveness of the approach in terms of 21st-century skills training with particular evidence on perspective-taking. © 2020, Springer Nature Switzerland AG.